Establishment of model of visceral pain due to colorectal distension and its behavioral assessment in rats

PubMed Central

Yang, Jian-Ping; Yao, Ming; Jiang, Xing-Hong; Wang, Li-Na

2006-01-01

AIM: To establish a visceral pain model via colorectal distension (CRD) and to evaluate the efficiency of behavioral responses of CRD by measuring the score of abdominal withdrawal reflex (AWR) in rats. METHODS: Thirty-eight male SD rats weighing 180-240g were used to establish the visceral pain model. The rat was inserted intra-anally with a 7 cm long flexible latex balloon under ether anesthesia, and colorectal distensions by inflating the balloon with air were made 30 min after recovering from the anesthesia. Five AWR scores (AWR0 to AWR4) were used to assess the intensity of noxious visceral stimuli. It was regarded as the threshold of the minimal pressure (kPa) for abdominal flatting was induced by colorectal distension. RESULTS: A vigorous AWR to distension of the descending colon and rectum was found in 100% of the awake rats tested. The higher the pressure of distension, the higher the score of AWR. The distension pressures of 0, 2.00, 3.33, 5.33 and 8.00 kPa produced different AWR scores (P < 0.05). The pain threshold of AWR was constant for up to 80 min after the initial windup (first 1-3 distensions), the mean threshold was 3.69 ± 0.35 kPa. Systemic administration of morphine sulfate elevated the threshold of visceral pain in a dose-dependent and naloxone reversible manner. CONCLUSION: Scoring the AWR during colorectal distensions can assess the intensity of noxious visceral stimulus. Flatting of abdomen (AWR 3) to CRD as the visceral pain threshold is clear, constant and reliable. This pain model and its behavioral assessment are good for research on visceral pain and analgesics. PMID:16718770

Effects of cocoa-enriched diet on orofacial pain in a murine model.

PubMed

Bowden, L N; Rohrs, E L; Omoto, K; Durham, P L; Holliday, L S; Morris, A D; Allen, K D; Caudle, R M; Neubert, J K

2017-06-01

To investigate and discuss the effects of cocoa on orofacial pain. The Department of Orthodontics at the University of Florida (UF). Male and female hairless rats (N=20/group) were tested. Rats were tested using the Orofacial Pain Assessment Device (OPAD) before and after changing their food from the standard chow to a cocoa-enriched or control-equivalent diet. Male rats fed the cocoa diet had a significantly higher operant pain index when tested at 37°C as compared to control diet-fed animals. Female rats on the cocoa diet had a significantly higher pain index when tested at 18°C and 44°C, as compared to animals fed the control diet. Capsaicin-induced pain was inhibited, with cocoa-diet male rats having a significantly higher pain index than control-diet male rats and cocoa-diet female rats at both 37°C and 44°C. Cocoa-diet female rats had a significantly higher pain index at 44°C than control-diet females. Mechanical sensitivity was affected following capsaicin cream, with a significantly decreased tolerated bottle distance in both cocoa- and control-diet animals, but there was no difference between cocoa- and control-diet groups. Using the OPAD operant system, we demonstrated that a diet rich in cocoa was effective in inhibiting neurogenic inflammatory pain in rats. This has implications for the use of novel alternative therapies such as diet modification for pain control. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of Sex and Stress on Trigeminal Neuropathic Pain-Like Behavior in Rats.

PubMed

Korczeniewska, Olga Anna; Khan, Junad; Tao, Yuanxiang; Eliav, Eli; Benoliel, Rafael

2017-01-01

To investigate the effects and interactions of sex and stress (provoked by chronic restraint [RS]) on pain-like behavior in a rat model of trigeminal neuropathic pain. The effects of sex and RS (carried out for 14 days as a model for stress) on somatosensory measures (reaction to pinprick, von Frey threshold) in a rat model of trigeminal neuropathic pain were examined. The study design was 2 × 4, with surgery (pain) and sham surgery (no pain) interacting with male restrained (RS) and unrestrained (nRS) rats and female RS and nRS rats. A total of 64 Sprague Dawley rats (32 males and 32 females) were used. Half of the animals in each sex group underwent RS, and the remaining half were left unstressed. Following the RS period, trigeminal neuropathic pain was induced by unilateral infraorbital nerve chronic constriction injury (IOCCI). Half of the animals in the RS group and half in the nRS group (both males and females) were exposed to IOCCI, and the remaining halves to sham surgery. Elevated plus maze (EPM) assessment and plasma interferon gamma (IFN-γ) levels were used to measure the effects of RS. Analysis of variance (ANOVA) was used to assess the effects of stress, sex, and their interactions on plasma IFN-γ levels, changes in body weight, EPM parameters, tactile allodynia, and mechanohyperalgesia. Pairwise comparisons were performed by using Tukey post hoc test corrected for multiple comparisons. Both male and female RS rats showed significantly altered exploratory behavior (as measured by EPM) and had significantly lower plasma IFN-γ levels than nRS rats. Rats exposed to RS gained weight significantly slower than the nRS rats, irrespective of sex. Following RS but before surgery, RS rats showed significant bilateral reductions in von Frey thresholds and significantly increased pinprick response difference scores compared to nRS rats, irrespective of sex. From 17 days postsurgery, RSIOCCI rats showed significantly reduced von Frey thresholds and significantly increased pinprick response difference scores compared to nRS-IOCCI rats, and the von Frey thresholds were significantly lower in females than in males. RS-sham females-but not RS-sham males-developed persistently reduced thresholds and increased pinprick response difference scores. RS produced an increased bilateral sensitivity to stimuli applied to the vibrissal pad following infraorbital nerve injury, irrespective of sex. This observed sensitivity subsequently persisted in RS-sham female rats but not in RS-sham male rats. Stress induced a significant but moderate increase in pain-like behavior in female rats compared to male rats. RS had no significant sex effects on IFN-γ levels, EPM parameters, or body weight gain. This suggests that stress may have a selective effect on pain-like behavior in both sexes, but the possible mechanisms are unclear.

Analgesic Effects of Tramadol, Tramadol–Gabapentin, and Buprenorphine in an Incisional Model of Pain in Rats (Rattus norvegicus)

PubMed Central

McKeon, Gabriel P; Pacharinsak, Cholawat; Long, Charles T; Howard, Antwain M; Jampachaisri, Katechan; Yeomans, David C; Felt, Stephen A

2011-01-01

Postoperative pain management in laboratory animals relies heavily on a limited number of drug classes, such as opioids and nonsteroidal antiinflammatory drugs. Here we evaluated the effects of saline, tramadol, tramadol with gabapentin, and buprenorphine (n = 6 per group) in a rat model of incisional pain by examining thermal hyperalgesia and weight-bearing daily for 6 d after surgery. All drugs were administered preemptively and continued for 2 consecutive days after surgery. Rats treated with saline or with tramadol only showed thermal hyperalgesia on days 1 through 4 and 1 through 3 after surgery, respectively. In contrast, buprenorphine-treated rats showed no thermal hyperalgesia on days 1 and 2 after surgery, and rats given tramadol with gabapentin showed reduced thermal hyperalgesia on days 2 and 4. For tests of weight-bearing, rats treated with saline or with tramadol only showed significantly less ipsilateral weight-bearing on day 1 after surgery, whereas rats given either buprenorphine or tramadol with gabapentin showed no significant change in ipsilateral weight-bearing after surgery. These data suggest that tramadol alone provides insufficient analgesia in this model of incisional pain; buprenorphine and, to a lesser extent, tramadol with gabapentin provide relief of thermal hyperalgesia and normalize weight-bearing. PMID:21439212

Tramadol reduces anxiety-related and depression-associated behaviors presumably induced by pain in the chronic constriction injury model of neuropathic pain in rats.

PubMed

Caspani, Ombretta; Reitz, Marie-Céline; Ceci, Angelo; Kremer, Andreas; Treede, Rolf-Detlef

2014-09-01

Depression and anxiety are common comorbidities of neuropathic pain (NP). Pharmacological preclinical studies on NP have given abundant information on the effects of drugs on reflex measures of stimulus-evoked pain. However, few preclinical studies focus on relief of comorbidities evoked by NP. In this study, we investigated the effects of tramadol on nociceptive reflex, depression-associated and anxiety-related behaviors in a NP model in rats. We used chronic constriction injury (CCI) of the sciatic nerve as an animal model of neuropathic pain. We performed electronic von Frey tests (evF) to measure mechanical sensitivity, elevated plus maze tests (EPM) to record anxiety-related behaviors and forced swimming tests (FST) to evaluate depression-associated behaviors. In the evF, CCI rats showed a decrease of 82% of the paw withdrawal threshold (PWT) compared to sham (P<0.001). Tramadol increased the PWT by 336% in CCI rats (P<0.001) and by 16% in sham (P<0.05). On the EPM, CCI rats spent 45% less time than sham on the open arms of the maze (P<0.05). Tramadol increased the time spent on the open arms of CCI rats by 67% (P<0.05) and had no significant effect on sham. During the FST, CCI rats showed 28% longer immobility than sham (P<0.01). Tramadol reduced the immobility time in CCI rats by 22% (P<0.001), while having no effect on sham. Tramadol reversed the changes in mechanical sensitivity as well as anxiety-related and depression-associated behaviors that are caused by injury of the sciatic nerve with only minor effects in the absence of injury. These data suggest that tramadol relieves chronic pain and its indirect consequences and comorbidities, and that this study also is a model for pharmacological studies seeking to investigate the effect of drugs on the major disabling symptoms of NP. Copyright © 2014 Elsevier Inc. All rights reserved.

Use of the Rat Grimace Scale to Evaluate Neuropathic Pain in a Model of Cervical Radiculopathy.

PubMed

Philips, Blythe H; Weisshaar, Christine L; Winkelstein, Beth A

2017-02-01

Although neck and low-back pain are common sources of neuropathic pain with high societal costs, the pathophysiology of neuropathic pain is not well-defined. Traditionally, most rodent pain studies rely on evoked reflex-based testing to measure pain. However, these testing methods do not reveal spontaneous pain, particularly early after injury. The rat grimace scale (RGS) for quantifying spontaneous pain has been validated after visceral, incisional, orthopedic, and inflammatory insults but not neuropathic pain. The current study used a rat model of radiculopathy to investigate the time course of RGS, the effect of the NSAID meloxicam on RGS, and the reliability and consistency of RGS across testers. RGS values at baseline and at 3, 6, 24, and 48 h after cervical nerve root compression (NRC) that induced robust evoked pain responses were compared with those obtained after sham surgery. The RGS was also evaluated at 6 h after NRC in another set of rats that had received meloxicam treatment prior to surgery. At 6 h, NRC induced higher RGS scores (1.27 ± 0.18) than did sham surgery (0.93 ± 0.20), and scores remained above baseline for as long as 48 h. Treatment with meloxicam before NRC reduced RGS at 6 h to sham levels, which were lower than those of injury without treatment. The RGS was associated with very good interobserver reliability (intraclass correlation coefficient, 0.91) and excellent internal consistency (Cronbach α, 0.87). These findings suggest that RGS is a useful approach to identifying and monitoring acute neuropathic pain in rats.

Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats.

PubMed

Fang, Jian-Qiao; Du, Jun-Ying; Liang, Yi; Fang, Jun-Fan

2013-03-22

Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain. EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat's paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression. The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats.

Electroacupuncture alleviates affective pain in an inflammatory pain rat model

PubMed Central

Zhang, Yu; Meng, Xianze; Li, Aihui; Xin, Jiajia; Berman, Brian M.; Lao, Lixing; Tan, Ming; Ren, Ke; Zhang, Rui-Xin

2011-01-01

Pain has both sensory-discriminative and emotional-affective dimensions. Previous studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension but do not address the affective. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance (CPA) test to determine whether EA inhibits spontaneous pain-induced affective response and, if so, to study the possibility that rostral anterior cingulate cortex (rACC) opioids underlie this effect. Male Sprague-Dawley rats (250–275g, Harlan) were used. The rats showed place aversion (i.e. affective pain) by spending less time in a pain-paired compartment after conditioning than during a preconditioning test. Systemic non-analgesic morphine (0.5 and 1.0 mg/ kg, i.p.) inhibited the affective reaction, suggesting that the affective dimension is underpinned by mechanisms different from those of the sensory dimension of pain. Morphine at 0.5 and at 1 mg/kg did not induce reward. Rats given EA treatment before pain-paired conditioning at GB 30 showed no aversion to the pain-paired compartment, indicating that EA inhibited the affective dimension. EA treatment did not produce reward or aversive effect. Intra-rACC administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP), a selective mu opioid receptor antagonist, but not norbinaltorphimine (nor-BNI), a selective kappa opioid receptor antagonist, blocked EA inhibition of the affective dimension. These data demonstrate that EA activates opioid receptors in the rACC to inhibit pain-induced affective responses and that EA may be an effective therapy for both the sensory-discriminative and the affective dimensions of pain. PMID:22323370

Weight bearing evaluation in inflammatory, neuropathic and cancer chronic pain in freely moving rats.

PubMed

Tétreault, Pascal; Dansereau, Marc-André; Doré-Savard, Louis; Beaudet, Nicolas; Sarret, Philippe

2011-09-01

Preclinical pain assessment remains a key step for the development of new and potent painkillers. Significant progress in pain evaluation has been achieved with the development of non-reflexive tools. Seeking efficient and clinically relevant devices for pain-related quality of life assessment, we evaluated a new Dynamic Weight Bearing (DWB) device based on pressure captors in three different preclinical chronic pain models. Inflammatory (CFA), neuropathic (CCI) and bone cancer pain (femoral tumor) models were evaluated in Sprague Dawley rats for mechanical allodynia using dynamic von Frey for pain-related behaviors and DWB for discomfort. We observed similar impairment patterns in all of the models for both von Frey (allodynia) and DWB (weight balance) during the complete observation period, starting at day 3 in CCI- and CFA-affected limbs and at day 14 in bone cancer-afflicted rats, indicating that the DWB could be a useful tool for supporting pain assessment. Interestingly, we demonstrated that the main compensation, when animals experienced pain, was seen in the forepaws, ranging from 46% to 69% of increased load compared to normal. Other pain-related coping behaviors were also measured, such as the time spent on each paw and the contact surface. Our results revealed that CFA, CCI and cancerous rats decreased the use of their ipsilateral hind paws by 30% and showed a 50% reduction in paw surface pressed against the floor. In conclusion, this new device improves methods for preclinical evaluation of discomfort and quality of life proxies and could be helpful in screening putative analgesics. Copyright © 2011 Elsevier Inc. All rights reserved.

PG110, A Humanized Anti-NGF Antibody, Reverses Established Pain Hypersensitivity in Persistent Inflammatory Pain, but not Peripheral Neuropathic Pain, Rat Models.

PubMed

Djouhri, Laiche

2016-11-01

Chronic inflammatory and peripheral neuropathic pain (PNP) is a major health problem for which effective drug treatment is lacking. The pathophysiology of these debilitating conditions is incompletely understood, but nerve growth factor (NGF) is believed to play a major role. NGF-antagonism has previously been shown to prevent pain hypersensitivity in rodent models of acute inflammatory pain and PNP, but most of those animal studies did not address the more clinically relevant issue of whether NGF-antagonism provides relief of established chronic pain behavior. Therefore, the aim of this study was to investigate whether blocking NGF actions with a humanized anti-NGF monoclonal antibody (PG110) would reverse/attenuate established pain hypersensitivity in rat models of chronic/persistent inflammatory pain and PNP. The complete Freund's adjuvant (CFA) rat model of persistent inflammatory pain, and the L5 spinal nerve axotomy (SNA) model of PNP, were used in the present study. The effect of a single intravenous injection (10, 30, and 300 µg/kg) of an anti-NGF antibody PG110 on heat and mechanical hypersensitivity was assessed 5 and 7 days after CFA and SNA, respectively. Compared to vehicle treated group, PG110 dose dependently attenuated established heat and mechanical hypersensitivity induced by CFA, but not that induced by SNA. The anti-allodynic and anti-hyperalgesic effects of PG110 in the CFA model were similar to those of the positive control naproxen (30 mg/kg, i.v.). These findings suggest that therapies that target NGF or its receptors may be effective for treatment of persistent/chronic inflammatory pain, but probably not PNP. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Use of dynamic weight bearing as a novel end-point for the assessment of abdominal pain in the LPS-induced peritonitis model in the rat.

PubMed

Gruen, Michael; Laux-Biehlmann, Alexis; Zollner, Thomas M; Nagel, Jens

2014-07-30

Chronic pelvic pain (CPP) is defined as long-lasting and severe pelvic pain persisting over six months in cyclic or non-cyclic chronic manner. Various pathologic conditions like endometriosis, abdominal infections, intra-peritoneal adhesions or infection, underlie CPP which is often the leading symptom of the associated diseases. Pharmacological approaches addressing CPP are hampered by the absence of a straight-forward, objective, and reliable method for the assessment of CPP in rodents. In the presented study, the dynamic weight bearing system (DWB) was employed for the first time for the evaluation of pelvic pain in a rat model of LPS-induced peritonitis. Rats were pretreated with the COX-2 inhibitor rofecoxib and PGE2 levels were evaluated in peritoneal lavage. DWB analysis revealed that rats treated with LPS showed a relief posture by a significantly increased weight distribution to the front when compared to vehicle-treated animals. This effect was prevented by rofecoxib treatment indicating the sensitivity of the model for pelvic pain related to peritonitis. Analysis of the PGE2 levels in the peritoneal fluid indicated a correlation with the relief posture intensity. In contrast to others weight bearing approaches, the use of DWB allows evaluation of spontaneous posture changes as a consequence of pelvic pain. Taken together, we were able to show, that DWB combined with LPS-induced peritonitis may deliver a new reliable animal model addressing pelvic pain with high construct validity (peritoneal inflammation), and face validity (pain related relief posture). Copyright © 2014 Elsevier B.V. All rights reserved.

Effect of the spider toxin Tx3-3 on spinal processing of sensory information in naive and neuropathic rats: an in vivo electrophysiological study.

PubMed

Dalmolin, Gerusa D; Bannister, Kirsty; Gonçalves, Leonor; Sikandar, Shafaq; Patel, Ryan; Cordeiro, Marta do Nascimento; Gomez, Marcus Vinícius; Ferreira, Juliano; Dickenson, Anthony H

2017-07-01

Drugs that counteract nociceptive transmission in the spinal dorsal horn preferentially after nerve injury are being pursued as possible neuropathic pain treatments. In a previous behavioural study, the peptide toxin Tx3-3, which blocks P/Q- and R-type voltage-gated calcium channels, was effective in neuropathic pain models. In the present study, we aimed to investigate the effect of Tx3-3 on dorsal horn neuronal responses in rats under physiological conditions and neuropathic pain condition induced by spinal nerve ligation (SNL). In vivo electrophysiological recordings of dorsal horn neuronal response to electrical and natural (mechanical and thermal) stimuli were made in rats under normal physiological state (naive rats) or after the SNL model of neuropathic pain. Tx3-3 (0.3-100 pmol/site) exhibited greater inhibitory effect on electrical-evoked neuronal response of SNL rats than naive rats, inhibiting nociceptive C-fibre and Aδ-fibre responses only in SNL rats. The wind-up of neurones, a measurement of spinal cord hyperexcitability, was also more susceptible to a dose-related inhibition by Tx3-3 after nerve injury. Moreover, Tx3-3 exhibited higher potency to inhibit mechanical- and thermal-evoked neuronal response in conditions of neuropathy. Tx3-3 mediated differential inhibitory effect under physiological and neuropathic conditions, exhibiting greater potency in conditions of neuropathic pain.

Antinociceptive efficacy of lacosamide in the monosodium iodoacetate rat model for osteoarthritis pain

PubMed Central

Beyreuther, Bettina; Callizot, Noëlle; Stöhr, Thomas

2007-01-01

The etiology of osteoarthritis is multifactorial, with inflammatory, metabolic, and mechanical causes. Pain in osteoarthritis is initiated by mild intra-articular inflammation and degeneration of articular cartilage and subchondral bone. The principle of treatment with acetaminophen or non-steroidal anti-inflammatory drugs is to reduce pain and improve joint function. Recently, animal models for osteoarthritic pain behavior have been established. The most frequently used rat model for analyzing properties of drugs on the pathology of osteoarthritis is the injection of the metabolic inhibitor monosodium iodoacetate into the joint, which inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase in chondrocytes. Here, we characterize the effect on pain behavior of lacosamide, a member of a family of functionalized amino acids that are analogues of endogenous amino acids and D-serine, in the monosodium iodoacetate rat model for osteoarthritis in comparison to diclofenac and morphine. Lacosamide (3, 10, and 30 mg/kg) was able to reduce secondary mechanical allodynia and hyperalgesia similarly to morphine (3 mg/kg). In contrast, diclofenac (30 mg/kg) was only effective in reducing secondary mechanical hyperalgesia. During the first week, pain is induced mainly by inflammation in the iodoacetate model, but afterwards inflammation plays only a minor role in pain. Lacosamide was able to inhibit pain at days 3, 7 and 14 after induction of arthritis. This shows that lacosamide is able to reduce pain behavior induced by multiple mechanisms in animals. PMID:17284318

Decreased sensitivity to thermal pain in rats bred for high anxiety-related behaviour is attenuated by citalopram or diazepam treatment.

PubMed

Jochum, Thomas; Boettger, Michael Karl; Wigger, Alexandra; Beiderbeck, Daniela; Neumann, Inga D; Landgraf, Rainer; Sauer, Heinrich; Bär, Karl-Jürgen

2007-10-01

Complex interactions between pain perception, anxiety and depressive symptoms have repeatedly been described. However, pathophysiological or biochemical mechanisms underlying the alterations of pain perception in patients suffering from anxiety or depression still remain a matter of debate. Thus, we aimed to perform an investigation on pain perception in an animal model of extremes in anxiety-related behaviour, which might provide a tool for future studies. Here, thermal pain thresholds were obtained from rats with a genetic predisposition to high anxiety-related behaviour (HAB), including signs of comorbid depression-like behaviour and from controls (low-anxiety rats (LAB); cross-bred HAB and LAB rats; Wistar rats). Furthermore, the effect of eight-week antidepressive treatment using citalopram and of short-term anxiolytic treatment with diazepam on pain-related behaviour was assessed. Simultaneously, anxiety-related behaviour was monitored. At baseline, HAB animals showed 35% higher thresholds for thermal pain than controls. These were normalized to control levels after eight weeks of continuous citalopram treatment paralleled by a reduction of anxiety-related behaviour, but also acutely after diazepam administration. Overall, thermal pain thresholds in HAB animals are shifted in a similar fashion as seen in patients suffering from major depressive disorder. Antidepressive, as well as anxiolytic treatments, attenuated these differences. As the relative importance of the factors anxiety and depression cannot be derived from this study with certainty, extending these investigations to additional animal models might represent a valuable tool for future investigations concerning the interrelations between anxiety, depression, and pain at a molecular level.

Objective validation of central sensitization in the rat UVB and heat rekindling model

PubMed Central

Weerasinghe, NS; Lumb, BM; Apps, R; Koutsikou, S; Murrell, JC

2014-01-01

Background The UVB and heat rekindling (UVB/HR) model shows potential as a translatable inflammatory pain model. However, the occurrence of central sensitization in this model, a fundamental mechanism underlying chronic pain, has been debated. Face, construct and predictive validity are key requisites of animal models; electromyogram (EMG) recordings were utilized to objectively demonstrate validity of the rat UVB/HR model. Methods The UVB/HR model was induced on the heel of the hind paw under anaesthesia. Mechanical withdrawal thresholds (MWTs) were obtained from biceps femoris EMG responses to a gradually increasing pinch at the mid hind paw region under alfaxalone anaesthesia, 96 h after UVB irradiation. MWT was compared between UVB/HR and SHAM-treated rats (anaesthetic only). Underlying central mechanisms in the model were pharmacologically validated by MWT measurement following intrathecal N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, or saline. Results Secondary hyperalgesia was confirmed by a significantly lower pre-drug MWT {mean [±standard error of the mean (SEM)]} in UVB/HR [56.3 (±2.1) g/mm2, n = 15] compared with SHAM-treated rats [69.3 (±2.9) g/mm2, n = 8], confirming face validity of the model. Predictive validity was demonstrated by the attenuation of secondary hyperalgesia by MK-801, where mean (±SEM) MWT was significantly higher [77.2 (±5.9) g/mm2 n = 7] in comparison with pre-drug [57.8 (±3.5) g/mm2 n = 7] and saline [57.0 (±3.2) g/mm2 n = 8] at peak drug effect. The occurrence of central sensitization confirmed construct validity of the UVB/HR model. Conclusions This study used objective outcome measures of secondary hyperalgesia to validate the rat UVB/HR model as a translational model of inflammatory pain. What's already known about this topic? Most current animal chronic pain models lack translatability to human subjects. Primary hyperalgesia is an established feature of the UVB/heat rekindling inflammatory pain model in rodents and humans, but the presence of secondary hyperalgesia, a hallmark feature of central sensitization and thus chronic pain, is contentious. What does this study add? Secondary hyperalgesia was demonstrated in the rat UVB/heat rekindling model using an objective outcome measure (electromyogram), overcoming the subjective limitations of previous behavioural studies. PMID:24590815

A Rat Model of Full Thickness Thermal Injury Characterized by Thermal Hyperalgesia, Mechanical Allodynia, Pronociceptive Peptide Release and Tramadol Analgesia

DTIC Science & Technology

2014-01-01

tramadol reduces acute, postoperative, neuropathic and cancer pain [9,10,12 14] and may have a lower propensity to induce addiction [15] with little to...opioid systems simultaneously, we next examined whether tramadol could attenuate burn evoked pain behaviors in our rat model of full thickness thermal...injury. Tramadol attenuated thermal hyperalgesia when administered one week following thermal injury, a time point when pain behaviors peak in this

Sensitization of TRPV1 by protein kinase C in rats with mono-iodoacetate-induced joint pain.

PubMed

Koda, K; Hyakkoku, K; Ogawa, K; Takasu, K; Imai, S; Sakurai, Y; Fujita, M; Ono, H; Yamamoto, M; Fukuda, I; Yamane, S; Morita, A; Asaki, T; Kanemasa, T; Sakaguchi, G; Morioka, Y

2016-07-01

To assess the functional changes of Transient receptor potential vanilloid 1 (TRPV1) receptor and to clarify its mechanism in a rat mono-iodoacetate (MIA)-induced joint pain model (MIA rats), which has joint degeneration with cartilage loss similar to osteoarthritis. Sensitization of TRPV1 in MIA rats was assessed by transient spontaneous pain behavior induced by capsaicin injection in knee joints and electrophysiological changes of dorsal root ganglion (DRG) neurons innervating knee joints in response to capsaicin. Mechanisms of TRPV1 sensitization were analyzed by a newly developed sandwich enzyme-linked immunosorbent assay that detects phosphorylated TRPV1, followed by functional and expression analyses of protein kinase C (PKC) in vivo and in vitro, which involves TRPV1 phosphorylation. Pain-related behavior induced by intra-articular injection of capsaicin was significantly increased in MIA rats compared with sham rats. In addition, capsaicin sensitivity, evaluated by capsaicin-induced inward currents, was significantly increased in DRG neurons of MIA rats. Protein levels of TRPV1 remained unchanged, but phosphorylated TRPV1 at Ser800 increased in DRG neurons of MIA rats. Phosphorylated-PKCɛ (p-PKCɛ) increased and co-localized with TRPV1 in DRG neurons of MIA rats. Capsaicin-induced pain-related behavior in MIA rats was inhibited by intra-articular pretreatment of the PKC inhibitor bisindolylmaleimide I. In addition, intra-articular injection of the PKC activator phorbol 12-myristate 13-acetate increased capsaicin-induced pain-related behavior in normal rats. TRPV1 was sensitized at the knee joint and at DRG neurons of MIA rats through PKC activation. Thus, TRPV1 sensitization might be involved in chronic pain caused by osteoarthritis. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats

PubMed Central

2013-01-01

Background Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain. Results EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat’s paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression. Conclusions The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats. PMID:23517865

Implantation of hyaluronic acid hydrogel prevents the pain phenotype in a rat model of intervertebral disc injury

PubMed Central

Sakai, Daisuke; Dockery, Peter

2018-01-01

Painful intervertebral disc degeneration is mediated by inflammation that modulates glycosylation and induces hyperinnervation and sensory sensitization, which result in discogenic pain. Hyaluronic acid (HA) used as a therapeutic biomaterial can reduce inflammation and pain, but the effects of HA therapy on glycosylation and pain associated with disc degeneration have not been previously determined. We describe a novel rat model of pain induced by intervertebral disc injury, with validation of the pain phenotype by morphine treatment. Using this model, we assessed the efficacy of HA hydrogel for the alleviation of pain, demonstrating that it reduced nociceptive behavior, an effect associated with down-regulation of nociception markers and inhibition of hyperinnervation. Furthermore, HA hydrogel altered glycosylation and modulated key inflammatory and regulatory signaling pathways, resulting in attenuation of inflammation and regulation of matrix components. Our results suggest that HA hydrogel is a promising clinical candidate for the treatment of back pain caused by degenerated discs. PMID:29632893

Effect of down-regulation of voltage-gated sodium channel Nav1.7 on activation of astrocytes and microglia in DRG in rats with cancer pain.

PubMed

Pan, Jun; Lin, Xiang-Jin; Ling, Zhi-Heng; Cai, You-Zhi

2015-05-01

To evaluate the effect of down-regulation of Nav1.7 on the activation of astrocytes and microglia in DRG of rats with cancer pain, and explore the transmission of the nociceptive information. Lentiviral vector harboring RNAi sequence targeting the Nav1.7 gene was constructed, and Walker 256 breast cancer cell and morphine was injected to build the bone cancer pain model and morphine tolerance model in rats. Lentiviral vector was injected. Rats in each model were divided into 4 groups: model group, PBS group, vehicle group and LV-Nav1.7 group. The expression levels of GFAP and OX42 in dorsal root ganglia (DRG) were measured. After the animal model was built, the level of Nav1.7, GFAP and OX42 was improved obviously with the time prolonged, which was statistically significant (P<0.05). The expression level of GFAP and OX42 in the DRG in the LV-Nav1.7 group declined obviously compared to the model group, PBS group and vehicle group (P<0.05). Intrathecal injection of Navl.7 shRNA lentiviral vector can reduce the expression of Nav1.7 and inhibit the activation of astrocytes and microglia in DRG. The effort is also effective in morphine tolerance bone cancer pain model rats. Copyright © 2015 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

Intervertebral disc degeneration-induced expression of pain-related molecules: glial cell-derived neurotropic factor as a key factor.

PubMed

Jung, Woon-Won; Kim, Hyun-Sook; Shon, Jong-Ryeul; Lee, Min; Lee, Sang-Heon; Sul, Donggeun; Na, Heung Sik; Kim, Joo Han; Kim, Byung-Jo

2011-10-01

Discogenic low back pain has been shown to develop into chronic intractable pain due to an unknown pathogenesis. To study the mechanism of discogenic pain, we analyzed the serial expression of pain-related molecules in the dorsal root ganglia (DRG) and thalamus using a newly developed rat model of disc degeneration. Ten microliters of complete Freund's adjuvant was injected into the L5-6 disc of male Sprague-Dawley rats for 10 minutes using a 26-gauge needle. Using a behavioral test, rats with significant pain were selected and subsequently serial gene expression of pain-related molecules in the DRG and the thalamus was analyzed by reverse transcriptase polymerase chain reaction. The expression of tumor necrosis factor-α and interleukin-1β significantly increased at 4 and 8 weeks in the DRG of rats with pain. Furthermore, interleukin-6 was significantly increased at 4 weeks in the DRG; however, these cytokines did not show a significant change in the thalamus. Calcitonin gene-related peptide and substance P were significantly increased in DRG at 4 and 8 weeks and in the thalamus at 2 and 4 weeks. The level of nerve growth factor-β did not significantly increase in the DRG or thalamus, whereas glial cell line-derived neurotropic factor (GDNF) was significantly increased at 2 weeks and was sustained through 8 weeks in both the DRG and thalamus. The disc degeneration rat model described herein led to significant pain of a chronic nature. The gradual and persistent increase of GDNF in both the thalamus and DRG suggests that GDNF might be a key factor in the development of intractable, chronic discogenic pain.

Forced treadmill running suppresses postincisional pain and inhibits upregulation of substance P and cytokines in rat dorsal root ganglion.

PubMed

Chen, Yu-Wen; Tzeng, Jann-Inn; Lin, Min-Fei; Hung, Ching-Hsia; Wang, Jhi-Joung

2014-08-01

Exercise causes a variety of psychophysical effects (eg, alterations in pain sensation). Tissue injury induces mediator releases in the spinal cord resulting in pain hypersensitivity; however, the contribution of the dorsal root ganglion (DRG) is poorly understood. In this study, we tested if forced treadmill running can attenuate postoperative pain and alter substance P (SP) or proinflammatory cytokine level in the DRG by using a rat model of skin/muscle incision and retraction (SMIR). We evaluated mechanical sensitivity to von Frey stimuli (6 and 15 g) and expression of SP, interleukin-1β, and interleukin-6 in the DRG of sham-operated sedentary rats, SMIR sedentary rats, sham-operated rats with forced treadmill running, and SMIR rats with forced treadmill running. At postoperative day 8, trained rats ran for 5 days per week for 4 weeks on a treadmill 70 minutes/d with an intensity of 18 m/min. On postoperative day 6, SMIR sedentary rats displayed a significant mechanical hypersensitivity that persisted until postoperative day 35. By comparison, SMIR-operated rats, which received forced treadmill running, exhibited a quick recovery from mechanical hypersensitivity. SMIR sedentary rats showed an upregulation of SP, interleukin-1β, and interleukin-6 in the DRG at postoperative days 14 and 28, whereas SMIR-operated rats receiving forced treadmill running reversed this upregulation at postoperative day 28. We concluded that forced treadmill running alleviated persistent postincisional pain caused by SMIR surgery. This appears to be protective against postoperative pain, which probably relates to the downturn in excess SP, interleukin-1β, and interleukin-6 in the DRG. Controlling the expression of SP, interleukin-6, and interleukin-1β in the DRG can help manage postoperative pain. This finding could potentially help clinicians and physical therapists who seek to examine how exercise may attenuate postsurgical pain and its mechanism. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

Possible mechanism of protective effect of thalidomide in STZ-induced-neuropathic pain behavior in rats.

PubMed

Taliyan, Rajeev; Sharma, Pyare Lal

2012-04-01

Diabetes-induced neuropathic pain is recognized as one of the most difficult type of pain to treat and conventional analgesics are well known to be partially effective or associated with potential toxicity. Recently, it has been demonstrated that thalidomide, besides its teratogenic potential, reduced chronic pain in an SNL experimental pain model. The present study was designed to investigate the effect of thalidomide on streptozotocin (STZ)-induced neuropathic pain in rats. Streptozotocin (20 mg/kg, i.p, daily × 4 days) was administered to induce diabetes in the rats. Nociceptive latency was measured using tail-flick and paw-withdrawal test. Thermal hyperalgesia and mechanical allodynia were measured using planter test and dynamic aesthesiometer (Ugo-Basile, Italy), respectively. Urinary and serum nitrite concentration was estimated using Greiss reagent method. Spleen homogenate supernatant was prepared from spleen of 28th day diabetic rats and administered to normal rats (400 ul, i.v) daily for 28 days. Pain threshold progressively decreased in STZ-treated rats, as compared with control rats. 3 weeks after induction of diabetes, the rat exhibited thermal hyperalgesia and mechanical allodynia. The analgesic effect of morphine (8 mg/kg, s.c.) was significantly decreased in both diabetic and in SHS-treated non-diabetic rats. Administration of thalidomide (25 and 50 mg/kg, i.p), a TNF-α inhibitor, significantly prevented hyperglycemia-induced thermal hyperalgesia and mechanical allodynia and also attenuated the increase in serum and urinary nitrite concentration, as compared with untreated diabetic rats. Also, thalidomide (25 and 50 mg/kg, i.p) 1 h before or concurrently with morphine significantly restored the analgesic effect of morphine in diabetic rats. It may be concluded that thalidomide has a beneficial effect in neuropathic pain by decreasing cytokines (TNF-α) and nitric oxide level and may provide a novel promising therapeutic approach for managing painful diabetic neuropathy.

Effects of an ethanol extract and the diterpene, xylopic acid, of Xylopia aethiopica fruits in murine models of musculoskeletal pain.

PubMed

Woode, Eric; Ameyaw, Elvis Ofori; Boakye-Gyasi, Eric; Abotsi, Wonder Kofi Mensah; Oppong Kyekyeku, James; Adosraku, Reimmel; Biney, Robert Peter

2016-12-01

Fruits of Xylopia aethiopica (Dunal) A. Rich. (Annonaceae) are used traditionally to manage arthritis, headache and other pain disorders. The analgesic properties of the X. aethiopica ethanol fruit extract (XAE) and xylopic acid (XA) were evaluated in musculoskeletal pain models. Acute muscle pain was induced in gastrocnemius muscle of Sprague-Dawley rats with 3% carrageenan (i.m.). Rats received XAE (30-300 mg/kg), XA (10-100 mg/kg) or morphine (1-10 mg/kg) after 12 h. Effects of XAE and XA on muscle pain were assessed by measuring post-treatment grip strength of the rats. Chronic muscle pain was similarly induced, but drug treatment was on the eighth day and effects of XAE and XA assessed with Randall-Selitto test for hyperlagesia. Acute-skeletal pain was induced in knee joints of rats with 3% carrageenan-kaolin mixture and effects determined 12-h later. Similar induction protocol was used for chronic knee pain with treatment and measurement as done for chronic muscle pain. XAE and XA significantly and dose-dependently ameliorated both acute muscle (ED 50 mg/kg: XAE = 22.9; XA = 6.2) and skeletal hyperalgesia (XAE = 39.9; XA = 17.7) induced by 3% carrageenan. Similarly, chronic skeletal hyperalgesia was reduced by XAE and XA treatment similar to morphine (ED 50 : XAE = 13.0; XA = 4.6). This reduction was also seen in chronic muscle hyperalgesia (ED 50 : XAE = 79.1; XA = 42.7). XAE and XA significantly reduced the spread of hyperalgesia to contralateral limbs in both models of chronic hyperalgesia. These findings establish analgesic properties of the ethanol fruit extract of X. aethiopica and xylopic acid in musculoskeletal pain.

Persistent Pain Maintains Morphine-Seeking Behavior after Morphine Withdrawal through Reduced MeCP2 Repression of Glua1 in Rat Central Amygdala

PubMed Central

Hou, Yuan-Yuan; Cai, You-Qing

2015-01-01

As long-term opioids are increasingly used for control of chronic pain, how pain affects the rewarding effect of opioids and hence risk of prescription opioid misuse and abuse remains a healthcare concern and a challenging issue in current pain management. In this study, using a rat model of morphine self-administration, we investigated the molecular mechanisms underlying the impact of pain on operant behavior of morphine intake and morphine seeking before and after morphine withdrawal. We found that rats with persistent pain consumed a similar amount of daily morphine to that in control rats without pain, but maintained their level-pressing behavior of morphine seeking after abstinence of morphine at 0.2 mg/kg, whereas this behavior was gradually diminished in control rats. In the central nucleus of amygdala (CeA), a limbic structure critically involved in the affective dimension of pain, proteins of GluA1 subunits of glutamate AMPA receptors were upregulated during morphine withdrawal, and viral knockdown of CeA GluA1 eliminated the morphine-seeking behavior in withdrawn rats of the pain group. Chromatin immunoprecipitation analysis revealed that the methyl CpG-binding protein 2 (MeCP2) was enriched in the promoter region of Gria1 encoding GluA1 and this enrichment was significantly attenuated in withdrawn rats of the pain group. Furthermore, viral overexpression of CeA MeCP2 repressed the GluA1 level and eliminated the maintenance of morphine-seeking behavior after morphine withdrawal. These results suggest direct MeCp2 repression of GluA1 function as a likely mechanism for morphine-seeking behavior maintained by long-lasting affective pain after morphine withdrawal. PMID:25716866

Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats

PubMed Central

Genaro, Karina; Fabris, Débora; Arantes, Ana L. F.; Zuardi, Antônio W.; Crippa, José A. S.; Prado, Wiliam A.

2017-01-01

Background: Pain involves different brain regions and is critically determined by emotional processing. Among other areas, the rostral anterior cingulate cortex (rACC) is implicated in the processing of affective pain. Drugs that interfere with the endocannabinoid system are alternatives for the management of clinical pain. Cannabidiol (CBD), a phytocannabinoid found in Cannabis sativa, has been utilized in preclinical and clinical studies for the treatment of pain. Herein, we evaluate the effects of CBD, injected either systemically or locally into the rACC, on mechanical allodynia in a postoperative pain model and on the negative reinforcement produced by relief of spontaneous incision pain. Additionally, we explored whether CBD underlies the reward of pain relief after systemic or rACC injection. Methods and Results: Male Wistar rats were submitted to a model of incision pain. All rats had mechanical allodynia, which was less intense after intraperitoneal CBD (3 and 10 mg/kg). Conditioned place preference (CPP) paradigm was used to assess negative reinforcement. Intraperitoneal CBD (1 and 3 mg/kg) inverted the CPP produced by peripheral nerve block even at doses that do not change mechanical allodynia. CBD (10 to 40 nmol/0.25 μL) injected into the rACC reduced mechanical allodynia in a dose-dependent manner. CBD (5 nmol/0.25 μL) did not change mechanical allodynia, but reduced peripheral nerve block-induced CPP, and the higher doses inverted the CPP. Additionally, CBD injected systemically or into the rACC at doses that did not change the incision pain evoked by mechanical stimulation significantly produced CPP by itself. Therefore, a non-rewarding dose of CBD in sham-incised rats becomes rewarding in incised rats, presumably because of pain relief or reduction of pain aversiveness. Conclusion: The study provides evidence that CBD influences different dimensions of the response of rats to a surgical incision, and the results establish the rACC as a brain area from which CBD evokes antinociceptive effects in a manner similar to the systemic administration of CBD. In addition, the study gives further support to the notion that the sensorial and affective dimensions of pain may be differentially modulated by CBD. PMID:28680401

Adolescent peer-rejection persistently alters pain perception and CB1 receptor expression in female rats.

PubMed

Schneider, Peggy; Hannusch, Christin; Schmahl, Christian; Bohus, Martin; Spanagel, Rainer; Schneider, Miriam

2014-02-01

Peer-interactions are particularly important during adolescence and teenagers display enhanced sensitivity toward rejection by peers. Social rejection has been shown to induce alterations in pain perception in humans. However, the neurobiological consequences of adolescent social rejection have yet to be extensively characterized, and no appropriate animal model is available. Here, we propose inadequate playful interactions in adolescent rats as a novel animal model for social peer-rejection and examine potential long-term consequences into adulthood. Acute social pairing of female adolescent Wistar rats with an age-matched rat from the less playful Fischer344 strain was found to alter social play and decrease pain reactivity, indicating Fischer rats as inadequate social partners for Wistar animals. Therefore, in a second experiment, adolescent female Wistar rats were either reared with another Wistar rat (adequate social rearing; control) or with a Fischer rat (inadequate social rearing; play-deprived). Beginning on day 50, all Wistar rats were group housed with same-strain partners and tested for behavioral, neurobiological and endocrine differences in adulthood. Playful peer-interactions were decreased during adolescence in play-deprived animals, without affecting social contact behavior. Consequently, adult play-deprived rats showed decreased pain sensitivity and increased startle reactivity compared to controls, but did not differ in activity, anxiety-related behavior or social interaction. Both groups also differed in their endocrine stress-response, and expression levels of the cannabinoid CB1 receptor were increased in the thalamus, whereas FAAH levels were decreased in the amygdala. The present animal model therefore represents a novel approach to assess the long-term consequences of peer-rejection during adolescence. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

Therapeutic Benefit for Late, but Not Early, Passage Mesenchymal Stem Cells on Pain Behaviour in an Animal Model of Osteoarthritis

PubMed Central

Chapman, Victoria; Markides, Hareklea; Sagar, Devi Rani; Xu, Luting; Burston, James J.; Mapp, Paul; Kay, Alasdair; Kehoe, Oksana

2017-01-01

Background Mesenchymal stem cells (MSCs) have a therapeutic potential for the treatment of osteoarthritic (OA) joint pathology and pain. The aims of this study were to determine the influence of a passage number on the effects of MSCs on pain behaviour and cartilage and bone features in a rodent model of OA. Methods Rats underwent either medial meniscal transection (MNX) or sham surgery under anaesthesia. Rats received intra-articular injection of either 1.5 × 106 late passage MSCs labelled with 10 μg/ml SiMAG, 1.5 × 106 late passage mesenchymal stem cells, the steroid Kenalog (200 μg/20 μL), 1.5 × 106 early passage MSCs, or serum-free media (SFM). Sham-operated rats received intra-articular injection of SFM. Pain behaviour was quantified until day 42 postmodel induction. Magnetic resonance imaging (MRI) was used to localise the labelled cells within the knee joint. Results Late passage MSCs and Kenalog attenuated established pain behaviour in MNX rats, but did not alter MNX-induced joint pathology at the end of the study period. Early passage MSCs exacerbated MNX-induced pain behaviour for up to one week postinjection and did not alter joint pathology. Conclusion Our data demonstrate for the first time the role of a passage number in influencing the therapeutic effects of MSCs in a model of OA pain. PMID:29434641

Trigeminal nerve injury-induced thrombospondin-4 up-regulation contributes to orofacial neuropathic pain states in a rat model.

PubMed

Li, K-W; Kim, D-S; Zaucke, F; Luo, Z D

2014-04-01

Injury to the trigeminal nerve often results in the development of chronic pain states including tactile allodynia, or hypersensitivity to light touch, in orofacial area, but its underlying mechanisms are poorly understood. Peripheral nerve injury has been shown to cause up-regulation of thrombospondin-4 (TSP4) in dorsal spinal cord that correlates with neuropathic pain development. In this study, we examined whether injury-induced TSP4 is critical in mediating orofacial pain development in a rat model of chronic constriction injury to the infraorbital nerve. Orofacial sensitivity to mechanical stimulation was examined in a unilateral infraorbital nerve ligation rat model. The levels of TSP4 in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 spinal cord (Vc/C2) from injured rats were examined at time points correlating with the initiation and peak orofacial hypersensitivity. TSP4 antisense and mismatch oligodeoxynucleotides were intrathecally injected into injured rats to see if antisense oligodeoxynucleotide treatment could reverse injury-induced TSP4 up-regulation and orofacial behavioural hypersensitivity. Our data indicated that trigeminal nerve injury induced TSP4 up-regulation in Vc/C2 at a time point correlated with orofacial tactile allodynia. In addition, intrathecal treatment with TSP4 antisense, but not mismatch, oligodeoxynucleotides blocked both injury-induced TSP4 up-regulation in Vc/C2 and behavioural hypersensitivity. Our data support that infraorbital nerve injury leads to TSP4 up-regulation in trigeminal spinal complex that contributes to orofacial neuropathic pain states. Blocking this pathway may provide an alternative approach in management of orofacial neuropathic pain states. © 2013 European Pain Federation - EFIC®

ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model.

PubMed

Miyazaki, Shingo; Diwan, Ashish D; Kato, Kenji; Cheng, Kevin; Bae, Won C; Sun, Yang; Yamada, Junichi; Muehleman, Carol; Lenz, Mary E; Inoue, Nozomu; Sah, Robert L; Kawakami, Mamoru; Masuda, Koichi

2018-04-01

To elucidate the effects of growth differentiation factor-6 (GDF6) on: (i) gene expression of inflammatory/pain-related molecules and structural integrity in the rabbit intervertebral disc (IVD) degeneration model, and (ii) sensory dysfunction and changes in pain-marker expression in dorsal nerve ganglia (DRGs) in the rat xenograft radiculopathy model. Forty-six adolescent rabbits received anular-puncture in two non-consecutive lumbar IVDs. Four weeks later, phosphate-buffered saline (PBS) or GDF6 (1, 10 or 100 µg) was injected into the nucleus pulposus (NP) of punctured discs and followed for 4 weeks for gene expression analysis and 12 weeks for structural analyses. For pain assessment, eight rabbits were sacrificed at 4 weeks post-injection and NP tissues of injected discs were transplanted onto L5 DRGs of 16 nude rats to examine mechanical allodynia. The rat DRGs were analyzed immunohistochemically. In GDF6-treated rabbit NPs, gene expressions of interleukin-6, tumor necrosis factor-α, vascular endothelial growth factor, prostaglandin-endoperoxide synthase 2, and nerve growth factor were significantly lower than those in the PBS group. GDF6 injections resulted in partial restoration of disc height and improvement of MRI disc degeneration grades with statistical significance in rabbit structural analyses. Allodynia induced by xenograft transplantation of rabbit degenerated NPs onto rat DRGs was significantly reduced by GDF6 injection. Staining intensities for ionized calcium-binding adaptor molecule-1 and calcitonin gene-related peptide in rat DRGs of the GDF6 group were significantly lower than those of the PBS group. GDF6 injection may change the pathological status of degenerative discs and attenuate degenerated IVD-induced pain.

Differential expression of miRNAs in the nervous system of a rat model of bilateral sciatic nerve chronic constriction injury.

PubMed

Li, Haixia; Shen, Le; Ma, Chao; Huang, Yuguang

2013-07-01

Chronic neuropathic pain is associated with global changes in gene expression in different areas of the nociceptive pathway. MicroRNAs (miRNAs) are small (~22 nt long) non-coding RNAs, which are able to regulate hundreds of different genes post-transcriptionally. The aim of this study was to determine the miRNA expression patterns in the different regions of the pain transmission pathway using a rat model of human neuropathic pain induced by bilateral sciatic nerve chronic constriction injury (bCCI). Using microarray analysis and quantitative reverse transcriptase-PCR, we observed a significant upregulation in miR-341 expression in the dorsal root ganglion (DRG), but not in the spinal dorsal horn (SDH), hippocampus or anterior cingulate cortex (ACC), in the rats with neuropathic pain compared to rats in the naïve and sham-operated groups. By contrast, the expression of miR-203, miR-181a-1* and miR-541* was significantly reduced in the SDH of rats with neuropathic pain. Our data indicate that miR-341 is upregulated in the DRG, whereas miR-203, miR-181a-1* and miR-541* are downregulated in the SDH under neuropathic pain conditions. Thus, the differential expression of miRNAs in the nervous system may play a role in the development of chronic pain. These observations may aid in the development of novel treatment methods for neuropathic pain, which may involve miRNA gene therapy in local regions.

Activation of spinal and supraspinal cannabinoid-1 receptors lead to antinociception in a rat model of neuropathic spinal cord injury pain

PubMed Central

Hama, Aldric; Sagen, Jacqueline

2011-01-01

Activation of CNS cannabinoid subtype-1 (CB1) receptors has been shown to mediate the antinociceptive and other effects of systemically administered CB receptor agonists. The endogenous peptide CB receptor ligand hemopressin (HE) has previously demonstrated an antinociceptive effect in rats with a hind paw inflammation, without exhibiting characteristic CB1 receptor-mediated side-effects. The current study evaluated the effect of intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of HE in a rat model of neuropathic spinal cord injury (SCI) pain. The non-subtype selective CB receptor agonist WIN 55,212-2 was also centrally administered in SCI rats as a comparator. Four weeks following an acute compression of the mid-thoracic spinal cord, rats displayed markedly decreased hind paw withdrawal thresholds, indicative of below-level neuropathic pain. Central administration of WIN 55,212-2 significantly increased withdrawal thresholds, whereas HE did not. Hemopressin has been reported to block CB1 receptors in vitro, similar to the CB1 receptor antagonist rimonabant. Pretreatment with rimonabant completely blocked the antinociceptive effect of centrally administered WIN 55,212-2, but pretreatment with HE did not. While the data confirm that activation of either supraspinal or spinal CB1 receptors leads to significant antinociception in SCI rats, the current data do not support an antinociceptive effect from an acute blockade of central CB1 receptors, HE’s putative antinociceptive mechanism, in neuropathic SCI rats. Although such a mechanism could be useful in other models of pain with a significant inflammatory component, the current data indicate that activation of CB1 receptors is needed to ameliorate neuropathic SCI pain. PMID:21813113

Randall Selitto pressure algometry for assessment of bone-related pain in rats.

PubMed

Falk, S; Ipsen, D H; Appel, C K; Ugarak, A; Durup, D; Dickenson, A H; Heegaard, A M

2015-03-01

Deep pain is neglected compared with cutaneous sources. Pressure algometry has been validated in the clinic for assessment of bone-related pain in humans. In animal models of bone-related pain, we have validated the Randall Selitto behavioural test for assessment of acute and pathological bone pain and compared the outcome with more traditional pain-related behaviour measures. Randall Selitto pressure algometry was performed over the anteromedial part of the tibia in naïve rats, sham-operated rats, and rats inoculated with MRMT-1 carcinoma cells in the left tibia, and the effect of morphine was investigated. Randall Selitto measures of cancer-induced bone pain were supplemented by von Frey testing, weight-bearing and limb use test. Contribution of cutaneous nociception to Randall Selitto measures were examined by local anaesthesia. Randall Selitto pressure algometry over the tibia resulted in reproducible withdrawal thresholds, which were dose-dependently increased by morphine. Cutaneous nociception did not contribute to Randall Selitto measures. In cancer-bearing animals, compared with sham, significant differences in pain-related behaviours were demonstrated by the Randall Selitto test on day 17 and 21 post-surgery. A difference was also demonstrated by von Frey testing, weight-bearing and limb use tests. Our results indicate that pressure applied by the Randall Selitto algometer on a region, where the bone is close to the skin, may offer a way to measure bone-related pain in animal models and could provide a supplement to the traditional behavioural tests and a means to study deep pain. © 2014 European Pain Federation - EFIC®

Central sensitization and neuropathic features of ongoing pain in a rat model of advanced osteoarthritis

PubMed Central

Havelin, Joshua; Imbert, Ian; Cormier, Jennifer; Allen, Joshua; Porreca, Frank; King, Tamara

2015-01-01

Osteoarthritis (OA) pain is most commonly characterized by movement-triggered joint pain. However, in advanced disease, OA pain becomes persistent, ongoing and resistant to treatment with NSAIDs. The mechanisms underlying ongoing pain in advanced OA are poorly understood. We recently showed that intra-articular (i.a.) injection of monosodium iodoacetate (MIA) into the rat knee joint produces concentration-dependent outcomes. Thus, a low dose of i.a. MIA produces NSAID-sensitive weight asymmetry without evidence of ongoing pain while a high i.a. MIA dose produces weight asymmetry and NSAID-resistant ongoing pain. In the present studies, palpation of the ipsilateral hindlimb of rats treated 14 days previously with high, but not low, doses of i.a. MIA produced FOS expression in the spinal dorsal horn. Inactivation of descending pain facilitatory pathways by microinjection of lidocaine within the rostral ventromedial medulla (RVM) induced conditioned place preference (CPP) selectively in rats treated with the high dose of MIA. CPP to intra-articular lidocaine was blocked by pretreatment with duloxetine (30 mg/kg, i.p. at −30 min). These observations are consistent with the likelihood of a neuropathic component of OA that elicits ongoing, NSAID resistant pain and central sensitization that is mediated, in part, by descending modulatory mechanisms. This model provides a basis for exploration of underlying mechanisms promoting neuropathic components of OA pain and for the identification of mechanisms that may guide drug discovery for treatment of advanced OA pain without the need for joint replacement. PMID:26694132

Periodontal CGRP contributes to orofacial pain following experimental tooth movement in rats.

PubMed

Long, Hu; Liao, Lina; Gao, Meiya; Ma, Wenqiang; Zhou, Yang; Jian, Fan; Wang, Yan; Lai, Wenli

2015-08-01

Calcitonin-related gene peptide (CGRP) plays an important role in orofacial inflammatory pain. The aim of this study was to determine whether periodontal CGRP contributes to orofacial pain induced by experimental tooth movement in rats. Male Sprague-Dawley rats were used in this study. Closed coil springs were used to deliver forces. Rats were euthanized on 0d, 1d, 3d, 5d, 7d, and 14d following experimental tooth movement. Then, alveolar bones were obtained for immunostaining of periodontal tissues against CGRP. Two hours prior to euthanasia on each day, orofacial pain levels were assessed through rat grimace scale. CGRP and olcegepant (CGRP receptor antagonist) were injected into periodontal tissues to verify the roles of periodontal CGRP in orofacial pain induced by experimental tooth movement. Periodontal CGRP expression levels and orofacial pain levels were elevated on 1d, 3d, 5d, and 7d following experimental tooth movement. The two indices were significantly correlated with each other and fitted into a dose-response model. Periodontal administration of CGRP could elevate periodontal CGRP expressions and exacerbate orofacial pain. Moreover, olcegepant administration could decrease periodontal CGRP expressions and alleviate orofacial pain. Therefore, periodontal CGRP plays an important role in pain transmission and modulation following experimental tooth movement. We suggest that it may participate in a positive feedback aiming to amplify orofacial pain signals. Copyright © 2015 Elsevier B.V. All rights reserved.

[Expressions of neuropathic pain-related proteins in the spinal cord dorsal horn in rats with bilateral chronic constriction injury].

PubMed

Shen, Le; Li, Xu; Wang, Hai-tang; Yu, Xue-rong; Huang, Yu-guang

2013-12-01

To evaluate the pain-related behavioral changes in rats with bilateral chronic constriction injury(bCCI)and identify the expressions of neuropathic pain-related proteins. The bCCI models were established by ligating the sciatic nerves in female Sprague Dawley rats. Both mechanical hyperalgesia and cold hyperalgesia were evaluated through electronic von Frey and acetone method. Liquid chromatography-mass spectrometry/mass spectrometry was applied to characterize the differentially expressed proteins. Both mechanical withdrawal threshold and cold hyperalgesia threshold decreased significantly on the postoperative day 7 and 14, when compared with na ve or sham rats(P <0.05). Twenty five differentially expressed proteins associated with bilateral CCI were discovered, with eighteen of them were upregulated and seven of them downregulated. The bCCT rats have remarkably decreased mechanical and cold hyperalgesia thresholds. Twenty five neuropathic pain-related proteins are found in the spinal cord dorsal horn.

A hydro-ethanolic extract of Synedrella nodiflora (L.) Gaertn ameliorates hyperalgesia and allodynia in vincristine-induced neuropathic pain in rats.

PubMed

Amoateng, Patrick; Adjei, Samuel; Osei-Safo, Dorcas; Ameyaw, Elvis Ofori; Ahedor, Believe; N'guessan, Benoit Banga; Nyarko, Alexander Kwadwo

2015-07-01

The hydro-ethanolic extract of Synedrella nodiflora (L.) Gaertn whole plant has demonstrated analgesic effects in acute pain models. The extract has also demonstrated anticonvulsant effects in murine models of experimental epilepsy. The present study illustrates an evaluation of the hydro-ethanolic extract of the plant for possible analgesic properties in hyperalgesia and allodynia associated with vincristine-induced neuropathy in rats. Neuropathic pain was induced in Sprague-Dawley rats by injecting 100 μg/kg of vincristine sulphate on alternative days for 6 days (days 0, 2, 4, 8, 10 and 12). Vincristine-induced cold allodynia, mechanical hyperalgesia and thermal hyperalgesia were measured pre-vincristine administration and on days 15, 17 and 19 post-vincristine administration. The rats were then treated with S. nodiflora extract (SNE) (100, 300 and 1000 mg/kg), pregabalin (10, 30 and 100 mg/kg) and distilled water as vehicle daily for 5 days and pain thresholds were measured on alternate days for 3 days. SNE and pregabalin produced analgesic properties observed as increased paw withdrawal latencies to mechanical, tactile, cold water stimuli and thermal hyperalgesic tests during the 5 days of treatment. The findings suggest that hydro-ethanolic extract of S. nodiflora possesses anti-hyperalgesic and anti-allodynic effects in vincristine-induced neuropathic pain in rats.

Effect of artemisinin on neuropathic pain mediated by P2X4 receptor in dorsal root ganglia.

PubMed

Ying, Mofeng; Liu, Hui; Zhang, Tengling; Jiang, Chenxu; Gong, Yingxin; Wu, Bing; Zou, Lifang; Yi, Zhihua; Rao, Shenqiang; Li, Guilin; Zhang, Chunping; Jia, Tianyu; Zhao, Shanhong; Yuan, Huilong; Shi, Liran; Li, Lin; Liang, Shangdong; Liu, Shuangmei

2017-09-01

Neuropathic pain is a type of chronic pain caused by nervous system damage and dysfunction. The pathogenesis of chronic pain is complicated, and there are no effective therapies for neuropathic pain. Studies show that the P2X 4 receptor expressed in the satellite glial cells (SGCs) of dorsal root ganglia (DRG) is related to neuropathic pain. Artemisinin is a monomeric component extracted from traditional Chinese medicine and has a variety of important pharmacological effects and potential applications. This study observed the effect of artemisinin on neuropathic pain and delineated its possible mechanism. The chronic constriction injury (CCI) rat model was used in this study. The results demonstrated that artemisinin relieved pain behaviors in the CCI rats, inhibited the expression of P2X 4 receptor in the DRG, and decreased the ATP-activated currents in HEK293 cells transfected with P2X 4 plasmid. Dual-labeling immunofluorescence showed that the coexpression of P2X 4 receptor and glial fibrillary acidic protein (GFAP) in the DRG of CCI rats was increased compared to control rats. After CCI rats were treated with artemisinin, the coexpression of P2X 4 receptor and GFAP in the DRG was significantly decreased compared to the CCI group. This finding suggested that artemisinin could inhibit the nociceptive transmission mediated by P2X 4 receptor in the DRG SGCs and thus relieve pain behaviors in the CCI rats. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of music therapy on pain behaviors in rats with bone cancer pain.

PubMed

Gao, Ji; Chen, Shaoqin; Lin, Suyong; Han, Hongjing

2016-01-01

To investigate the effects of music therapy on the pain behaviors and survival of rats with bone cancer pain and analyze the mediating mechanism of mitogen activated protein kinase (MAPK) signal transduction pathway. Male Wistar rats aged 5-8 weeks and weighing 160-200 g were collected. The rat models of colorectal cancer bone cancer pain was successfully established. Animals were divided into experimental and control group, each with 10 rats. The animals in the observation group were given Mozart K448 sonata, sound intensity of 60 db, played the sonata once every 1 hr in the daytime, stopped playing during the night, and this cycle was kept for 2 weeks. On the other hand, rats in the control group were kept under the same environment without music. Animals in the experimental group consumed more feed and gained significant weight in comparison to the control group. The tumor volume of the experimental group was significantly smaller than that of the control group (p<0.05). After 1-2 weeks of treatment, spontaneous foot withdrawal reflection caused by pain in the experimental group was significantly lower than that in the control group, heat pain threshold and free walking pain scoring in the experimental group were also significantly higher as compared with the control group (p<0.05). The expression of p38á and p38β in animals' spinal cord and dorsal root ganglion was significantly lower in the experimental group than in the control group (p< 0.05). Music therapy may improve the pain behaviors in rats with bone cancer pain, which might be related with low expression of p38á and p38β in the MAPK signal transduction pathway.

Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation.

PubMed

Pitcher, Mark H; Tarum, Farid; Rauf, Imran Z; Low, Lucie A; Bushnell, Catherine

2017-06-01

Aerobic exercise improves outcomes in a variety of chronic health conditions, yet the support for exercise-induced effects on chronic pain in humans is mixed. Although many rodent studies have examined the effects of exercise on persistent hypersensitivity, the most used forced exercise paradigms that are known to be highly stressful. Because stress can also produce analgesic effects, we studied how voluntary exercise, known to reduce stress in healthy subjects, alters hypersensitivity, stress, and swelling in a rat model of persistent hind paw inflammation. Our data indicate that voluntary exercise rapidly and effectively reduces hypersensitivity as well as stress-related outcomes without altering swelling. Moreover, the level of exercise is unrelated to the analgesic and stress-reducing effects, suggesting that even modest amounts of exercise may impart significant benefit in persistent inflammatory pain states. Modest levels of voluntary exercise reduce pain- and stress-related outcomes in a rat model of persistent inflammatory pain, independently of the amount of exercise. As such, consistent, self-regulated activity levels may be more relevant to health improvement in persistent pain states than standardized exercise goals. Published by Elsevier Inc.

Effects of intra-fourth ventricle injection of crocin on capsaicin-induced orofacial pain in rats.

PubMed

Tamaddonfard, Esmaeal; Tamaddonfard, Sina; Pourbaba, Salar

2015-01-01

Crocin, a constituent of saffron and yellow gardenia, possesses anti-nociceptive effects. In the present study, we investigated the effects of intra-fourth ventricle injection of crocin in a rat model of orofacial pain. The contribution of opioid system was assessed using intra-fourth ventricle injection of naloxone, an opioid receptor antagonist. A guide cannula was implanted into the fourth ventricle of brain in anesthetized rats. Orofacial pain was induced by subcutaneous (s.c.) injection of capsaicin (1.5 µg/20 µl) into the right vibrissa pad. The time spent face rubbing/grooming was recorded for a period of 20 min. Locomotor activity was measured using an open-field test. Intra-fourth ventricle injection of crocin (10 and 40 µg/rat) and morphine (10 and 40 µg/rat) and their co-administration (2.5 and 10 µg/rat of each) suppressed capsaicin-induced orofacial pain. The analgesic effect induced by 10 µg/rat of morphine, but not crocin (10 µg/rat), was prevented by 20 µg/rat of naloxone pretreatment. The above-mentioned chemical compounds did not affect locomotor activity. The results of this study showed that the injection of crocin into the cerebral fourth ventricle attenuates capsaicin-induced orofacial pain in rats. The anti-nociceptive effect of crocin was not attributed to the central opioid receptors.

Protective Effects of Sinomenine on CFA-Induced Inflammatory Pain in Rats.

PubMed

Yuan, Yan; Zhang, Yongjun; He, Xiaofeng; Fan, Shengdeng

2018-04-05

BACKGROUND The purpose of this study was to investigate the effects of sinomenine (SIN) on CFA-induced inflammatory pain in rats, and to explore the underlying molecular mechanisms. MATERIAL AND METHODS To determine the potential influences of SIN in the pathogenesis of inflammatory pain, an inflammatory pain (IP) mouse model was established and rats were treated with SIN (30 mg/kg). Behavioral tests were used to assess the MWT and TWL of the rats. ELISA assay was used to detect the level of inflammation cytokines. Western blotting and qRT-PCR were carried out to measure the related protein and mRNA expression level, respectively. RESULTS We found that the MWT and TWL of the CFA-treated rats were markedly lower than that of the control rats, and they were significantly increased by SIN administration. The results suggest that IP rats had higher levels of TNF-α, IL-1β and IL-6 compared with the control rats. SIN administration decreased the levels of TNF-α, IL-1β, and IL-6. In addition, we found that p-p65 and p-p38 expression notably decreased after SIN treatment in IP rats. Moreover, the results showed that SIN inhibited Cox-2 and PGE2 expression in IP rats. CONCLUSIONS The data indicate that SIN had a protective role in inflammatory pain through repressing inflammatory mediators via preventing the p38MAPK-NF-κB pathway.

Inducible nitric oxide synthase inhibition by 1400W limits pain hypersensitivity in a neuropathic pain rat model.

PubMed

Staunton, C A; Barrett-Jolley, R; Djouhri, L; Thippeswamy, T

2018-04-01

What is the central question of this study? Can modulation of inducible NO synthase reduce pain behaviour and pro-inflammatory cytokine signalling in a rat model of neuropathic pain? What is the main finding and its importance? Nitric oxide synthase-based therapies could be effective for the treatment of peripheral neuropathic pain. Peripheral neuropathic pain (PNP), resulting from injury to or dysfunction of a peripheral nerve, is a major health problem that affects 7-8% of the population. It is inadequately controlled by current drugs and is characterized by pain hypersensitivity, which is believed to be attributable to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: (i) whether reducing levels of nitric oxide (NO) with 1400W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent or attenuate pain hypersensitivity; and (ii) the effects of 1400W on plasma concentrations of several cytokines that are secreted after iNOS upregulation during chronic pain states. The L5 spinal nerve axotomy (SNA) model of PNP was used, and 1400W (20 mg kg -1 ) was administered i.p. at 8 h intervals for 3 days starting at 18 h post-SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400W were examined using multiplex enzyme-linked immunosorbent assay. The SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400W significantly: (i) limited development of mechanical hypersensitivity at 66 h post-SNA and of heat hypersensitivity at 42 h and at several time points tested thereafter; and (ii) increased the plasma concentrations of interleukin (IL)-1α, IL-1β and IL-10 in the SNA rats. The findings suggest that 1400W might exert its analgesic effects by reducing iNOS and altering the balance between the pro-inflammatory (IL-1β and IL-1α) and anti-inflammatory (IL-10) cytokines and that therapies targeting NO or its enzymes might be effective for the treatment of PNP. © 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.

DEET potentiates the development and persistence of anticholinesterase dependent chronic pain signs in a rat model of Gulf War Illness pain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Flunker, L.K., E-mail: lflunker@dental.ufl.edu

Exposure to DEET (N,N-diethyl-meta-toluamide) may have influenced the pattern of symptoms observed in soldiers with GWI (Gulf War Illness; Haley and Kurt, 1997). We examined how the addition of DEET (400 mg/kg; 50% topical) to an exposure protocol of permethrin (2.6 mg/kg; topical), chlorpyrifos (CP; 120 mg/kg), and pyridostigmine bromide (PB;13 mg/kg) altered the emergence and pattern of pain signs in an animal model of GWI pain (). Rats underwent behavioral testing before, during and after a 4 week exposure: 1) hindlimb pressure withdrawal threshold; 2) ambulation (movement distance and rate); and 3) resting duration. Additional studies were conducted tomore » assess the influence of acute DEET (10–100 μM) on muscle and vascular nociceptor K{sub v}7, K{sub DR}, Na{sub v}1.8 and Na{sub v}1.9. We report that a 50% concentration of DEET enhanced the development and persistence of pain-signs. Rats exposed to all 4 compounds exhibited ambulation deficits that appeared 5–12 weeks post-exposure and persisted through weeks 21–24. Rats exposed to only three agents (CP or PB excluded), did not fully develop ambulation deficits. When PB was excluded, rats also developed rest duration pain signs, in addition to ambulation deficits. There was no evidence that physiological doses of DEET acutely modified nociceptor K{sub v}7, K{sub DR}, Na{sub v}1.8 or Na{sub v}1.9 activities. Nevertheless, DEET augmented protocols decreased the conductance of K{sub v}7 expressed in vascular nociceptors harvested from chronically exposed rats. We concluded that DEET enhanced the development and persistence of pain behaviors, but the anticholinesterases CP and PB played a determinant role. - Highlights: • DEET accelerated and prolonged pain-like behaviors in a rat model of Gulf War Illness. • The development of pain behaviors were dependent upon chlorpyrifos and pyridostigmine. • Conductance of vascular nociceptor Kv7 was diminished 12 weeks following exposures. • DEET did not have any acute influence on nociceptor Kv7, Nav1.8, Nav1.9 or KDR.« less

[The role of brain-derived neurotrophic factor in pain facilitation and spinal mechanism in rat model of bone cancer pain].

PubMed

Wang, Li-na; Yang, Jian-ping; Ji, Fu-hai; Wang, Xiu-yun; Zuo, Jian-ling; Xu, Qi-nian; Jia, Xiao-ming; Zhou, Jing; Ren, Chun-guang; Li, Wei

2011-05-10

To investigate the role of brain-derived neurotrophic factor (BDNF) in pain facilitation and spinal mechanisms in the rat model of bone cancer pain. The bone cancer pain model was developed by inoculated Walker 256 mammary gland carcinoma cells into the tibia medullary cavity. Sixty SD female rats were divided into 5 groups (n = 12 each) randomly; group I: control group (sham operation); group II: model group; group III: control group + anti-BDNF intrathecal (i.t.); group IV: model group + control IgG i.t.; group V: model group + anti-BDNF i.t.. Anti-BDNF or control IgG was injected i.t. during 7 to 9th day. Von-Frey threshold was measured one day before operation and every 2 days after operation. On the 9th day after threshold tested, rats were sacrificed after i.t. injection of either anti-BDNF or control IgG, the lumbar 4-6 spinal cord was removed. The expression of the spinal BDNF and the phosphorylation of extracellular signal-regulated protein kinase 1/2 (p-ERK1/2) were detected by immunohistochemistry assay and Western-Blot. Co-expression pattern of BDNF and p-ERK1/2 were determined by double-labeling immunofluorescence. We demonstrated the coexistence of BDNF and p-ERK1/2 in the spinal cord of rats. From the 7 to 9th day after operation, von-Frey threshold in groups II and IV was significantly lower than that in group I and group V (P < 0.01), group V was remarkly higher than that in group IV (P < 0.01). The spinal BDNF and p-ERK1/2 expression in group II or IV were significantly increased compared with that in group I or V (P < 0.01), intrathecal anti-BDNF was significantly suppressed BDNF and p-ERK1/2 expression (P < 0.01). BDNF and p-ERK1/2 was coexistence in the spinal cord of rats, and it maybe involved in the bone cancer pain.

Effects of transcutaneous electrical nerve stimulation on rats with the third lumbar vertebrae transverse process syndrome.

PubMed

Li, Huan; Shang, Xiao-Jun; Dong, Qi-Rong

2015-10-01

To investigate the analgesic and anti-inflammatory effects of transcutaneous electrical nerve stimulation (TENS) at local or distant acupuncture points in a rat model of the third lumbar vertebrae transverse process syndrome. Forty Sprague-Dawley rats were randomly divided into control, model, model plus local acupuncture point stimulation at BL23 (model+LAS) and model plus distant acupuncture point stimulation at ST36 (model+DAS) groups. All rats except controls underwent surgical third lumbar vertebrae transverse process syndrome modelling on day 2. Thereafter, rats in the model+LAS and model+DAS groups were treated daily with TENS for a total of six treatments (2/100 Hz, 30 min/day) from day 16 to day 29. Thermal pain thresholds were measured once a week during treatment and were continued until day 57, when local muscle tissue was sampled for RT-PCR and histopathological examination after haematoxylin and eosin staining. mRNA expression of interleukin-1 β (IL-1β), tumour necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) was determined. Thermal pain thresholds of all model rats decreased relative to the control group. Both LAS and DAS significantly increased the thermal pain threshold at all but one point during the treatment period. Histopathological assessment revealed that the local muscle tissues around the third lumbar vertebrae transverse process recovered to some degree in both the model+LAS and model+DAS groups; however, LAS appeared to have a greater effect. mRNA expression of IL-1β, TNF-α and iNOS in the local muscle tissues was increased after modelling and attenuated in both model+LAS and model+DAS groups. The beneficial effect was greater after LAS than after DAS. TENS at both local (BL23) and distant (ST36) acupuncture points had a pain-relieving effect in rats with the third lumbar vertebrae transverse process syndrome, and LAS appeared to have greater anti-inflammatory and analgesic effects than DAS. 09073. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Sex differences in pain-related behavior and expression of calcium/calmodulin-dependent protein kinase II in dorsal root ganglia of rats with diabetes type 1 and type 2.

PubMed

Ferhatovic, Lejla; Banozic, Adriana; Kostic, Sandra; Sapunar, Damir; Puljak, Livia

2013-06-01

Sex differences in pain-related behavior and expression of calcium/calmodulin dependent protein kinase II (CaMKII) in dorsal root ganglia were studied in rat models of Diabetes mellitus type 1 (DM1) and type 2 (DM2). DM1 was induced with 55mg/kg streptozotocin, and DM2 with a combination of high-fat diet and 35mg/kg of streptozotocin. Pain-related behavior was analyzed using thermal and mechanical stimuli. The expression of CaMKII was analyzed with immunofluorescence. Sexual dimorphism in glycemia, and expression of CaMKII was observed in the rat model of DM1, but not in DM2 animals. Increased expression of total CaMKII (tCaMKII) in small-diameter dorsal root ganglia neurons, which are associated with nociception, was found only in male DM1 rats. None of the animals showed increased expression of the phosphorylated alpha CaMKII isoform in small-diameter neurons. The expression of gamma and delta isoforms of CaMKII remained unchanged in all analyzed animal groups. Different patterns of glycemia and tCaMKII expression in male and female model of DM1 were not associated with sexual dimorphism in pain-related behavior. The present findings do not suggest sex-related differences in diabetic painful peripheral neuropathy in male and female diabetic rats. Copyright © 2012 Elsevier GmbH. All rights reserved.

[Study on relationship of dose-effect and time-effect of APA microencapsulated bovine chromaffin cells on pain treatment].

PubMed

Hui, Jianfeng; Li, Tao; Du, Zhi; Song, Jichang

2011-12-01

This study was to investigate the relationship of dose-effect and time-effect of Alginate-Polylysine-Alginate (APA) microencapsulated bovine chromaffin cells on the treatment of pain model rats. Using a rat model of painful peripheral neuropathy, the antinociceptive effects of APA microencapsulated bovine cells transplanted into the subarachnoid space was evaluated by cold allodynia test and hot hyperalgesia test. Compared with control group, the withdrawal difference with cell number 50 thousands groups, 100 thousands groups and 200 thousands groups was reduced (P < 0.05), and the difference decreased with the cells increases, indicating a significant analgesic effect. There was no significant difference between 400 thousands groups and 200 thousands groups. This analgesic effect maintained longer than 12 weeks. There was a positive correlation between the analgesic effect and the quantity of APA microencapsulated bovine chromaffin cells which were transplanted to treat pain model rats, and the effective antinociception remained longer than 12 weeks.

Cannabinoid-mediated diversity of antinociceptive efficacy of parecoxib in Wistar and Sprague Dawley rats in the chronic constriction injury model of neuropathic pain.

PubMed

Becker, Axel; Geisslinger, Gerd; Murín, Radovan; Grecksch, Gisela; Höllt, Volker; Zimmer, Andreas; Schröder, Helmut

2013-05-01

We studied nociceptive behavior and the effects of analgesics in Wistar (Wist) and Sprague Dawley (SPD) rats and in CB1 receptor-deficient mice with neuropathic pain experimentally. Neuropathic pain was induced by loose ligation of the sciatic nerve (chronic constriction injury, CCI). In CCI rats from both strains, cold allodynia and a reduced thermal pain threshold were detected, whereas no effect was found in the hot plate test. Thermal pain threshold was used to study the antinociceptive effects of morphine, gabapentin, and parecoxib 5 days after surgery. Doses of gabapentin and morphine which had no effect on sham-operated animals provoked antinociceptive activity in CCI rats from both strains. An antinociceptive effect of parecoxib was only found in CCI Wist rats. No pharmacokinetic differences were detected between the two strains in parecoxib metabolism. Antinociceptive activity caused by parecoxib was attenuated by the CB1 antagonist rimonabant. To further clarify parecoxib-CB1 interaction, the effect of parecoxib was investigated in CB1-deficient mice and wild-type animals. CCI did not affect thermal pain threshold and mechanical pain threshold was decreased. Parecoxib normalized the altered mechanical pain threshold in CCI wild-type animals, whereas it had only a marginal effect in CB1 receptor deficient mice. Receptor binding experiments showed increased CB1 binding in parecoxib-treated CCI Wist rats. Levels of the CB1 receptor mRNA remained constant in both strains of rats 5 days after surgery. Differences in antinociceptive activity might be due to modification of the cannabinoid system.

Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain.

PubMed

Ragavendran, J Vaigunda; Laferrière, André; Xiao, Wen Hua; Bennett, Gary J; Padi, Satyanarayana S V; Zhang, Ji; Coderre, Terence J

2013-01-01

Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain. This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

An evaluation of the antinociceptive effects of Phα1β, a neurotoxin from the spider Phoneutria nigriventer, and ω-conotoxin MVIIA, a cone snail Conus magus toxin, in rat model of inflammatory and neuropathic pain.

PubMed

de Souza, Alessandra Hubner; Castro, Célio J; Rigo, Flavia Karine; de Oliveira, Sara Marchesan; Gomez, Renato Santiago; Diniz, Danuza Montijo; Borges, Marcia Helena; Cordeiro, Marta Nascimento; Silva, Marco Aurélio Romano; Ferreira, Juliano; Gomez, Marcus Vinicius

2013-01-01

Voltage-sensitive calcium channels (VSCCs) underlie cell excitability and are involved in the mechanisms that generate and maintain neuropathic and inflammatory pain. We evaluated in rats the effects of two VSCC blockers, ω-conotoxin MVIIA and Phα1β, in models of inflammatory and neuropathic pain induced with complete Freund's adjuvant (CFA) and chronic constrictive injury (CCI), respectively. We also evaluated the effects of the toxins on capsaicin-induced Ca(2+) influx in dorsal root ganglion (DRG) neurons obtained from rats exposed to both models of pain. A single intrathecal injection of Phα1β reversibly inhibits CFA and CCI-induced mechanical hyperalgesia longer than a single injection of ω-conotoxin MVIIA. Phα1β and MVIIA also inhibited capsaicin-induced Ca(2+) influx in DRG neurons. The inhibitory effect of Phα1β on capsaicin-induced calcium transients in DRG neurons was greater in the CFA model of pain, while the inhibitory effect of ω-conotoxin MVIIA was greater in the CCI model. The management of chronic inflammatory and neuropathic pain is still a major challenge for clinicians. Phα1β, a reversible inhibitor of VSCCs with a preference for N-type Ca(2+) channels, has potential as a novel therapeutic agent for inflammatory and neuropathic pain. Clinical studies are necessary to establish the role of Phα1β in the treatment of chronic pain.

Role of Complement in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy.

PubMed

Xu, Jijun; Zhang, Lingjun; Xie, Mian; Li, Yan; Huang, Ping; Saunders, Thomas L; Fox, David A; Rosenquist, Richard; Lin, Feng

2018-06-15

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating side effect of cancer chemotherapy with an unclear pathogenesis. Consequently, the available therapies for this neuropathic pain syndrome are inadequate, leading to a significantly reduced quality of life in many patients. Complement, a key component of the innate immune system, has been associated with neuroinflammation, a potentially important trigger of some types of neuropathic pain. However, the role of complement in CIPN remains unclear. To address this issue, we developed a C3 knockout (KO) rat model and induced CIPN in these KO rats and wild-type littermates via the i.p. administration of paclitaxel, a chemotherapeutic agent associated with CIPN. We then compared the severity of mechanical allodynia, complement activation, and intradermal nerve fiber loss between the groups. We found that 1) i.p. paclitaxel administration activated complement in wild-type rats, 2) paclitaxel-induced mechanical allodynia was significantly reduced in C3 KO rats, and 3) the paclitaxel-induced loss of intradermal nerve fibers was markedly attenuated in C3 KO rats. In in vitro studies, we found that paclitaxel-treated rat neuronal cells activated complement, leading to cellular injury. Our findings demonstrate a previously unknown but pivotal role of complement in CIPN and suggest that complement may be a new target for the development of novel therapeutics to manage this painful disease. Copyright © 2018 by The American Association of Immunologists, Inc.

Dissecting the contribution of knee joint NGF to spinal nociceptive sensitization in a model of OA pain in the rat

PubMed Central

Sagar, D.R.; Nwosu, L.; Walsh, D.A.; Chapman, V.

2015-01-01

Summary Objective Although analgesic approaches targeting nerve growth factor (NGF) for the treatment of osteoarthritis (OA) pain remain of clinical interest, neurophysiological mechanisms by which NGF contribute to OA pain remain unclear. We investigated the impact of local elevation of knee joint NGF on knee joint, vs remote (hindpaw), evoked responses of spinal neurones in a rodent model of OA pain. Design In vivo spinal electrophysiology was carried out in anaesthetised rats with established pain behaviour and joint pathology following intra-articular injection of monosodium iodoacetate (MIA), vs injection of saline. Neuronal responses to knee joint extension and flexion, mechanical punctate stimulation of the peripheral receptive fields over the knee and at a remote site (ipsilateral hind paw) were studied before, and following, intra-articular injection of NGF (10 μg/50 μl) or saline. Results MIA-injected rats exhibited significant local (knee joint) and remote (lowered hindpaw withdrawal thresholds) changes in pain behaviour, and joint pathology. Intra-articular injection of NGF significantly (P < 0.05) increased knee extension-evoked firing of spinal neurones and the size of the peripheral receptive fields of spinal neurones (100% increase) over the knee joint in MIA rats, compared to controls. Intra-articular NGF injection did not significantly alter responses of spinal neurones following noxious stimulation of the ipsilateral hind paw in MIA-injected rats. Conclusion The facilitatory effects of intra-articular injection of NGF on spinal neurones receiving input from the knee joint provide a mechanistic basis for NGF mediated augmentation of OA knee pain, however additional mechanisms may contribute to the spread of pain to remote sites. PMID:25623624

Sympathetic regulation and anterior cingulate cortex volume are altered in a rat model of chronic back pain.

PubMed

Touj, Sara; Houle, Sébastien; Ramla, Djamel; Jeffrey-Gauthier, Renaud; Hotta, Harumi; Bronchti, Gilles; Martinoli, Maria-Grazia; Piché, Mathieu

2017-06-03

Chronic pain is associated with autonomic disturbance. However, specific effects of chronic back pain on sympathetic regulation remain unknown. Chronic pain is also associated with structural changes in the anterior cingulate cortex (ACC), which may be linked to sympathetic dysregulation. The aim of this study was to determine whether sympathetic regulation and ACC surface and volume are affected in a rat model of chronic back pain, in which complete Freund Adjuvant (CFA) is injected in back muscles. Sympathetic regulation was assessed with renal blood flow (RBF) changes induced by electrical stimulation of a hind paw, while ACC structure was examined by measuring cortical surface and volume. RBF changes and ACC volume were compared between control rats and rats injected with CFA in back muscles segmental (T10) to renal sympathetic innervation or not (T2). In rats with CFA, chronic inflammation was observed in the affected muscles in addition to increased nuclear factor-kappa B (NF-kB) protein expression in corresponding spinal cord segments (p=0.01) as well as decreased ACC volume (p<0.05). In addition, intensity-dependent decreases in RBF during hind paw stimulation were attenuated by chronic pain at T2 (p's<0.05) and T10 (p's<0.05), but less so at T10 compared with T2 (p's<0.05). These results indicate that chronic back pain alters sympathetic functions through non-segmental mechanisms, possibly by altering descending regulatory pathways from ACC. Yet, segmental somato-sympathetic reflexes may compete with non-segmental processes depending on the back region affected by pain and according to the segmental organization of the sympathetic nervous system. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Dissecting the contribution of knee joint NGF to spinal nociceptive sensitization in a model of OA pain in the rat.

PubMed

Sagar, D R; Nwosu, L; Walsh, D A; Chapman, V

2015-06-01

Although analgesic approaches targeting nerve growth factor (NGF) for the treatment of osteoarthritis (OA) pain remain of clinical interest, neurophysiological mechanisms by which NGF contribute to OA pain remain unclear. We investigated the impact of local elevation of knee joint NGF on knee joint, vs remote (hindpaw), evoked responses of spinal neurones in a rodent model of OA pain. In vivo spinal electrophysiology was carried out in anaesthetised rats with established pain behaviour and joint pathology following intra-articular injection of monosodium iodoacetate (MIA), vs injection of saline. Neuronal responses to knee joint extension and flexion, mechanical punctate stimulation of the peripheral receptive fields over the knee and at a remote site (ipsilateral hind paw) were studied before, and following, intra-articular injection of NGF (10 μg/50 μl) or saline. MIA-injected rats exhibited significant local (knee joint) and remote (lowered hindpaw withdrawal thresholds) changes in pain behaviour, and joint pathology. Intra-articular injection of NGF significantly (P < 0.05) increased knee extension-evoked firing of spinal neurones and the size of the peripheral receptive fields of spinal neurones (100% increase) over the knee joint in MIA rats, compared to controls. Intra-articular NGF injection did not significantly alter responses of spinal neurones following noxious stimulation of the ipsilateral hind paw in MIA-injected rats. The facilitatory effects of intra-articular injection of NGF on spinal neurones receiving input from the knee joint provide a mechanistic basis for NGF mediated augmentation of OA knee pain, however additional mechanisms may contribute to the spread of pain to remote sites. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Effect of electroacupuncture on expression of ionotropic glutamate receptor subunits and their genes in lumbar segments of spinal cord in rats with neuropathic pain].

PubMed

Ma, Cheng; Yu, Li; Yan, Li-ping

2010-12-01

To observe the effect of electroacupuncture (EA) on the expression of ionotropic glutamate receptor (iGluR) subunits and their mRNAs in the lumbar segments of spinal cord in rats with neuropathic pain, so as to explore its underlying mechanism in relieving spinal hyperalgesia. Thirty SD rats were randomly divided into control, model, and EA groups, with 10 rats in each. The spared nerve injury (SNI) model was established by ligature of the sural nerve after cutting off the common peroneal nerve and anterior tibial nerve. EA (2 Hz, 1 mA) was applied to "Huantiao" (GB 30) and "Weizhong" (BL 40) for 30 min, once daily for 7 days. Mechanical pain threshold was detected before and after modeling and before and after EA treatment. The expression levels of N-methyl-d-aspartic acid (NMDA) receptor subunits NR1 and NR 2 B,and AMPA receptor subunit GluR 1 of iGluR and their genes were assayed by Western blot and reverse transcription polymerase chain reaction (RT-PCR) separately. In comparison with control group, the mechanical pain thresholds were decreased significantly on day 2, 7 and day 14 following modeling in the model group (P < 0.05, P < 0.01). While compared with the model group, the pain threshold was increased considerably on day 14 in the EA group (P < 0.01). Compared with the control group, the expression levels of lumbar spinal cord NR 2 B and NR 2 B mRNA in the model group were increased significantly (P < 0.05), and those of lumbar spinal cord NR 1 and NR 1 mRNA, GluR 1 and GluR 1 mRNA in the model group increased slightly (P > 0.05). In comparison with the model group, the expression levels of lumbar spinal cord NR 2 B and NR 2 B mRNA in the EA group were downregulated remarkably (P < 0.05), and those of lumbar spinal cord NR 1 and NR 1 mRNA, GluR 1 and GluR 1 mRNA in the EA group down-regulated slightly (P > 0.05). EA can significantly suppress pain reaction in rats with neuropathic pain probably through down-regulating the expression of lumbar spinal cord NR 2 B protein and NR 2 B mRNA.

Mu-Opioid (MOP) receptor mediated G-protein signaling is impaired in specific brain regions in a rat model of schizophrenia.

PubMed

Szűcs, Edina; Büki, Alexandra; Kékesi, Gabriella; Horváth, Gyöngyi; Benyhe, Sándor

2016-04-21

Schizophrenia is a complex mental health disorder. Clinical reports suggest that many patients with schizophrenia are less sensitive to pain than other individuals. Animal models do not interpret schizophrenia completely, but they can model a number of symptoms of the disease, including decreased pain sensitivities and increased pain thresholds of various modalities. Opioid receptors and endogenous opioid peptides have a substantial role in analgesia. In this biochemical study we investigated changes in the signaling properties of the mu-opioid (MOP) receptor in different brain regions, which are involved in the pain transmission, i.e., thalamus, olfactory bulb, prefrontal cortex and hippocampus. Our goal was to compare the transmembrane signaling mediated by MOP receptors in control rats and in a recently developed rat model of schizophrenia. Regulatory G-protein activation via MOP receptors were measured in [(35)S]GTPγS binding assays in the presence of a highly selective MOP receptor peptide agonist, DAMGO. It was found that the MOP receptor mediated activation of G-proteins was substantially lower in membranes prepared from the 'schizophrenic' model rats than in control animals. The potency of DAMGO to activate MOP receptor was also decreased in all brain regions studied. Taken together in our rat model of schizophrenia, MOP receptor mediated G-proteins have a reduced stimulatory activity compared to membrane preparations taken from control animals. The observed distinct changes of opioid receptor functions in different areas of the brain do not explain the augmented nociceptive threshold described in these animals. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Long-Term Effects of Neonatal Pain and Stress on Reactivity of the Nociceptive System.

PubMed

Butkevich, I P; Mikhailenko, V A

2016-10-01

The influence of inflammatory pain and/or weaning stress at different terms of neonatal development on functional activity of the nociceptive system during adulthood was studied in rats. Repeated stress in 1-2-day-old rat pups (a premature baby model) enhanced pain sensitivity to peripheral inflammation in both males and females. Repeated inflammatory pain experienced by male pups aged 1-2 or 7-8 days (models of preterm and full-term baby), even in presence of mother, enhanced pain behavior under conditions of repeated inflammatory pain in adulthood. Pain sensitivity in adult animals before (hot plate test) and after formation of the inflammatory focus (formalin test) depended on the age when the animals were subjected to the injury, type of exposure, and on animal sex. The priority data obtained by us will help to understand the mechanisms of long-term effects of early injuries and are important for pediatricians and neonatologists.

Nasal inhalation of butorphanol in combination with ketamine quickly elevates the mechanical pain threshold in the model of chronic constriction injury to the sciatic nerve of rat.

PubMed

Chen, Feng; Wang, LiQin; Chen, ShuJun; Li, ZhiGao; Chen, ZhouLin; Zhou, XinHua; Zhai, Dong

2014-01-01

The aim of the present study is to explore the impact of butorphanol in combination with ketamine via nasal inhalation (NI) on neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve in a rat model. CCI rats (n = 12) were equally randomized to four groups based on the treatments received as follows: 100 μL of 0.9% normal saline via NI (NS/NI group); 100 μg of butorphanol plus 1 mg of ketamine via NI (B + K/NI group); 100 μg of butorphanol alone via NI (B/NI group); and 100 μg of butorphanol plus 1 mg of ketamine via subcutaneous injection (B + K/SC group). Mechanical pain threshold was measured at 10 min, 30 min, 2 h, 4 h, and 6 h after drug administration. The mechanical pain threshold in the B + K/NI group was improved significantly 4 h after drug administration as compared with that in the B/NI or B + K/SC group (P < 0.05). The onset and intensity of drug action in the B + K/NI group were better than those of the other two groups, but the duration of drug action was not prolonged. NI of butorphanol in combination with ketamine quickly elevates the mechanical pain threshold in a rat neuropathic pain model induced by CCI to the sciatic nerve. Copyright © 2014 Elsevier Inc. All rights reserved.

Central Sensitization and Neuropathic Features of Ongoing Pain in a Rat Model of Advanced Osteoarthritis.

PubMed

Havelin, Joshua; Imbert, Ian; Cormier, Jennifer; Allen, Joshua; Porreca, Frank; King, Tamara

2016-03-01

Osteoarthritis (OA) pain is most commonly characterized by movement-triggered joint pain. However, in advanced disease, OA pain becomes persistent, ongoing and resistant to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). The mechanisms underlying ongoing pain in advanced OA are poorly understood. We recently showed that intra-articular (i.a.) injection of monosodium iodoacetate (MIA) into the rat knee joint produces concentration-dependent outcomes. Thus, a low dose of i.a. MIA produces NSAID-sensitive weight asymmetry without evidence of ongoing pain and a high i.a. MIA dose produces weight asymmetry and NSAID-resistant ongoing pain. In the present study, palpation of the ipsilateral hind limb of rats treated 14 days previously with high, but not low, doses of i.a. MIA produced expression of the early oncogene, FOS, in the spinal dorsal horn. Inactivation of descending pain facilitatory pathways using a microinjection of lidocaine within the rostral ventromedial medulla induced conditioned place preference selectively in rats treated with the high dose of MIA. Conditioned place preference to intra-articular lidocaine was blocked by pretreatment with duloxetine (30 mg/kg, intraperitoneally at -30 minutes). These observations are consistent with the likelihood of a neuropathic component of OA that elicits ongoing, NSAID-resistant pain and central sensitization that is mediated, in part, by descending modulatory mechanisms. This model provides a basis for exploration of underlying mechanisms promoting neuropathic components of OA pain and for the identification of mechanisms that might guide drug discovery for treatment of advanced OA pain without the need for joint replacement. Difficulty in managing advanced OA pain often results in joint replacement therapy in these patients. Improved understanding of mechanisms driving NSAID-resistant ongoing OA pain might facilitate development of alternatives to joint replacement therapy. Our findings suggest that central sensitization and neuropathic features contribute to NSAID-resistant ongoing OA joint pain. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

[Effect of Medicated-catgut Embedding at "Changqiang" (GV 1) on Mechanical Pain Threshold and P 38 MAPK Expression in Spinal Cord Tissue in Anus Incisional Pain Rats].

PubMed

Shu, Tao; Zhang, Shi-Ti; Yan, Feng; Ke, Yu-Pei; Wang, Jun

2017-10-25

To observe the effect of medicated-catgut embedding at "Changqiang"(GV 1) on regional pain reaction and expression of p 38 MAPK in the dorsal horn of spinal cord in anus incisional pain rats, so as to explore its analgesic mechanism. Forty male SD rats were randomly divided into control, model, GV 1-embedding and sham acupoint embedding groups ( n =10 rats in each group). The anus incisional pain model was established by making a radial incision (about 10 mm length) at the left lithotomy position of the anus with a surgical knife, and the mechanical pain threshold (PT) was measured by using a Von Frey before and 4, 8, 12, 24 h after operation. The medicated-catgut (about 12.5 mm length/kg body weight) was implanted in the subcutaneous tissue of GV 1 region. The immunoactivity of p 38 MAPK was determined by immunohistochemistry. Compared with the control group, the mechanical PTs were significantly decreased 4, 8, 12 and 24 h after operation both at the site of incision and about 15 mm proximal to the site of incision in the model group ( P <0.05), and the immunoactivity of phosphorylated (p)-p 38 MAPK in the superficial layer of dorsal horns of lumbar spinal cord was significantly increased(24 h)after operation( P <0.05). Compared with the model group, the PTs were significantly increased 8, 12 and 24 h after operation at the site of incision, and 12 h and 24 h at the site about 15 mm proximal to the incision region ( P <0.05), and the immunoactivity level of p-p 38 MAPK was significantly down-regulated in the GV 1-embedding group ( P <0.05). No significant changes were found in the PT and p-p 38 MAPK immunoactivity levels in the sham acupoint embedding group ( P <0.05). Medicated-catgut embedding at "Changqiang"(GV 1) has an analgesic effect in anus incisional pain model rats, which may be related to its effect in down-regulating the expression of p 38 MAPK in the dorsal horn of lumbar spinal cord.

Antinociceptive Effect of Intrathecal Injection of Genetically Engineered Human Bone Marrow Stem Cells Expressing the Human Proenkephalin Gene in a Rat Model of Bone Cancer Pain.

PubMed

Sun, Yi; Tian, Yuke; Li, Haifeng; Zhang, Dengwen; Sun, Qiang

2017-01-01

Background . This study aimed to investigate the use of human bone marrow mesenchymal stem cells (hBMSCs) genetically engineered with the human proenkephalin (hPPE) gene to treat bone cancer pain (BCP) in a rat model. Methods . Primary cultured hBMSCs were passaged and modified with hPPE, and the cell suspensions (6 × 10 6 ) were then intrathecally injected into a rat model of BCP. Paw mechanical withdrawal threshold (PMWT) was measured before and after BCP. The effects of hPPE gene transfer on hBMSC bioactivity were analyzed in vitro and in vivo. Results . No changes were observed in the surface phenotypes and differentiation of hBMSCs after gene transfer. The hPPE-hBMSC group showed improved PMWT values on the ipsilateral side of rats with BCP from day 12 postoperatively, and the analgesic effect was reversed by naloxone. The levels of proinflammatory cytokines such as IL-1 β and IL-6 were ameliorated, and leucine-enkephalin (L-EK) secretion was augmented, in the hPPE-engineered hBMSC group. Conclusion . The intrathecal administration of BMSCs modified with the hPPE gene can effectively relieve pain caused by bone cancer in rats and might be a potentially therapeutic tool for cancer-related pain in humans.

HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in a rat model of bone cancer pain by restoring μ-opioid receptor in spinal cord.

PubMed

Hou, Xinran; Weng, Yingqi; Ouyang, Bihan; Ding, Zhuofeng; Song, Zongbin; Zou, Wangyuan; Huang, Changsheng; Guo, Qulian

2017-08-15

Bone cancer pain (BCP) is a common complication with inadequate management in patients suffering from advanced cancer. Histone deacetylase inhibitors showed significant analgesic effect in multiple inflammatory and neuropathic pain models, but their effect in bone cancer pain has never been explored. In this study, we utilized a BCP rat model with intra-tibial inoculation of Walker 256 mammary gland carcinoma cells, which developed progressive mechanical hypersensitivity but not thermal hypersensitivity. Intrathecal application of trichostatin A (TSA), a classic pan-HDAC inhibitor, ameliorated tactile hypersensitivity and enhanced the analgesic effect of morphine in BCP rats. The analgesic effect of TSA was blocked by co-administration of CTAP, a specific MOR antagonist, confirming the involvement of mu-opioid receptor (MOR). A reduction of MOR expression was observed in the lumbar spinal cord of BCP rats and TSA treatment was able to partially reverse it. In vitro study in PC12 cells also demonstrated the dose-dependent enhancement of MOR expression by TSA treatment. Taking all into consideration, we could draw the conclusion that HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in BCP rats, probably by restoring MOR expression in spinal cord. Copyright © 2017 Elsevier B.V. All rights reserved.

P2Y12 shRNA treatment decreases SGC activation to relieve diabetic neuropathic pain in type 2 diabetes mellitus rats.

PubMed

Wang, Shouyu; Wang, Zilin; Li, Lin; Zou, Lifang; Gong, Yingxin; Jia, Tianyu; Zhao, Shanhong; Yuan, Huilong; Shi, Liran; Liu, Shuangmei; Wu, Bing; Yi, Zhihua; Liu, Hui; Gao, Yun; Li, Guilin; Deussing, Jan M; Li, Man; Zhang, Chunping; Liang, Shangdong

2018-06-26

Diabetic neuropathic pain is a common complication of type 2 diabetes mellitus (DM). Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in neuropathic pain through the release of proinflammatory cytokines. The P2Y12 receptor is expressed in SGCs of the DRG. In this study, our aim was to investigate the role of the P2Y12 receptor on the pathological changes in diabetic neuropathic pain. The present study showed that diabetic neuropathic pain increased mechanical and thermal hyperalgesia in type 2 DM model rats. The results showed that the expression levels of P2Y12 messenger RNA (mRNA) and protein in DRG SGCs were increased in DM model rats compared with control rats. Glial fibrillary acidic protein (GFAP) and interleukin-1β (IL-1β) expression levels in the DRG were increased in DM rats. Upregulation of GFAP is a marker of SGC activation. Targeting the P2Y12 receptor by short hairpin RNA (shRNA) decreased the upregulated expression of P2Y12 mRNA and protein, coexpression of P2Y12 and GFAP, the expression of GFAP, IL-1β, and tumor necrosis factor-receptor 1 in the DRG of DM rats, and relieved mechanical and thermal hyperalgesia in DM rats. After treatment with the P2Y12 receptor shRNA, the enhancing integrated OPTICAL density (IOD) ratios of p-P38 MAPK to P38 mitogen activated protein kinase (MAPK) in the DM rats treated with P2Y12 shRNA were significantly lower than that in the untreated DM rats. Therefore, P2Y12 shRNA treatment decreased SGC activation to relieve mechanical and thermal hyperalgesia in DM rats. © 2018 Wiley Periodicals, Inc.

Superior analgesic effect of H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA), a multifunctional opioid peptide, compared to morphine in a rat model of neuropathic pain.

PubMed

Shimoyama, Megumi; Schiller, Peter W; Shimoyama, Naohito; Toyama, Satoshi; Szeto, Hazel H

2012-11-01

H-Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA) is a synthetic tetrapeptide with extraordinary selectivity for the mu-opioid receptor and is an extremely potent analgesic. [Dmt(1) ]DALDA is unusual in the way that the greater part of its analgesic potency appears to be produced by its actions in the spinal cord. Furthermore, [Dmt(1) ]DALDA inhibits norepinephrine re-uptake and is a mitochondria-targeted antioxidant. Such characteristics may make [Dmt(1)]DALDA particularly effective against neuropathic pain. The present study was designed to compare the effects of [Dmt(1)]DALDA and morphine on thermal hyperalgesia in an experimental neuropathic pain model. Neuropathic pain was induced in rats by surgical ligation of the L5 spinal nerve, and thermal pain thresholds were assessed by latencies of paw withdrawal to radiant heat. The increase in paw withdrawal latency was greater after the administration of [Dmt(1) ]DALDA than that of morphine in neuropathic rats at doses that were equianalgesic in naïve animals. We conclude that [Dmt(1)]DALDA is more effective than morphine against thermal hyperalgesia in this experimental model of neuropathic pain. © 2012 John Wiley & Sons A/S.

Differences in carbachol dose, pain condition, and sex following lateral hypothalamic stimulation.

PubMed

Holden, J E; Wang, E; Moes, J R; Wagner, M; Maduko, A; Jeong, Y

2014-06-13

Lateral hypothalamic (LH) stimulation produces antinociception in female rats in acute, nociceptive pain. Whether this effect occurs in neuropathic pain or whether male-female sex differences exist is unknown. We examined the effect of LH stimulation in male and female rats using conditions of nociceptive and neuropathic pain. Neuropathic groups received chronic constriction injury (CCI) to induce thermal hyperalgesia, a sign of neuropathic pain. Nociceptive rats were naive for CCI, but received the same thermal stimulus following LH stimulation. To demonstrate that CCI ligation produced thermal hyperalgesia, males and females received either ligation or sham surgery for control. Both males and females demonstrated significant thermal hyperalgesia following CCI ligation (p<0.05), but male sham surgery rats also showed a significant left-right difference not present in female sham rats. In the second experiment, rats randomly assigned to CCI or nociceptive groups were given one of three doses of the cholinergic agonist carbachol (125, 250, or 500 nmol) or normal saline for control, microinjected into the left LH. Paw withdrawal from a thermal stimulus (paw withdrawal latency; PWL) was measured every 5 min for 45 min. Linear mixed models analysis showed that males and females in both pain conditions demonstrated significant antinociception, with the 500-nmol dose producing the greatest effect across groups compared with controls for the left paw (p<0.05). Female CCI rats showed equivalent responses to the three doses, while male CCI rats showed more variability for dose. However, nociceptive females responded only to the 500-nmol dose, while nociceptive males responded to all doses (p<0.05). For right PWL, only nociceptive males showed a significant carbachol dose response. These findings are suggestive that LH stimulation produces antinociception in male and female rats in both nociceptive and neuropathic pain, but dose response differences exist based on sex and pain condition. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Electroconvulsive stimulation (ECS) increases the expression of neuropeptide Y (NPY) in rat brains in a model of neuropathic pain: a quantitative real-time polymerase chain reaction (RT-PCR) study.

PubMed

Okabe, Tadashi; Sato, Chiyo; Matsumoto, Keisuke; Ozawa, Hitoshi; Sakamoto, Atsuhiro

2009-11-01

Electroconvulsive shock therapy (ECT) has been widely used as an effective and established treatment for refractory depression and schizophrenia. Some reports have shown that ECT is also effective for treating refractory neuropathic pain. In a rat model of neuropathic pain produced by chronic constrictive injury (CCI) of the sciatic nerve, thermal hyperalgesia, and mechanical allodynia were observed from day 2 after surgery. An electroconvulsive shock (ECS) was administered to rodents once daily for 6 days on days 7-12 after CCI operation using a pulse generator. Thermal and mechanical stimulation tests were performed to assess pain thresholds. Real-time polymerase chain reaction was used to measure the gene expression levels for 5HT(1A)R, 5HT(2A)R, neuropeptide Y (NPY), and GABAA(alpha1)R in the brain. After ECS, the latency to withdrawal from thermal stimulation was significantly increased; however, pain withdrawal thresholds in response to mechanical stimulation were not significantly changed. Expression ratios of NPY were significantly greater after ECS. Symptoms of neuropathic pain improved and expression of NPY in the brain was increased in CCI model rats after ECS, suggesting that changes in the expression of NPY in the brain may be related to the mechanism of action of ECT in treating neuropathic pain.

Identifying the integrated neural networks involved in capsaicin-induced pain using fMRI in awake TRPV1 knockout and wild-type rats

PubMed Central

Yee, Jason R.; Kenkel, William; Caccaviello, John C.; Gamber, Kevin; Simmons, Phil; Nedelman, Mark; Kulkarni, Praveen; Ferris, Craig F.

2015-01-01

In the present study, we used functional MRI in awake rats to investigate the pain response that accompanies intradermal injection of capsaicin into the hindpaw. To this end, we used BOLD imaging together with a 3D segmented, annotated rat atlas and computational analysis to identify the integrated neural circuits involved in capsaicin-induced pain. The specificity of the pain response to capsaicin was tested in a transgenic model that contains a biallelic deletion of the gene encoding for the transient receptor potential cation channel subfamily V member 1 (TRPV1). Capsaicin is an exogenous ligand for the TRPV1 receptor, and in wild-type rats, activated the putative pain neural circuit. In addition, capsaicin-treated wild-type rats exhibited activation in brain regions comprising the Papez circuit and habenular system, systems that play important roles in the integration of emotional information, and learning and memory of aversive information, respectively. As expected, capsaicin administration to TRPV1-KO rats failed to elicit the robust BOLD activation pattern observed in wild-type controls. However, the intradermal injection of formalin elicited a significant activation of the putative pain pathway as represented by such areas as the anterior cingulate, somatosensory cortex, parabrachial nucleus, and periaqueductal gray. Notably, comparison of neural responses to capsaicin in wild-type vs. knock-out rats uncovered evidence that capsaicin may function in an antinociceptive capacity independent of TRPV1 signaling. Our data suggest that neuroimaging of pain in awake, conscious animals has the potential to inform the neurobiological basis of full and integrated perceptions of pain. PMID:25745388

Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache

PubMed Central

Oshinsky, Michael L.; Sanghvi, Menka M.; Maxwell, Christina R.; Gonzalez, Dorian; Spangenberg, Rebecca J.; Cooper, Marnie; Silberstein, Stephen D.

2014-01-01

Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated? In the process of obtaining baseline periorbital von Frey thresholds in a wild-type Sprague-Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders. To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold. This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment. PMID:22963523

The refined biomimetic NeuroDigm GEL™ model of neuropathic pain in a mature rat

PubMed Central

Hannaman, Mary R.; Fitts, Douglas A.; Doss, Rose M.; Weinstein, David E.; Bryant, Joseph L.

2017-01-01

Background: Many humans suffering with chronic neuropathic pain have no objective evidence of an etiological lesion or disease. Frequently their persistent pain occurs after the healing of a soft tissue injury. Based on clinical observations over time, our hypothesis was that after an injury in mammals the process of tissue repair could cause chronic neural pain. Our objectives were to create the delayed onset of neuropathic pain in rats with minimal nerve trauma using a physiologic hydrogel, and characterize the rats’ responses to known analgesics and a targeted biologic. Methods: In mature male Sprague Dawley rats (age 9.5 months) a percutaneous implant of tissue-derived hydrogel was placed in the musculofascial tunnel of the distal tibial nerve. Subcutaneous morphine (3 mg/kg), celecoxib (10 mg/kg), gabapentin (25 mg/kg) and duloxetine (10 mg/kg) were each screened in the model three times each over 5 months after pain behaviors developed. Sham and control groups were used in all screenings. A pilot study followed in which recombinant human erythropoietin (200 units) was injected by the GEL™ neural procedure site. Results: The GEL group gradually developed mechanical hypersensitivity lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses demonstrated profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months, p ≤ 0.001. Histology of the GEL group tibial nerve revealed a site of focal neural remodeling, with neural regeneration, as found in nerve biopsies of patients with neuropathic pain. Conclusion: The refined NeuroDigm GEL™ model induces a neural response resulting in robust neuropathic pain behavior. The analgesic responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin at the ectopic neural lesion appears to alleviate the persistent pain behavior in the GEL™ model rodents. PMID:28620451

Pressure application measurement (PAM): a novel behavioural technique for measuring hypersensitivity in a rat model of joint pain.

PubMed

Barton, Nicola J; Strickland, Iain T; Bond, Susan M; Brash, Harry M; Bate, Simon T; Wilson, Alex W; Chessell, Iain P; Reeve, Alison J; McQueen, Daniel S

2007-06-15

Chronic joint pain affects physical well being and can lead to severe psychological and social problems, therefore successful long-term management is highly sought-after. No current behavioural measures of pain used in pre-clinical models mimic the clinical dolorimeter, which provides an objective measure of joint hypersensitivity. In this study we aim to use a novel behavioural readout alongside an established measure to mimic the multifactorial measurements taken in the clinic. Using the pressure application measurement (PAM) device a gradually increasing squeeze was applied across the knee joint of rats until the animal gave an indication of pain or discomfort. PAM and the incapacitance tester were used to detect joint hypersensitivity in a well-established rodent model of adjuvant-induced arthritis. Subsequently, the analgesic effects of prednisolone (1, 3 or 10 mg kg(-1)), morphine (3 mg kg(-1)) and celecoxib (15 mg kg(-1)) were assessed. Both PAM and the incapacitance tester detected a reversal of hypersensitivity 1h post-drug administration. Furthermore, the two readouts were highly correlated, and power analysis indicated that PAM was highly reproducible. In conclusion, PAM provides a novel, accurate behavioural tool for detecting a primary mechanical hypersensitivity in a rat model of chronic inflammatory joint pain.

Minocycline Effects on IL-6 Concentration in Macrophage and Microglial Cells in a Rat Model of Neuropathic Pain.

PubMed

Moini-Zanjani, Taraneh; Ostad, Seyed-Nasser; Labibi, Farzaneh; Ameli, Haleh; Mosaffa, Nariman; Sabetkasaei, Masoumeh

2016-11-01

Evidence indicates that neuropathic pain pathogenesis is not confined to changes in the activity of neuronal systems but involves interactions between neurons, inflammatory immune and immune-like glial cells. Substances released from immune cells during inflammation play an important role in development and maintenance of neuropathic pain. It has been found that minocycline suppresses the development of neuropathic pain. Here, we evaluated the analgesic effect of minocycline in a chronic constriction injury (CCI) model of neuropathic pain in rat and assessed IL-6 concentration from cultured macrophage and microglia cells. Male Wistar rat (n=6, 150-200 g) were divided into three different groups: 1) CCI+vehicle, 2) sham+vehicle, and 3) CCI+drug. Minocycline (10, 20, and 40 mg/kg) was injected one hour before surgery and continued daily to day 14 post ligation. Von Frey filaments and acetone, as pain behavioral tests, were used for mechanical allodynia and cold allodynia, respectively. Experiments were performed on day 0 (before surgery) and days 1, 3, 5, 7, 10, and 14 post -injury. At day 14, rats were killed and monocyte-derived macrophage from right ventricle and microglia from lumbar part of the spinal cord were isolated and cultured in RPMI and Leibovitz's media, respectively. IL-6 concentration was evaluated in cell culture supernatant after 24 h. Minocycline (10, 20, and 40 mg/kg) attenuated pain behavior, and a decrease in IL-6 concentration was observed in immune cells compared to CCI vehicle-treated animals. Minocycline reduced pain behavior and decreased IL-6 concentration in macrophage and microglial cells.

Prior stress exposure increases pain behaviors in a rat model of full thickness thermal injury.

PubMed

Nyland, Jennifer E; McLean, Samuel A; Averitt, Dayna L

2015-12-01

Thermal burns among individuals working in highly stressful environments, such as firefighters and military Service Members, are common. Evidence suggests that pre-injury stress may exaggerate pain following thermal injury; however current animal models of burn have not evaluated the potential influence of pre-burn stress. This sham-controlled study evaluated the influence of prior stress exposure on post-burn thermal and mechanical sensitivity in male Sprague-Dawley rats. Rats were exposed to 20 min of inescapable swim stress or sham stress once per day for three days. Exposure to inescapable swim stress (1) increased the intensity and duration of thermal hyperalgesia after subsequent burn and (2) accelerated the onset of thermal hyperalgesia and mechanical allodynia after subsequent burn. This stress-induced exacerbation of pain sensitivity was reversed by pretreatment and concurrent treatment with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine. These data suggest a better understanding of mechanisms by which prior stress augments pain after thermal burn may lead to improved pain treatments for burn survivors. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

Silencing of FKBP51 alleviates the mechanical pain threshold, inhibits DRG inflammatory factors and pain mediators through the NF-kappaB signaling pathway.

PubMed

Yu, Hong-Mei; Wang, Qi; Sun, Wen-Bo

2017-09-05

Neuropathic pain is chronic pain caused by lesions or diseases of the somatosensory system, currently available analgesics provide only temporal relief. The precise role of FK506 binding protein 51 (FKBP51) in neuropathic pain induced by chronic constriction injury (CCI) is not clear. The purpose of the present study was to investigate the effects and possible mechanisms of FKBP51 in neuropathic pain in the rat model of CCI. Our results showed that FKBP51 was obviously upregulated in a time-dependent manner in the dorsal root ganglion (DRG) of CCI rats. Additionally, silencing of FKBP51 remarkably attenuated mechanical allodynia and thermal hyperalgesia as reflected by paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in CCI rats. Moreover, knockdown of FKBP51 reduced the production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRG of CCI rats. Furthermore, we revealed that inhibition of FKBP51 greatly suppressed the activation of the NF-kappaB (NF-κB) signaling in the DRG of CCI rats. Interestingly, similar to the FKBP51 siRNA (si-FKBP51), ammonium pyrrolidinedithiocarbamate (PDTC, an inhibitor of NF-κB) also alleviated neuropathic pain and neuro-inflammation, indicating that knockdown of FKBP51 alleviated neuropathic pain development of CCI rats by inhibiting the activation of NF-κB signaling pathway. Taken together, our findings indicate that FKBP51 may serve as a novel therapeutic target for neuropathic pain. Copyright © 2017. Published by Elsevier B.V.

Opiate self-administration as a measure of chronic nociceptive pain in arthritic rats.

PubMed

Colpaert, F C; Tarayre, J P; Alliaga, M; Bruins Slot, L A; Attal, N; Koek, W

2001-03-01

The study examined the validity of oral fentanyl self-administration (FSA) as a measure of the chronic nociceptive pain that develops in rats with adjuvant arthritis independently of acute noxious challenges. Arthritic rats self-administered more of a 0.008 mg/ml fentanyl solution (up to 3.4 g/rat per day) than non-arthritic controls (0.5 g/rat per day) and did so with a biphasic time course that reached peak during weeks 3 and 4 after inoculation with Mycobacterium butyricum. The time course paralleled both the disease process and the chronic pain. Continuous infusion of dexamethasone during weeks 3 and 4 via subcutaneous osmotic pumps at 0.0025-0.04 mg/rat per day disrupted the arthritic disease and decreased FSA to a level (i.e. by 65%) similar to that observed in non-arthritic rats. Continuous naloxone (2.5 mg/rat per day) decreased FSA (by 55%) in arthritic but not in non-arthritic animals. Continuous, subcutaneous infusion of fentanyl also decreased arthritic FSA in a manner that varied with dose at 0.04-0.16 mg/rat per day doses, but leveled off at 47% of controls with 0.31 mg/rat per day. The effects of continuous fentanyl on arthritic FSA occurred only with those doses and dose-dependent dynamics with which fentanyl also induced dependence in non-arthritic rats. The findings indicate that pain, rather than the rewarding or dependence-inducing action of fentanyl mediates FSA in arthritic rats. Paralleling patient-controlled analgesic drug intake, FSA offers a specific measure allowing the dynamic effects of neurobiological agents to be studied in this unique animal model of persistent nociceptive pain.

A novel method for delivering ramped cooling reveals rat behaviours at innocuous and noxious temperatures: A comparative study of human psychophysics and rat behaviour.

PubMed

Dunham, James P; Hulse, Richard P; Donaldson, Lucy F

2015-07-15

Thermal sensory testing in rodents informs human pain research. There are important differences in the methodology for delivering thermal stimuli to humans and rodents. This is particularly true in cold pain research. These differences confound extrapolation and de-value nociceptive tests in rodents. We investigated cooling-induced behaviours in rats and psychophysical thresholds in humans using ramped cooling stimulation protocols. A Peltier device mounted upon force transducers simultaneously applied a ramped cooling stimulus whilst measuring contact with rat hind paw or human finger pad. Rat withdrawals and human detection, discomfort and pain thresholds were measured. Ramped cooling of a rat hind paw revealed two distinct responses: Brief paw removal followed by paw replacement, usually with more weight borne than prior to the removal (temperature inter-quartile range: 19.1 °C to 2.8 °C). Full withdrawal was evoked at colder temperatures (inter quartile range: -11.3 °C to -11.8 °C). The profile of human cool detection threshold and cold pain threshold were remarkably similar to that of the rat withdrawals behaviours. Previous rat cold evoked behaviours utilise static temperature stimuli. By utilising ramped cold stimuli this novel methodology better reflects thermal testing in patients. Brief paw removal in the rat is driven by non-nociceptive afferents, as is the perception of cooling in humans. This is in contrast to the nociceptor-driven withdrawal from colder temperatures. These findings have important implications for the interpretation of data generated in older cold pain models and consequently our understanding of cold perception and pain. Copyright © 2015. Published by Elsevier B.V.

[Role of pendoxifiline (PTX) in different and cute and chronic models of pain in rats].

PubMed

Nowak, Łukasz; Zurowski, Daniel; Garlicki, Jarosław; Thor, Piotr J

2008-01-01

Pentoxifilne (PTX) is a non specific inhibitor of cytokines release, which suppress mainly TNF production. The aim of this study was to evaluate behavioural activity changes in response to acute and chronic nociceptive stimulus. PTX was more effective in neuropathic pain than acute pain model. Use of cytokine inhibitors might offer new strategies of drug-resistant chronic pain treatment.

Molecular mechanisms underlying the effects of acupuncture on neuropathic pain

PubMed Central

Ju, Ziyong; Cui, Huashun; Guo, Xiaohui; Yang, Huayuan; He, Jinsen; Wang, Ke

2013-01-01

Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity following chronic constriction injury, es-pecially electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function. PMID:25206545

Molecular mechanisms underlying the effects of acupuncture on neuropathic pain.

PubMed

Ju, Ziyong; Cui, Huashun; Guo, Xiaohui; Yang, Huayuan; He, Jinsen; Wang, Ke

2013-09-05

Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity following chronic constriction injury, es-pecially electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function.

Sigma-1 Receptor Antagonist BD1047 Reduces Mechanical Allodynia in a Rat Model of Bone Cancer Pain through the Inhibition of Spinal NR1 Phosphorylation and Microglia Activation

PubMed Central

Zhu, Shanshan; Wang, Chenchen; Han, Yuan; Song, Chao; Hu, Xueming; Liu, Yannan

2015-01-01

Previous studies have demonstrated that sigma-1 receptor plays important roles in the induction phase of rodent neuropathic pain; however, whether it is involved in bone cancer pain (BCP) and the underlying mechanisms remain elusive. The aim of this study was to examine the potential role of the spinal sigma-1 receptor in the development of bone cancer pain. Walker 256 mammary gland carcinoma cells were implanted into the intramedullary space of the right tibia of Sprague-Dawley rats to induce ongoing bone cancer-related pain behaviors; our findings indicated that, on days 7, 10, 14, and 21 after operation, the expression of sigma-1 receptor in the spinal cord was higher in BCP rats compared to the sham rats. Furthermore, intrathecal injection of 120 nmol of sigma-1 receptor antagonist BD1047 on days 5, 6, and 7 after operation attenuated mechanical allodynia as well as the associated induction of c-Fos and activation of microglial cells, NR1, and the subsequent Ca2+-dependent signals of BCP rats. These results suggest that sigma-1 receptor is involved in the development of bone cancer pain and that targeting sigma-1 receptor may be a new strategy for the treatment of bone cancer pain. PMID:26696751

Baclofen reversed thermal place preference in rats with chronic constriction injury.

PubMed

Salte, K; Lea, G; Franek, M; Vaculin, S

2016-06-20

Chronic constriction injury to the sciatic nerve was used as an animal model of neuropathic pain. Instead of frequently used reflex-based tests we used an operant thermal place preference test to evaluate signs of neuropathic pain and the effect of baclofen administration in rats with neuropathy. Chronic constriction injury was induced by four loose ligations of the sciatic nerve. Thermal place preference (45 °C vs. 22 °C and 45 °C vs. 11 °C) was measured after the ligation and after the administration of baclofen in sham and experimental rats. Rats with the chronic constriction injury spent significantly less time on the colder plate compared to sham operated animals at the combination 45 °C vs. 11 °C. After administration of baclofen (10 mg/kg s.c.), the aversion to the colder plate in rats with chronic constriction injury disappeared. At the combination 45 °C vs. 22 °C, no difference in time spent on colder and/or warmer plate was found between sham and experimental animals. These findings show the importance of cold allodynia evaluation in rats with chronic constriction injury and the effectiveness of baclofen in this neuropathic pain model.

Correlation of intact sensibility and neuropathic pain-related behaviors in eight inbred and outbred rat strains and selection lines.

PubMed

Shir, Y; Zeltser, R; Vatine, J J; Carmi, G; Belfer, I; Zangen, A; Overstreet, D; Raber, P; Seltzer, Z

2001-02-01

In some rat strains, total hindpaw denervation triggers autotomy, a behavior of self mutilation presumably related to neuropathic pain. Partial sciatic ligation (PSL) in rats produces tactile allodynia and heat hyperalgesia but not autotomy. Our aims in this study were to examine: (1) whether sensibility of intact rats to noxious and non-noxious stimuli is strain-dependent; (2) whether sensibility of intact rats could predict levels of autotomy, or of allodynia and hyperalgesia in the PSL model; and (3) whether autotomy levels are correlated with levels of allodynia or hyperalgesia. Here we report that in two inbred rat strains (Lewis and Fisher 344), two outbred rat strains (Sabra and Sprague-Dawley) and four selection lines of rats (Genetically Epilepsy-Prone Rats, High Autotomy, Low Autotomy and Flinders Sensitive Line), tactile sensitivity and response duration to noxious heat of intact animals were strain-dependent. Levels of autotomy following hindpaw denervation and of allodynia and hyperalgesia in the PSL model were also strain-dependent. Thus, these traits are determined in part by genetic factors. Sensory sensibility of intact rats was not correlated with levels of autotomy following total denervation, or allodynia and hyperalgesia following partial denervation. We suggest that preoperative sensibility of intact rats is not a predictor of levels of neuropathic disorders following nerve injury. Likewise, no correlation was found between autotomy, allodynia and hyperalgesia, suggesting that neuropathic pain behaviors triggered by nerve injury of different etiologies are mediated by differing mechanisms.

Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain.

PubMed

Deng, Bo; Jia, Liqun; Pan, Lin; Song, Aiping; Wang, Yuanyuan; Tan, Huangying; Xiang, Qing; Yu, Lili; Ke, Dandan

2016-01-01

One of the main dose-limiting complications of the chemotherapeutic agent oxaliplatin (OXL) is painful neuropathy. Glial activation and nociceptive sensitization may be responsible for the mechanism of neuropathic pain. The Traditional Chinese Medicine (TCM) Wen-luo-tong (WLT) has been widely used in China to treat chemotherapy induced neuropathic pain. However, there is no study on the effects of WLT on spinal glial activation induced by OXL. In this study, a rat model of OXL-induced chronic neuropathic pain was established and WLT was administrated. Pain behavioral tests and morphometric examination of dorsal root ganglia (DRG) were conducted. Glial fibrillary acidic protein (GFAP) immunostaining was performed, glial activation was evaluated, and the excitatory neurotransmitter substance P (SP) and glial-derived proinflammatory cytokine tumor necrosis factor-α (TNF-α) were analyzed. WLT treatment alleviated OXL-induced mechanical allodynia and mechanical hyperalgesia. Changes in the somatic, nuclear, and nucleolar areas of neurons in DRG were prevented. In the spinal dorsal horn, hypertrophy and activation of GFAP-positive astrocytes were averted, and the level of GFAP mRNA decreased significantly. Additionally, TNF-α mRNA and protein levels decreased. Collectively, these results indicate that WLT reversed both glial activation in the spinal dorsal horn and nociceptive sensitization during OXL-induced chronic neuropathic pain in rats.

Effects of NO-modulating agents on the development of acute painful reaction in rats.

PubMed

Dyuizen, I V; Lamash, N E

2008-08-01

Painful reaction of rats to intraperitoneal injections of L-arginine, Nw-nitro-L-arginine, and agmatine was studied on the model of formalin-induced inflammation. All drugs exhibited a dubious effect on the patterns of nociceptive behavior depending on the phase of painful reaction. The dynamics of nitrate/nitrite content in animal blood and serum indicated the presence of NO-dependent and NO-independent components in the mechanisms of pharmacological effects of these drugs.

Benefits of Preventive Administration of Chlorella sp. on Visceral Pain and Cystitis Induced by a Single Administration of Cyclophosphamide in Female Wistar Rat.

PubMed

Hidalgo-Lucas, Sophie; Rozan, Pascale; Guérin-Deremaux, Laetitia; Baert, Blandine; Violle, Nicolas; Saniez-Degrave, Marie-Hélène; Bisson, Jean-François

2016-05-01

Chlorella sp. is a green microalgae containing nutrients, vitamins, minerals, and chlorophyll. In some communities, Chlorella sp. is a traditional medicinal plant used for the management of inflammation-related diseases. In a rat model, ROQUETTE Chlorella sp. (RCs) benefits were investigated on visceral pain and associated inflammatory parameters related to cystitis both induced by cyclophosphamide (CYP). RCs was orally administered every day from day 1-16 (250 and 500 mg/kg body weight). Six hours after an intraperitoneal injection of 200 mg/kg body weight of CYP, body temperature, general behavior, food intake, and body weight were recorded. Twenty-four hours after CYP injection, rats were tested in two behavioral tests, an open field and the aversive light stimulus avoidance conditioning test, to evaluate the influence of pain on general activity and learning ability of rats. After euthanasia, bladders were weighed, their thickness was scored, and the urinary hemoglobin was measured. RCs orally administered at the two dosages significantly reduced visceral pain and associated inflammatory parameters related to cystitis both induced by CYP injection, and improved rat behavior. To conclude, RCs demonstrated beneficial effects against visceral pain and cystitis.

The Locus Coeruleus–Norepinephrine System Mediates Empathy for Pain through Selective Up-Regulation of P2X3 Receptor in Dorsal Root Ganglia in Rats

PubMed Central

Lü, Yun-Fei; Yang, Yan; Li, Chun-Li; Wang, Yan; Li, Zhen; Chen, Jun

2017-01-01

Empathy for pain (vicariously felt pain), an ability to feel, recognize, understand and share the painful emotions of others, has been gradually accepted to be a common identity in both humans and rodents, however, the underlying neural and molecular mechanisms are largely unknown. Recently, we have developed a rat model of empathy for pain in which pain can be transferred from a cagemate demonstrator (CD) in pain to a naïve cagemate observer (CO) after 30 min dyadic priming social interaction. The naïve CO rats display both mechanical pain hypersensitivity (hyperalgesia) and enhanced spinal nociception. Chemical lesions of bilateral medial prefrontal cortex (mPFC) abolish the empathic pain response completely, suggesting existence of a top-down facilitation system in production of empathy for pain. However, the social transfer of pain was not observed in non-cagemate observer (NCO) after dyadic social interaction with a non-cagemate demonstrator (NCD) in pain. Here we showed that dyadic social interaction with a painful CD resulted in elevation of circulating norepinephrine (NE) and increased neuronal activity in the locus coeruleus (LC) in the CO rats. Meanwhile, CO rats also had over-expression of P2X3, but not TRPV1, in the dorsal root ganglia (DRG). Chemical lesion of the LC-NE neurons by systemic DSP-4 and pharmacological inhibition of central synaptic release of NE by clonidine completely abolished increase in circulating NE and P2X3 receptor expression, as well as the sympathetically-maintained development of empathic mechanical hyperalgesia. However, in the NCO rats, neither the LC-NE neuronal activity nor the P2X3 receptor expression was altered after dyadic social interaction with a painful NCD although the circulating corticosterone and NE were elevated. Finally, in the periphery, both P2X3 receptor and α1 adrenergic receptor were found to be involved in the development of empathic mechanical hyperalgesia. Taken together with our previous results, empathy for pain observed in the CO rats is likely to be mediated by activation of the top-down mPFC-LC/NE-sympathoadrenomedullary (SAM) system that further up-regulates P2X3 receptors in the periphery, however, social stress observed in the NCO rats is mediated by activation of both hypothalamic-pituitary-adrenocortical axis and SAM axis. PMID:28979194

Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats.

PubMed

Chaumette, T; Chapuy, E; Berrocoso, E; Llorca-Torralba, M; Bravo, L; Mico, J A; Chalus, M; Eschalier, A; Ardid, D; Marchand, F; Sors, A

2018-01-01

Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists. The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin. While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus. These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain. S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus. © 2017 European Pain Federation - EFIC®.

Reduced epidermal thickness, nerve degeneration and increased pain-related behavior in rats with diabetes type 1 and 2.

PubMed

Boric, Matija; Skopljanac, Ivan; Ferhatovic, Lejla; Jelicic Kadic, Antonia; Banozic, Adriana; Puljak, Livia

2013-11-01

To examine the mechanisms contributing to pain genesis in diabetic neuropathy, we investigated epidermal thickness and number of intraepidermal nerve fibers in rat foot pad of the animal model of diabetes type 1 and type 2 in relation to pain-related behavior. Male Sprague-Dawley rats were used. Diabetes type 1 was induced with intraperitoneal injection of streptozotocin (STZ) and diabetes type 2 was induced with a combination of STZ and high-fat diet. Control group for diabetes type 1 was fed with regular laboratory chow, while control group for diabetes type 2 received high-fat diet. Body weights and blood glucose levels were monitored to confirm induction of diabetes. Pain-related behavior was analyzed using thermal (hot, cold) and mechanical stimuli (von Frey fibers, number of hyperalgesic responses). Two months after induction of diabetes, glabrous skin samples from plantar surface of the both hind paws were collected. Epidermal thickness was evaluated with hematoxylin and eosin staining. Intraepidermal nerve fibers quantification was performed after staining skin with polyclonal antiserum against protein gene product 9.5. We found that induction of diabetes type 1 and type 2 causes significant epidermal thinning and loss of intraepidermal nerve fibers in a rat model, and both changes were more pronounced in diabetes type 1 model. Significant increase of pain-related behavior two months after induction of diabetes was observed only in a model of diabetes type 1. In conclusion, animal models of diabetes type 1 and diabetes type 2 could be used in pharmacological studies, where cutaneous changes could be used as outcome measures for predegenerative markers of neuropathies. Copyright © 2013 Elsevier B.V. All rights reserved.

Endomorphin-2 Inhibition of Substance P Signaling within Lamina I of the Spinal Cord Is Impaired in Diabetic Neuropathic Pain Rats

PubMed Central

Wan, Fa-Ping; Bai, Yang; Kou, Zhen-Zhen; Zhang, Ting; Li, Hui; Wang, Ya-Yun; Li, Yun-Qing

2017-01-01

Opiate analgesia in the spinal cord is impaired in diabetic neuropathic pain (DNP), but until now the reason is unknown. We hypothesized that it resulted from a decreased inhibition of substance P (SP) signaling within the dorsal horn of the spinal cord. To investigate this possibility, we evaluated the effects of endomorphin-2 (EM2), an endogenous ligand of the μ-opioid receptor (MOR), on SP release within lamina I of the spinal dorsal horn (SDH) in rats with DNP. We established the DNP rat model and compared the analgesic efficacy of EM2 between inflammation pain and DNP rat models. Behavioral results suggested that the analgesic efficacy of EM2 was compromised in the condition of painful diabetic neuropathy. Then, we measured presynaptic SP release induced by different stimulating modalities via neurokinin-1 receptor (NK1R) internalization. Although there was no significant change in basal and evoked SP release between control and DNP rats, EM2 failed to inhibit SP release by noxious mechanical and thermal stimuli in DNP but not in control and inflammation pain model. We also observed that EM2 decreased the number of FOS-positive neurons within lamina I of the SDH but did not change the amount of FOS/NK1R double-labeled neurons. Finally, we identified a remarkable decrease in MORs within the primary afferent fibers and dorsal root ganglion (DRG) neurons by Western blot (WB) and immunohistochemistry (IHC). Taken together, these data suggest that reduced presynaptic MOR expression might account for the loss of the inhibitory effect of EM2 on SP signaling, which might be one of the neurobiological foundations for decreased opioid efficacy in the treatment of DNP. PMID:28119567

Effects of XIST/miR-137 axis on neuropathic pain by targeting TNFAIP1 in a rat model.

PubMed

Zhao, Ying; Li, Sen; Xia, Nin; Shi, Yan; Zhao, Chang-Ming

2018-05-01

Non-coding RNAs have been reported to participate in the pathophysiology of neuropathic pain. The objective of our study was to investigate the biological role of XIST in neuropathic pain development. In our study, we identify and validate that lncRNA XIST was markedly increased and miR-137 was significantly decreased in chronic constriction injury (CCI) rats. XIST silencing alleviated pain behaviors including both mechanical and thermal hyperalgesia in the CCI rats. XIST was predicted to interact with miR-137 by bioinformatics technology and dual-luciferase reporter assays confirmed the correlation between XIST and miR-137. miR-137 was negatively modulated by XIST and upregulation of miR-137 greatly reduced neuropathic pain development in CCI rats. Moreover, we observed that tumor necrosis factor alpha-induced protein 1 (TNFAIP1) was enhanced in CCI rats and 3'-untranslated region (UTR) of TNFAIP1 was exhibited to be a target of miR-137 by bioinformatics prediction. TNFAIP1 can act as a crucial inflammation regulator by activating NF-kB activity. Overexpression of miR-137 significantly suppressed TNFAIP1 both in vitro and in vivo. Furthermore, upregulation of XIST reversed the inhibitory role of miR-137 in neuropathic pain development by inhibiting TNFAIP1. In conclusion, our current study indicates that XIST can positively regulate neuropathic pain in rats through regulating the expression of miR-137 and TNFAIP1. Our results imply that XIST/miR-137/TNFAIP1 axis may serve as a novel therapeutic target in neuropathic pain. © 2017 Wiley Periodicals, Inc.

Concurrent validity of different functional and neuroproteomic pain assessment methods in the rat osteoarthritis monosodium iodoacetate (MIA) model.

PubMed

Otis, Colombe; Gervais, Julie; Guillot, Martin; Gervais, Julie-Anne; Gauvin, Dominique; Péthel, Catherine; Authier, Simon; Dansereau, Marc-André; Sarret, Philippe; Martel-Pelletier, Johanne; Pelletier, Jean-Pierre; Beaudry, Francis; Troncy, Eric

2016-06-23

Lack of validity in osteoarthritis pain models and assessment methods is suspected. Our goal was to 1) assess the repeatability and reproducibility of measurement and the influence of environment, and acclimatization, to different pain assessment outcomes in normal rats, and 2) test the concurrent validity of the most reliable methods in relation to the expression of different spinal neuropeptides in a chemical model of osteoarthritic pain. Repeatability and inter-rater reliability of reflexive nociceptive mechanical thresholds, spontaneous static weight-bearing, treadmill, rotarod, and operant place escape/avoidance paradigm (PEAP) were assessed by the intraclass correlation coefficient (ICC). The most reliable acclimatization protocol was determined by comparing coefficients of variation. In a pilot comparative study, the sensitivity and responsiveness to treatment of the most reliable methods were tested in the monosodium iodoacetate (MIA) model over 21 days. Two MIA (2 mg) groups (including one lidocaine treatment group) and one sham group (0.9 % saline) received an intra-articular (50 μL) injection. No effect of environment (observer, inverted circadian cycle, or exercise) was observed; all tested methods except mechanical sensitivity (ICC <0.3), offered good repeatability (ICC ≥0.7). The most reliable acclimatization protocol included five assessments over two weeks. MIA-related osteoarthritic change in pain was demonstrated with static weight-bearing, punctate tactile allodynia evaluation, treadmill exercise and operant PEAP, the latter being the most responsive to analgesic intra-articular lidocaine. Substance P and calcitonin gene-related peptide were higher in MIA groups compared to naive (adjusted P (adj-P) = 0.016) or sham-treated (adj-P = 0.029) rats. Repeated post-MIA lidocaine injection resulted in 34 times lower downregulation for spinal substance P compared to MIA alone (adj-P = 0.029), with a concomitant increase of 17 % in time spent on the PEAP dark side (indicative of increased comfort). This study of normal rats and rats with pain established the most reliable and sensitive pain assessment methods and an optimized acclimatization protocol. Operant PEAP testing was more responsive to lidocaine analgesia than other tests used, while neuropeptide spinal concentration is an objective quantification method attractive to support and validate different centralized pain functional assessment methods.

MiR-19a targets suppressor of cytokine signaling 1 to modulate the progression of neuropathic pain

PubMed Central

Wang, Conghui; Jiang, Qi; Wang, Min; Li, Dong

2015-01-01

Purpose: we aimed to investigate whether miR-19a is associated with neuropathic pain and elucidate the underlying regulatory mechanism. Methods: We established a neuropathic pain model of bilateral chronic constriction injury (bCCI). Then bCCI rats were injected with mo-miR-19a, siR-SOCS1 or blank expression vector through a microinjection syringe via an intrathecal catheter on 3 day before surgery and after surgery. Behavioral tests, such as mechanical allodynia, thermal hyperalgesia and acetone induced cold allodynia, were performed to evaluate the pain threshold. Besides, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the expression of miR-19a and western blotting was carried out to measure the expression of SOCS1. Results: miR-19a expression levels were markedly increased in neuropathic pain models. Moreover, miR-19a significantly attenuated mechanical allodynia and thermal hyperalgesia, and similar results were obtained after knockdown of SOCS1 expression. However, miR-19a markedly increased the times that the rats appeared a sign of cold allodynia, and knockdown of SOCS1 expression had similar effects. Besides, the results of bioinformatics analysis and western blotting analysis were all confirmed that SOCS1 was a direct target of miR-19a in neuropathic pain models. Conclusions: Our finding indicate that SOCS1 is a direct target of miR-19a in neuropathic pain rats and miR-19a may play a critical role in regulating of neuropathic pain via targeting SOCS1. PMID:26617805

MiR-19a targets suppressor of cytokine signaling 1 to modulate the progression of neuropathic pain.

PubMed

Wang, Conghui; Jiang, Qi; Wang, Min; Li, Dong

2015-01-01

We aimed to investigate whether miR-19a is associated with neuropathic pain and elucidate the underlying regulatory mechanism. We established a neuropathic pain model of bilateral chronic constriction injury (bCCI). Then bCCI rats were injected with mo-miR-19a, siR-SOCS1 or blank expression vector through a microinjection syringe via an intrathecal catheter on 3 day before surgery and after surgery. Behavioral tests, such as mechanical allodynia, thermal hyperalgesia and acetone induced cold allodynia, were performed to evaluate the pain threshold. Besides, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the expression of miR-19a and western blotting was carried out to measure the expression of SOCS1. miR-19a expression levels were markedly increased in neuropathic pain models. Moreover, miR-19a significantly attenuated mechanical allodynia and thermal hyperalgesia, and similar results were obtained after knockdown of SOCS1 expression. However, miR-19a markedly increased the times that the rats appeared a sign of cold allodynia, and knockdown of SOCS1 expression had similar effects. Besides, the results of bioinformatics analysis and western blotting analysis were all confirmed that SOCS1 was a direct target of miR-19a in neuropathic pain models. Our finding indicate that SOCS1 is a direct target of miR-19a in neuropathic pain rats and miR-19a may play a critical role in regulating of neuropathic pain via targeting SOCS1.

Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents.

PubMed

Sarabia-Estrada, Rachel; Ruiz-Valls, Alejandro; Guerrero-Cazares, Hugo; Ampuero, Ana M; Jimenez-Estrada, Ismael; De Silva, Samantha; Bernhardt, Lydia J; Goodwin, Courtney Rory; Ahmed, Ali Karim; Li, Yuxin; Phillips, Neil A; Gokaslan, Ziya L; Quiñones-Hinojosa, Alfredo; Sciubba, Daniel M

2017-09-01

Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques. The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats. This is a basic science study. Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining. Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups. We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis. Copyright © 2017 Elsevier Inc. All rights reserved.

Antinociceptive effect of intrathecal microencapsulated human pheochromocytoma cell in a rat model of bone cancer pain.

PubMed

Li, Xiao; Li, Guoqi; Wu, Shaoling; Zhang, Baiyu; Wan, Qing; Yu, Ding; Zhou, Ruijun; Ma, Chao

2014-07-08

Human pheochromocytoma cells, which are demonstrated to contain and release met-enkephalin and norepinephrine, may be a promising resource for cell therapy in cancer-induced intractable pain. Intrathecal injection of alginate-poly (l) lysine-alginate (APA) microencapsulated human pheochromocytoma cells leads to antinociceptive effect in a rat model of bone cancer pain, and this effect was blocked by opioid antagonist naloxone and alpha 2-adrenergic antagonist rauwolscine. Neurochemical changes of cerebrospinal fluid are in accordance with the analgesic responses. Taken together, these data support that human pheochromocytoma cell implant-induced antinociception was mediated by met-enkephalin and norepinephrine secreted from the cell implants and acting at spinal receptors. Spinal implantation of microencapsulated human pheochromocytoma cells may provide an alternative approach for the therapy of chronic intractable pain.

Differential contributions of peripheral and central mechanisms to pain in a rodent model of osteoarthritis.

PubMed

Haywood, Adrian R; Hathway, Gareth J; Chapman, Victoria

2018-05-08

The mechanisms underlying the transition from acute nociceptive pain to centrally maintained chronic pain are not clear. We have studied the contributions of the peripheral and central nervous systems during the development of osteoarthritis (OA) pain. Male Sprague-Dawley rats received unilateral intra-articular injections of monosodium iodoacetate (MIA 1 mg) or saline, and weight-bearing (WB) asymmetry and distal allodynia measured. Subgroups of rats received intra-articular injections of, QX-314 (membrane impermeable local anaesthetic) + capsaicin, QX-314, capsaicin or vehicle on days 7, 14 or 28 post-MIA and WB and PWT remeasured. On days 7&14 post-MIA, but not day 28, QX-314 + capsaicin signficantly attenuated changes in WB induced by MIA, illustrating a crucial role for TRPV1 expressing nociceptors in early OA pain. The role of top-down control of spinal excitability was investigated. The mu-opioid receptor agonist DAMGO was microinjected into the rostroventral medulla, to activate endogenous pain modulatory systems, in MIA and control rats and reflex excitability measured using electromyography. DAMGO (3 ng) had a significantly larger inhibitory effect in MIA treated rats than in controls. These data show distinct temporal contribtuions of TRPV1 expressing nociceptors and opioidergic pain control systems at later timepoints.

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis

PubMed Central

Sagar, Devi Rani; Ashraf, Sadaf; Xu, Luting; Burston, James J; Menhinick, Matthew R; Poulter, Caroline L; Bennett, Andrew J; Walsh, David A; Chapman, Victoria

2014-01-01

Background Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA). Objectives To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain. Methods Male Sprague Dawley rats (140–260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1–15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group. Results Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage. Conclusions Our data suggest that early targeting of osteoclasts may reduce pain associated with OA. PMID:23723320

Development of neuropathic pain is affected by bedding texture in two models of peripheral nerve injury in rats.

PubMed

Robinson, Ian; Dowdall, Tom; Meert, Theo F

2004-09-16

It has long been known that there are numerous genetic and environmental factors that affect the in vivo research of neuropathic pain. In this letter, we describe the impact that bedding material can have on the development of neuropathic pain behaviors in rodents. In two models of neuropathic pain, the Chronic Constriction Injury (CCI) and the partial axotomy, we demonstrated that features of the sawdust on which the animals are housed during experimentation have a clear effect on the development of mechanical hyperalgesia and chemical hypersensitivity. Rats housed on coarse sawdust presented with a much-reduced response to a pinprick and acetone test compared to counterparts housed on fine sawdust. It is therefore concluded that the development of specific stimulus modalities of neuropathic pain behavior following peripheral nerve injury can be influenced in part by environmental factors, in this case bedding texture.

Intervertebral Foramen Injection of Ozone Relieves Mechanical Allodynia and Enhances Analgesic Effect of Gabapentin in Animal Model of Neuropathic Pain.

PubMed

Luo, Wen-Jun; Yang, Fan; Yang, Fei; Sun, Wei; Zheng, Wei; Wang, Xiao-Liang; Wu, Fang-Fang; Wang, Jiang-Lin; Wang, Jia-Shuang; Guan, Su-Min; Chen, Jun

2017-07-01

In a 5-year follow-up study in a hospital in southern China, it was shown that intervertebral foramen (IVF) injection of ozone at the involved segmental levels could significantly alleviate paroxysmal spontaneous pain and mechanical allodynia in patients with chronic, intractable postherpetic neuralgia (PHN) and improve the quality of life. However, so far no proof-of-concept studies in animals have been available. This study was designed to investigate whether IVF ozone has an analgesic effect on animal models of neuropathic and inflammatory pain. Experimental trial in rats. Institute for Biomedical Sciences of Pain. By IVF injection, a volume of 50 µl containing 30 µg/mL ozone-oxygen mixture or 50 µl air was carried out on male Sprague-Dawley rats of naïve, inflammatory pain states produced by injections of either bee venom or complete Freud's adjuvant, and neuropathic pain state produced by spared nerve injury, respectively. The effects of IVF ozone on pain-related behaviors were evaluated for 2 weeks or one month. Then combined use of gabapentin (100 mg/1 kg body weight) with IVF ozone was evaluated in rats with neuropathic pain by intraperitoneal administration 5 days after the ozone treatment. Finally, the analgesic effects of another 4 drugs, AMD3100 (a CXCR4 antagonist), A-803467 (a selective Nav1.8 blocker), rapamycin (the mTOR inhibitor), and MGCD0103 (a selective histone deacetylase inhibitor) were evaluated for long term through IVF injection, respectively. (1) IVF injection of ozone at L4-5 was only effective in suppression of mechanical allodynia in rats with neuropathic pain but not with inflammatory pain; (2) the analgesic effects of IVF ozone lasted much longer (> 14 days) than other selective molecular target drugs (< 48 hours) inhibiting or antagonizing at Nav1.8 (A-803467), CXCR4 (AMD3100), mTOR (rapamycin), and histone deacetylase (MGCD0103); (3) combined use of systemic gabapentin and IVF ozone produced a synergistic analgesic effect in rats with neuropathic pain. Evaluation of the possible analgesic effects of the intraplantar injection of ozone was not performed. In the present study, we provided a line of evidence for the first time that IVF injection of ozone selectively relieved neuropathic pain but not inflammatory pain, and enhanced the analgesic effect of gabapentin. Chronic pain, neuropathic pain, inflammatory pain, ozone therapy, interventional therapy, gabapentin, spared nerve injury, bee venom, complete Freud's adjuvant.

Gene Transfer of Glutamic Acid Decarboxylase 67 by Herpes Simplex Virus Vectors Suppresses Neuropathic Pain Induced by Human Immunodeficiency Virus gp120 Combined with ddC in Rats.

PubMed

Kanao, Megumi; Kanda, Hirotsugu; Huang, Wan; Liu, Shue; Yi, Hyun; Candiotti, Keith A; Lubarsky, David A; Levitt, Roy C; Hao, Shuanglin

2015-06-01

Human immunodeficiency virus (HIV)-related painful sensory neuropathies primarily consist of the HIV infection-related distal sensory polyneuropathy and antiretroviral toxic neuropathies. Pharmacotherapy provides only partial relief of pain in patients with HIV/acquired immune deficiency syndrome because little is known about the exact neuropathological mechanisms for HIV-associated neuropathic pain (NP). Hypofunction of γ-aminobutyric acid (GABA) GABAergic inhibitory mechanisms has been reported after peripheral nerve injury. In this study, we tested the hypothesis that HIV gp120 combined with antiretroviral therapy reduces spinal GABAergic inhibitory tone and that restoration of GABAergic inhibitory tone will reduce HIV-related NP in a rat model. The application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve plus systemic ddC (one antiretroviral drug) induced mechanical allodynia. The hind paws of rats were inoculated with replication-defective herpes simplex virus (HSV) vectors genetically encoding gad1 gene to express glutamic acid decarboxylase 67 (GAD67), an enzyme that catalyzes the decarboxylation of glutamate to GABA. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The expression of GAD67 in both the lumbar spinal cord and the L4-5 dorsal root ganglia was examined using western blots. The expression of mitochondrial superoxide in the spinal dorsal horn was examined using MitoSox imaging. The immunoreactivity of spinal GABA, pCREB, and pC/EBPβ was tested using immunohistochemistry. In the gp120 with ddC-induced neuropathic pain model, GAD67 expression mediated by the HSV vector caused an elevation of mechanical threshold that was apparent on day 3 after vector inoculation. The antiallodynic effect of the single HSV vector inoculation expressing GAD67 lasted >28 days. The area under the time-effect curves in the HSV vector expressing GAD67 was increased compared with that in the control vectors (P = 0.0005). Intrathecal GABA-A/B agonists elevated mechanical threshold in the pain model. The HSV vectors expressing GAD67 reversed the lowered GABA immunoreactivity in the spinal dorsal horn in the neuropathic rats. HSV vectors expressing GAD67 in the neuropathic rats reversed the increased signals of mitochondrial superoxide in the spinal dorsal horn. The vectors expressing GAD67 reversed the upregulated immunoreactivity expression of pCREB and pC/EBPβ in the spinal dorsal horn in rats exhibiting NP. Based on our results, we suggest that GAD67 mediated by HSV vectors acting through the suppression of mitochondrial reactive oxygen species and transcriptional factors in the spinal cord decreases pain in the HIV-related neuropathic pain model, providing preclinical evidence for gene therapy applications in patients with HIV-related pain states.

Face-to-face comparison of the predictive validity of two models of neuropathic pain in the rat: analgesic activity of pregabalin, tramadol and duloxetine.

PubMed

Le Cudennec, Camille; Castagné, Vincent

2014-07-15

We compared the preclinical analgesic activity of three marketed drugs with different pharmacological properties, pregabalin, tramadol and duloxetine, described as effective against neuropathic pain in the clinic. These drugs were tested against evoked pain in two different neuropathic models in the rat, the Bennett (CCI) and the Chung (SNL) models. The selected endpoints were tactile allodynia, tactile hyperalgesia, heat hyperalgesia and cold allodynia. Although all three drugs displayed analgesic activity, the effects observed varied according to the behavioral evaluation. Pregabalin showed clear analgesic effects against cold allodynia and tactile hyperalgesia in both the CCI and Chung models. Tramadol was active against all four endpoints in the Chung model with similar effects in the CCI model, apart from tactile allodynia. Duloxetine inhibited tactile allodynia and heat hyperalgesia in both neuropathic pain models. It also displayed efficacy against tactile hyperalgesia in the CCI model and against cold allodynia in the Chung model. These data confirm that the CCI and the Chung models of neuropathic pain do not detect the activity of analgesics with the same sensitivity. Furthermore, the mode of stimulation (tactile or thermal) and the type of endpoint (allodynia or hyperalgesia) can further influence the observed efficacy of gold standards as well as novel compounds developed for treating neuropathic pain symptoms. Copyright © 2014. Published by Elsevier B.V.

A Chinese Herbal Decoction, Shaoyao-Gancao Tang, Exerts Analgesic Effect by Down-Regulating the TRPV1 Channel in a Rat Model of Arthritic Pain.

PubMed

Sui, Feng; Zhou, Hai-Yu; Meng, Jing; Du, Xin-Liang; Sui, Yun-Peng; Zhou, Zhi-Kun; Dong, Cheng; Wang, Zhu-Ju; Wang, Wei-Hao; Dai, Li; Ma, Hai; Huo, Hai-Ru; Jiang, Ting-Liang

2016-01-01

Shaoyao-Gancao Tang (SGT) is one of the most frequently used compound formulas in the treatment of pain-related diseases in the medical practice of traditional Chinese medicine (TCM). To investigate the anti-inflammatory and antinociceptive effects, as well as to uncover the molecular mechanism of SGT, the rat pain model of arthritis was experimentally induced by single unilateral injection of rats' left hind paw with Freund's complete adjuvant (FCA). SGT was orally administered to the rats daily at three doses individually for a period of 16 days post-model induction. Swollen degrees and pain thresholds of the rats in different groups were measured for evaluation of the anti-inflammatory and anti-nociceptive effects of SGT. Furthermore, the mRNA and protein expression levels of transient receptor potential ion channel protein vanilloid receptor 1 (TRPV1) channel as well as its calcium-mediating function in the isolated DRG neurons were further detected to provide indexes for exploration of the molecular mechanisms mediating anti-arthritic activities of SGT. As a result, FCA injection induced significant allodynia, inflammation and edema, accompanied by a significant increase in both expression and calcium-mediating function of the TRPV1 channel. Pharmacologically, oral administration of SGT at a high or middle dose demonstrated a significant relief from the above-mentioned pathological conditions in a dose-dependent manner. Simultaneously the mRNA and protein expressional levels of TRPV1 channel, as well as its calcium-mediating function, were down-regulated greatly. These findings suggest that SGT possesses a significant analgesic and anti-inflammatory effect on arthritis rats; its therapeutic activities might be achieved through reversing the elevated expression and function of TRPV1 channel evoked by FCA.

Monosodium iodoacetate-induced joint pain is associated with increased phosphorylation of mitogen activated protein kinases in the rat spinal cord.

PubMed

Lee, Younglim; Pai, Madhavi; Brederson, Jill-Desiree; Wilcox, Denise; Hsieh, Gin; Jarvis, Michael F; Bitner, Robert S

2011-05-20

Intra-articular injection of monosodium iodoacetate (MIA) in the knee joint of rats disrupts chondrocyte metabolism resulting in cartilage degeneration and subsequent nociceptive behavior that has been described as a model of osteoarthritis (OA) pain. Central sensitization through activation of mitogen activated protein kinases (MAPKs) is recognized as a pathogenic mechanism in chronic pain. In the present studies, induction of central sensitization as indicated by spinal dorsal horn MAPK activation, specifically ERK and p38 phosphorylation, was assessed in the MIA-OA model. Behaviorally, MIA-injected rats displayed reduced hind limb grip force 1, 2, and 3 weeks post-MIA treatment. In the same animals, activation of phospho ERK1/2 was gradually increased, reaching a significant level at post injection week 3. Conversely, phosphorylation of p38 MAPK was enhanced maximally at post injection week 1 and decreased, but remained elevated, thereafter. Double labeling from 3-wk MIA rats demonstrated spinal pERK1/2 expression in neurons, but not glia. In contrast, p-p38 was expressed by microglia and a subpopulation of neurons, but not astrocytes. Additionally, there was increased ipsilateral expression of microglia, but not astrocytes, in 3-wk MIA-OA rats. Consistent with increased MAPK immunoreactivity in the contralateral dorsal horn, mechanical allodynia to the contralateral hind-limb was observed 3-wk following MIA. Finally, intrathecal injection of the MEK1 inhibitor PD98059 blocked both reduced hind-limb grip force and pERK1/2 induction in MIA-OA rats. Results of these studies support the role of MAPK activation in the progression and maintenance of central sensitization in the MIA-OA experimental pain model.

Chronic Constriction Injury of the Infraorbital Nerve in the Rat using modified syringe needle

PubMed Central

Kernisant, Melanie; Gear, Robert; Jasmin, Luc; Vit, Jean-Philippe; Ohara, Peter T.

2008-01-01

Here we report a method for performing a chronic constriction injury (CCI) of the infraorbital nerve (ION) in the rat as a component of a chronic pain model. The surgical approach to the ION is described together with the use of a modified dental syringe needle that simplifies placing two chromic gut ligatures around the ION. This method makes the surgical procedure easier, the nerve injury more consistent across animals and reduces secondary damage to the ION and surrounding tissue. Pain behavior testing together with immunostaining for markers of nerve injury in the spinal trigeminal nucleus show the suitability of this procedure as a model of orofacial pain. PMID:18501433

Establishment of a rat model of chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) induced by immunization with a novel peptide T2.

PubMed

Ihsan, Awais Ullah; Khan, Farhan Ullah; Nawaz, Waqas; Khan, Muhammad Zahid; Yang, Mengqi; Zhou, Xiaohui

2017-07-01

The exact etiological mechanism of Chronic Prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still unclear however autoimmunity is the most valid theory. We developed a rat model of Chronic Prostatitis/chronic pelvic pain syndrome by using a novel peptide (T2) isolated from TRPM8. This model might be beneficial in elucidating mechanisms involved in the pathogenesis of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS). 40 male Sprague-Dawley rats with an average weight of 180-220g were equally distributed into five groups. The normal control group was injected with normal saline (.9% NACL), the CFA group with CFA, AL(OH)3 group was given AL(OH)3 injection, T2 group using a novel peptide T2 and T2+AL(OH)3+CFA group was injected with T2+AL(OH)3+CFA. Dosing to all rat groups were injected subcutaneously. Hematoxylin and eosin staining and Immunohistochemistry were used to investigate inflammatory cell infiltration and IL-1β in the prostate tissue respectively. ELISA technique was used to measure the serum level of CRP and TNF-α. T-test was used to analyze the results. Maximum infiltration of inflammatory cells and the highest level of IL-1β in the prostate tissue was observed in T2+AL(OH)3+CFA group as revealed by histopathology and Immunohistochemistry, respectively. Furthermore, T2+AL(OH)3+CFA group attained the peak value of serum TNF-α and CRP as determined by ELISA technique. Our results demonstrated that T2 in combination with AL(OH)3 and CFA induced severe Prostatitis in rats. We believe that our present model will be highly beneficial for investigation of the pathophysiology of Chronic Prostatitis/Chronic Pelvic Pain Syndrome. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Behavioral and anatomical characterization of the bilateral sciatic nerve chronic constriction (bCCI) injury: correlation of anatomic changes and responses to cold stimuli

PubMed Central

2010-01-01

Background Unilateral constrictive sciatic nerve injury (uCCI) is a common neuropathic pain model. However, the bilateral constrictive injury (bCCI) model is less well studied, and shows unique characteristics. In the present study, we sought to correlate effects of bCCI on nocifensive responses to cold and mechanical stimuli with selected dorsal horn anatomic markers. bCCI or sham ligation of both rat sciatic nerves were followed up to 90 days of behavioural testing. Additional rats sacrificed at 15, 30 and 90 days were used for anatomic analyses. Behavioural tests included hindpaw withdrawal responses to topical acetone, cold plate testing, an operant thermal preference task and hindpaw withdrawal thresholds to mechanical probing. Results All nocifensive responses to cold increased and remained enhanced for >45 days. Mechanical withdrawal thresholds decreased for 25 days only. Densitometric analyses of immunoperoxidase staining in the superficial dorsal horn at L4-5 revealed decreased cholecystokinin (CCK) staining at all times after bCCI, decreased mu opiate receptor (MOR) staining, maximal at 15 days, increased neuropeptide Y (NPY) staining only at days 15 and 30, and increased neurokinin-1 receptor (NK-1R) staining at all time points, maximal at 15 days. Correlation analyses at 45 days post-bCCI, were significant for individual rat nocifensive responses in each cold test and CCK and NK-1R, but not for MOR or NPY. Conclusions These results confirm the usefulness of cold testing in bCCI rats, a new approach using CCI to model neuropathic pain, and suggest a potential value of studying the roles of dorsal horn CCK and substance P in chronic neuropathic pain. Compared to human subjects with neuropathic pain, responses to cold stimuli in rats with bCCI may be a useful model of neuropathic pain. PMID:20105332

Behavioral and anatomical characterization of the bilateral sciatic nerve chronic constriction (bCCI) injury: correlation of anatomic changes and responses to cold stimuli.

PubMed

Datta, Sukdeb; Chatterjee, Koel; Kline, Robert H; Wiley, Ronald G

2010-01-27

Unilateral constrictive sciatic nerve injury (uCCI) is a common neuropathic pain model. However, the bilateral constrictive injury (bCCI) model is less well studied, and shows unique characteristics. In the present study, we sought to correlate effects of bCCI on nocifensive responses to cold and mechanical stimuli with selected dorsal horn anatomic markers. bCCI or sham ligation of both rat sciatic nerves were followed up to 90 days of behavioural testing. Additional rats sacrificed at 15, 30 and 90 days were used for anatomic analyses. Behavioural tests included hindpaw withdrawal responses to topical acetone, cold plate testing, an operant thermal preference task and hindpaw withdrawal thresholds to mechanical probing. All nocifensive responses to cold increased and remained enhanced for >45 days. Mechanical withdrawal thresholds decreased for 25 days only. Densitometric analyses of immunoperoxidase staining in the superficial dorsal horn at L4-5 revealed decreased cholecystokinin (CCK) staining at all times after bCCI, decreased mu opiate receptor (MOR) staining, maximal at 15 days, increased neuropeptide Y (NPY) staining only at days 15 and 30, and increased neurokinin-1 receptor (NK-1R) staining at all time points, maximal at 15 days. Correlation analyses at 45 days post-bCCI, were significant for individual rat nocifensive responses in each cold test and CCK and NK-1R, but not for MOR or NPY. These results confirm the usefulness of cold testing in bCCI rats, a new approach using CCI to model neuropathic pain, and suggest a potential value of studying the roles of dorsal horn CCK and substance P in chronic neuropathic pain. Compared to human subjects with neuropathic pain, responses to cold stimuli in rats with bCCI may be a useful model of neuropathic pain.

[Prostatic inflammation-induced chronic pelvic pain: Roles of substance P and c-fos in the spinal cord].

PubMed

Liu, Ying-jia; Song, Guo-hong; Zhang, Chen

2015-08-01

To explore the possible pain mechanism of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The models of CP/CPPS were established in male Wistar rats by the autoimmune method. The paw withdrawal threshold (PWT) was detected using Von Frey filament. The expressions of the substance P and c-fos in the prostate and spinal L5-S2 segments were determined by immunohistochemistry followed by analysis of their correlation with CP/CPPS. Compared with the control rats, the CP/CPPS models showed significantly decreased PWT (P < 0.05), remarkable prostatic inflammation, enlarged scope of lesions, and obvious interstitial lymphocytic infiltration (P < 0.05). Both the expressions of substance P and c-fos were markedly elevated in the prostate and spinal dorsal horn (L5-S2) of the rat models (P < 0.05), but the expression of substance P in the prostate exhibited no correlation with that in the spinal cord (r = 0.099, P = 0.338), nor did that of c-fos (r = 0.027, P = 0.454). The upregulated expressions of substance P and c-fos in the spinal cord L5-S2 sections may be associated with the pain mechanism of CP/CPPS.

Depression of home cage wheel running is an objective measure of spontaneous morphine withdrawal in rats with and without persistent pain

PubMed Central

Kandasamy, Ram; Lee, Andrea T.; Morgan, Michael M.

2017-01-01

Opioid withdrawal in humans is often subtle and almost always spontaneous. In contrast, most preclinical studies precipitate withdrawal by administration of an opioid receptor antagonist such as naloxone. These animal studies rely on measurement of physiological symptoms (e.g., wet dog shakes) in the period immediately following naloxone administration. To more closely model the human condition, we tested the hypothesis that depression of home cage wheel running will provide an objective method to measure the magnitude and duration of spontaneous morphine withdrawal. Rats were allowed access to a running wheel in their home cage for 8 days prior to implantation of two 75 mg morphine or placebo pellets. The pellets were removed 3 or 5 days later to induce spontaneous withdrawal. In normal pain-free rats, removal of the morphine pellets depressed wheel running for 48 hours compared to rats that had placebo pellets removed. Morphine withdrawal-induced depression of wheel running was greatly enhanced in rats with persistent inflammatory pain induced by injection of Complete Freund’s Adjuvant (CFA) into the hindpaw. Removal of the morphine pellets following 3 days of treatment depressed wheel running in these rats for over 6 days. These data demonstrate that home cage wheel running provides an objective and more clinically relevant method to assess spontaneous morphine withdrawal compared to precipitated withdrawal in laboratory rats. Moreover, the enhanced withdrawal in rats with persistent inflammatory pain suggests that pain patients may be especially susceptible to opioid withdrawal. PMID:28366799

Activation of mesocorticolimbic reward circuits for assessment of relief of ongoing pain: a potential biomarker of efficacy.

PubMed

Xie, Jennifer Y; Qu, Chaoling; Patwardhan, Amol; Ossipov, Michael H; Navratilova, Edita; Becerra, Lino; Borsook, David; Porreca, Frank

2014-08-01

Preclinical assessment of pain has increasingly explored operant methods that may allow behavioral assessment of ongoing pain. In animals with incisional injury, peripheral nerve block produces conditioned place preference (CPP) and activates the mesolimbic dopaminergic reward pathway. We hypothesized that activation of this circuit could serve as a neurochemical output measure of relief of ongoing pain. Medications commonly used clinically, including gabapentin and nonsteroidal anti-inflammatory drugs (NSAIDs), were evaluated in models of post-surgical (1 day after incision) or neuropathic (14 days after spinal nerve ligation [SNL]) pain to determine whether the clinical efficacy profile of these drugs in these pain conditions was reflected by extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell. Microdialysis was performed in awake rats. Basal DA levels were not significantly different between experimental groups, and no significant treatment effects were seen in sham-operated animals. Consistent with clinical observation, spinal clonidine produced CPP and produced a dose-related increase in net NAc DA release in SNL rats. Gabapentin, commonly used to treat neuropathic pain, produced increased NAc DA in rats with SNL but not in animals with incisional, injury. In contrast, ketorolac or naproxen produced increased NAc DA in animals with incisional but not neuropathic pain. Increased extracellular NAc DA release was consistent with CPP and was observed selectively with treatments commonly used clinically for post-surgical or neuropathic pain. Evaluation of NAc DA efflux in animal pain models may represent an objective neurochemical assay that may serve as a biomarker of efficacy for novel pain-relieving mechanisms. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Differential Effectiveness of Clinically-Relevant Analgesics in a Rat Model of Chemotherapy-Induced Mucositis.

PubMed

Whittaker, Alexandra L; Lymn, Kerry A; Wallace, Georgia L; Howarth, Gordon S

2016-01-01

Chemotherapy-induced intestinal mucositis is characterized by pain and a pro-inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8). Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg) and NSAID (carprofen; 15mg/kg) in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg). Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001). Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy-induced mucositis.

The selective 5-hydroxytryptamine 1A antagonist, AZD7371 [3(R)-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate monohydrate] (robalzotan tartrate monohydrate), inhibits visceral pain-related visceromotor, but not autonomic cardiovascular, responses to colorectal distension in rats.

PubMed

Lindström, E; Ravnefjord, A; Brusberg, M; Hjorth, S; Larsson, H; Martinez, V

2009-06-01

5-Hydroxytryptamine 1A (5-HT(1A)) receptors have been suggested as a target for the treatment of irritable bowel syndrome (IBS). A recent clinical trial investigating the efficacy of the selective 5-HT(1A) antagonist AZD7371 [3(R)-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate monohydrate] showed no symptomatic improvement in IBS patients. We characterized the mechanisms mediating potential analgesic effects of AZD7371 in a model of colorectal distension (CRD)-induced visceral pain in rats to understand its mechanism of action and the lack of clinical efficacy. Visceromotor and cardiovascular responses (telemetry) were assessed in conscious rats during noxious CRD (80 mm Hg). Effects of AZD7371 (3-300 nmol/kg i.v.; 1-30 micromol/kg p.o.) and a reference 5-HT(1A) antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide maleate salt; 3-300 nmol/kg i.v.), were assessed. Effects of intracerebroventricular AZD7371 were also evaluated. Intravenous AZD7371 or WAY-100635 and oral AZD7371 dose-dependently inhibited visceromotor responses to CRD (ED(50), 203, 231, and 14 micromol/kg, respectively). In telemetrized rats, oral AZD7371 inhibited visceromotor responses to CRD without affecting the concomitant hypertensive and tachycardic responses. Intracerebroventricular AZD7371 did not affect visceromotor responses, whereas it inhibited micturition. None of the doses tested induced visible gross side effects. AZD7371, likely acting at a spinal site, inhibited the visceromotor but not the cardiovascular responses to visceral pain in the CRD model in rats. Although agents effective on multiple pain-related readouts in the CRD model (e.g., pregabalin or clonidine) alleviate IBS symptoms, AZD7371, which is effective on only one pain-related pseudoaffective readout, does not. Data from preclinical CRD models of visceral pain need to be interpreted cautiously as it relates to their clinical translational value.

Effect of the Combined Use of Tramadol and Milnacipran on Pain Threshold in an Animal Model of Fibromyalgia

PubMed Central

Song, Junhwa; Mun, Hyunil; Park, Keon Uk

2009-01-01

Background/Aims Acidic saline injections produce mechanical hyperresponsiveness in male Sprague-Dawley rats. We investigated the effect of milnacipran in conjunction with tramadol on the pain threshold in an acidic saline animal model of pain. Methods The left gastrocnemius muscle of 20 male rats was injected with 100 µL of saline at pH 4.0 under brief isoflurane anesthesia on days 0 and 5. Rats administered acidic saline injections were separated into four study subgroups. After determining the pre-drug pain threshold, rats were injected intraperitoneally with one of the following regimens; saline, milnacipran alone (60 mg/kg), milnacipran (40 mg/kg) plus tramadol (20 mg/kg), or milnacipran (40 mg/kg) plus tramadol (40 mg/kg). Paw withdrawal in response to pressure was measured at 30 min, 120 min, and 5 days after injection. Nociceptive thresholds, expressed in grams, were measured with a Dynamic Plantar Aesthesiometer (Ugo Basile, Italy) by applying increasing pressure to the right or left hind paw until the rat withdrew the paw. Results A potent antihyperalgesic effect was observed when tramadol and milnacipran were used in combination (injected paw, p=0.001; contralateral paw, p=0.012). This finding was observed only at 30 min after the combination treatment. Conclusions We observed potentiation of the antihyperalgesic effect when milnacipran and tramadol were administered in combination in an animal model of fibromyalgia. Further research is required to determine the efficacy of various combination treatments in fibromyalgia in humans. PMID:19543493

Depressive-like symptoms in a reserpine-induced model of fibromyalgia in rats.

PubMed

Blasco-Serra, Arantxa; Escrihuela-Vidal, Francesc; González-Soler, Eva M; Martínez-Expósito, Fernando; Blasco-Ausina, M Carmen; Martínez-Bellver, Sergio; Cervera-Ferri, Ana; Teruel-Martí, Vicent; Valverde-Navarro, Alfonso A

2015-11-01

Since the pathogenesis of fibromyalgia is unknown, treatment options are limited, ineffective and in fact based on symptom relief. A recently proposed rat model of fibromyalgia is based on central depletion of monamines caused by reserpine administration. This model showed widespread musculoskeletal pain and depressive-like symptoms, but the methodology used to measure such symptoms has been criticized. Evidence relates the high prevalence of pain and depression in fibromyalgia to common pathogenic pathways, most probably focused on the monoaminergic system. The present study aims at a validation of the reserpine model of fibromyalgia. For this purpose, rats undergoing this model have been tested for depressive-like symptoms with a Novelty-Suppressed Feeding Test adaptation. Animals administered with reserpine and subjected to forced food deprivation performed a smaller number of incursions to the center of the open field, evidenced by a decrease in the per-minute rate of the rats' approaching, smelling or touching the food. They also took more time to eat from the central food than control rats. These NSFT findings suggest the presence of depressive-like disorders in this animal model of fibromyalgia. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of oxidative stress induced by intracranial iron overload on central pain after spinal cord injury.

PubMed

Meng, Fan Xing; Hou, Jing Ming; Sun, Tian Sheng

2017-02-08

Central pain (CP) is a common clinical problem in patients with spinal cord injury (SCI). Recent studies found the pathogenesis of CP was related to the remodeling of the brain. We investigate the roles of iron overload and subsequent oxidative stress in the remodeling of the brain after SCI. We established a rat model of central pain after SCI. Rats were divided randomly into four groups: SCI, sham operation, SCI plus deferoxamine (DFX) intervention, and SCI plus nitric oxide synthase (NOS) inhibitor treatment. Pain behavior was observed and thermal pain threshold was measured regularly, and brain levels of iron, transferrin receptor 1 (TfR1), ferritin (Fn), and lactoferrin (Lf), were detected in the different groups 12 weeks after establishment of the model. Rats demonstrated self-biting behavior after SCI. Furthermore, the latent period of thermal pain was reduced and iron levels in the hind limb sensory area, hippocampus, and thalamus increased after SCI. Iron-regulatory protein (IRP) 1 levels increased in the hind limb sensory area, while Fn levels decreased. TfR1 mRNA levels were also increased and oxidative stress was activated. Oxidative stress could be inhibited by ferric iron chelators and NOS inhibitors. SCI may cause intracranial iron overload through the NOS-iron-responsive element/IRP pathway, resulting in central pain mediated by the oxidative stress response. Iron chelators and oxidative stress inhibitors can effectively relieve SCI-associated central pain.

Evaluation of heat hyperalgesia and anxiety like-behaviors in a rat model of orofacial cancer.

PubMed

Gambeta, Eder; Kopruszinski, Caroline Machado; Dos Reis, Renata Cristiane; Zanoveli, Janaina Menezes; Chichorro, Juliana Geremias

2016-04-21

Pain and anxiety are commonly experienced by cancer patients and both significantly impair their quality of life. Some authors claim that there is a relationship between pain and anxiety, while others suggest that there is not a direct association. In any case, there is indeed a consensus that anxiety impairs the pain condition beyond be under diagnosed and undertreated in cancer pain patients. Herein we investigated if rats presenting heat hyperalgesia induced by orofacial cancer cell inoculation would display anxiety-like behaviors. In addition, we evaluated if pain blockade would result in alleviation of anxiety behaviors, as well as, if blockade of anxiety would result in pain relief. Orofacial cancer was induced in male Wistar rats by inoculation of Walker-256 cells into the right vibrissal pad. Heat facial hyperalgesia was assessed on day 6 after the inoculation, and on this time point rats were submitted to the elevated plus maze and the light-dark transition tests. The influence of lidocaine and midazolam on heat hyperalgesia and anxiety-like behaviors was assessed. The peak of facial heat hyperalgesia was detected 6 days after cancer cells inoculation, and at this time point, rats exhibited increased anxiety-like behaviors. Local treatment with lidocaine (2%/50μL) caused a marked reduction of heat hyperalgesia, but failed to affect the anxiety-like behaviors, while midazolam (0.5mg/kg, i.p.) treatment failed to change the heat threshold, but induced an anxiolytic-like effect. Altogether, our data demonstrated that rats with orofacial cancer present pain- and anxiety-like behaviors, but brief heat hyperalgesia relief does not affect the anxiety-like behaviors, and vice-versa, in our experimental conditions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

PubMed Central

Kostich, Walter; Hamman, Brian D.; Li, Yu-Wen; Naidu, Sreenivasulu; Dandapani, Kumaran; Feng, Jianlin; Easton, Amy; Bourin, Clotilde; Baker, Kevin; Allen, Jason; Savelieva, Katerina; Louis, Justin V.; Dokania, Manoj; Elavazhagan, Saravanan; Vattikundala, Pradeep; Sharma, Vivek; Das, Manish Lal; Shankar, Ganesh; Kumar, Anoop; Holenarsipur, Vinay K.; Gulianello, Michael; Molski, Ted; Brown, Jeffrey M.; Lewis, Martin; Huang, Yanling; Lu, Yifeng; Pieschl, Rick; O’Malley, Kevin; Lippy, Jonathan; Nouraldeen, Amr; Lanthorn, Thomas H.; Ye, Guilan; Wilson, Alan; Balakrishnan, Anand; Denton, Rex; Grace, James E.; Lentz, Kimberley A.; Santone, Kenneth S.; Bi, Yingzhi; Main, Alan; Swaffield, Jon; Carson, Ken; Mandlekar, Sandhya; Vikramadithyan, Reeba K.; Nara, Susheel J.; Dzierba, Carolyn; Bronson, Joanne; Macor, John E.; Zaczek, Robert; Westphal, Ryan; Kiss, Laszlo; Bristow, Linda; Conway, Charles M.

2016-01-01

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans. PMID:27411717

Coenzyme Q10 ameliorates pain and cartilage degradation in a rat model of osteoarthritis by regulating nitric oxide and inflammatory cytokines.

PubMed

Lee, Jennifer; Hong, Yeon Sik; Jeong, Jeong Hee; Yang, Eun Ji; Jhun, Joo Yeon; Park, Mi Kyoung; Jung, Young Ok; Min, Jun Ki; Kim, Ho Youn; Park, Sung Hwan; Cho, Mi-La

2013-01-01

To investigate the effect of CoenzymeQ10 (CoQ10) on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA). OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration of CoQ10 was initiated on day 4 after MIA injection. Pain severity was assessed by measuring secondary tactile allodynia using the von Frey assessment test. The degree of cartilage degradation was determined by measuring cartilage thickness and the amount of proteoglycan. The mankin scoring system was also used. Expressions of matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), IL-6, IL-15, inducible nitric oxide synthase (iNOS), nitrotyrosine and receptor for advanced glycation end products (RAGE) were analyzed using immunohistochemistry. Treatment with CoQ10 demonstrated an antinociceptive effect in the OA animal model. The reduction in secondary tactile allodynia was shown by an increased pain withdrawal latency and pain withdrawal threshold. CoQ10 also attenuated cartilage degeneration in the osteoarthritic joints. MMP-13, IL-1β, IL-6, IL-15, iNOS, nitrotyrosine and RAGE expressions were upregulated in OA joints and significantly reduced with CoQ10 treatment. CoQ10 exerts a therapeutic effect on OA via pain suppression and cartilage degeneration by inhibiting inflammatory mediators, which play a vital role in OA pathogenesis.

Rat experimental model of myocardial ischemia/reperfusion injury: an ethical approach to set up the analgesic management of acute post-surgical pain.

PubMed

Ciuffreda, Maria Chiara; Tolva, Valerio; Casana, Renato; Gnecchi, Massimiliano; Vanoli, Emilio; Spazzolini, Carla; Roughan, John; Calvillo, Laura

2014-01-01

During the past 30 years, myocardial ischemia/reperfusion injury in rodents became one of the most commonly used model in cardiovascular research. Appropriate pain-prevention appears critical since it may influence the outcome and the results obtained with this model. However, there are no proper guidelines for pain management in rats undergoing thoracic surgery. Accordingly, we evaluated three analgesic regimens in cardiac ischemia/reperfusion injury. This study was strongly focused on 3R's ethic principles, in particular the principle of Reduction. Rats undergoing surgery were treated with pre-surgical tramadol (45 mg/kg intra-peritoneal), or carprofen (5 mg/kg sub-cutaneous), or with pre-surgical administration of carprofen followed by 2 post-surgery tramadol injections (multi-modal group). We assessed behavioral signs of pain and made a subjective evaluation of stress and suffering one and two hours after surgery. Multi-modal treatment significantly reduced the number of signs of pain compared to carprofen alone at both the first hour (61±42 vs 123±47; p<0.05) and the second hour (43±21 vs 74±24; p<0.05) post-surgery. Tramadol alone appeared as effective as multi-modal treatment during the first hour, but signs of pain significantly increased one hour later (from 66±72 to 151±86, p<0.05). Carprofen alone was more effective at the second hour post-surgery when signs of pain reduced to 74±24 from 113±40 in the first hour (p<0.05). Stress behaviors during the second hour were observed in only 20% of rats in the multimodal group compared to 75% and 86% in the carprofen and tramadol groups, respectively (p<0.05). Multi-modal treatment with carprofen and tramadol was more effective in preventing pain during the second hour after surgery compared with both tramadol or carprofen. Our results suggest that the combination of carprofen and tramadol represent the best therapy to prevent animal pain after myocardial ischemia/reperfusion. We obtained our results accordingly with the ethical principle of Reduction.

Rat Experimental Model of Myocardial Ischemia/Reperfusion Injury: An Ethical Approach to Set up the Analgesic Management of Acute Post-Surgical Pain

PubMed Central

Ciuffreda, Maria Chiara; Tolva, Valerio; Casana, Renato; Gnecchi, Massimiliano; Vanoli, Emilio; Spazzolini, Carla; Roughan, John; Calvillo, Laura

2014-01-01

Rationale During the past 30 years, myocardial ischemia/reperfusion injury in rodents became one of the most commonly used model in cardiovascular research. Appropriate pain-prevention appears critical since it may influence the outcome and the results obtained with this model. However, there are no proper guidelines for pain management in rats undergoing thoracic surgery. Accordingly, we evaluated three analgesic regimens in cardiac ischemia/reperfusion injury. This study was strongly focused on 3R’s ethic principles, in particular the principle of Reduction. Methods Rats undergoing surgery were treated with pre-surgical tramadol (45 mg/kg intra-peritoneal), or carprofen (5 mg/kg sub-cutaneous), or with pre-surgical administration of carprofen followed by 2 post-surgery tramadol injections (multi-modal group). We assessed behavioral signs of pain and made a subjective evaluation of stress and suffering one and two hours after surgery. Results Multi-modal treatment significantly reduced the number of signs of pain compared to carprofen alone at both the first hour (61±42 vs 123±47; p<0.05) and the second hour (43±21 vs 74±24; p<0.05) post-surgery. Tramadol alone appeared as effective as multi-modal treatment during the first hour, but signs of pain significantly increased one hour later (from 66±72 to 151±86, p<0.05). Carprofen alone was more effective at the second hour post-surgery when signs of pain reduced to 74±24 from 113±40 in the first hour (p<0.05). Stress behaviors during the second hour were observed in only 20% of rats in the multimodal group compared to 75% and 86% in the carprofen and tramadol groups, respectively (p<0.05). Conclusions Multi-modal treatment with carprofen and tramadol was more effective in preventing pain during the second hour after surgery compared with both tramadol or carprofen. Our results suggest that the combination of carprofen and tramadol represent the best therapy to prevent animal pain after myocardial ischemia/reperfusion. We obtained our results accordingly with the ethical principle of Reduction. PMID:24756074

Correlation between the cumulative analgesic effect of electroacupuncture intervention and synaptic plasticity of hypothalamic paraventricular nucleus neurons in rats with sciatica☆

PubMed Central

Xu, Qiuling; Liu, Tao; Chen, Shuping; Gao, Yonghui; Wang, Junying; Qiao, Lina; Liu, Junling

2013-01-01

In the present study, a rat model of chronic neuropathic pain was established by ligation of the sciatic nerve and a model of learning and memory impairment was established by ovariectomy to investigate the analgesic effect of repeated electroacupuncture stimulation at bilateral Zusanli (ST36) and Yanglingquan (GB34). In addition, associated synaptic changes in neurons in the paraventricular nucleus of the hypothalamus were examined. Results indicate that the thermal pain threshold (paw withdrawal latency) was significantly increased in rats subjected to 2-week electroacupuncture intervention compared with 2-day electroacupuncture, but the analgesic effect was weakened remarkably in ovariectomized rats with chronic constrictive injury. 2-week electroacupuncture intervention substantially reversed the chronic constrictive injury-induced increase in the synaptic cleft width and thinning of the postsynaptic density. These findings indicate that repeated electroacupuncture at bilateral Zusanli and Yanglingquan has a cumulative analgesic effect and can effectively relieve chronic neuropathic pain by remodeling the synaptic structure of the hypothalamic paraventricular nucleus. PMID:25206591

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain.

PubMed

Bannister, Kirsty; Qu, Chaoling; Navratilova, Edita; Oyarzo, Janice; Xie, Jennifer Yanhua; King, Tamara; Dickenson, Anthony H; Porreca, Frank

2017-12-01

Gabapentin (GBP) is a first-line therapy for neuropathic pain, but its mechanisms and sites of action remain uncertain. We investigated GBP-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal GBP reversed evoked mechanical hypersensitivity and produced conditioned place preference (CPP) and dopamine (DA) release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal GBP also significantly inhibited dorsal horn wide-dynamic-range neuronal responses to a range of evoked stimuli in SNL rats. By contrast, GBP microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP, and elicited NAc DA release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on wide-dynamic-range neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous GBP-induced CPP and NAc DA release but failed to block its inhibition of tactile allodynia. Gabapentin, therefore, can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity, and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from nonopioid analgesics, GBP requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain-motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of GBP's analgesic effects in patients.

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain

PubMed Central

Bannister, Kirsty; Qu, Chaoling; Navratilova, Edita; Oyarzo, Janice; Xie, Jennifer Yanhua; King, Tamara; Dickenson, Anthony H.; Porreca, Frank

2017-01-01

Gabapentin is a first-line therapy for neuropathic pain but its mechanisms and sites of action remain uncertain. We investigated gabapentin-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal gabapentin reversed evoked mechanical hypersensitivity, produced conditioned place preference (CPP) and dopamine release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal gabapentin also significantly inhibited dorsal horn wide dynamic range (WDR) neuronal responses to a range of evoked stimuli in SNL rats. In contrast, gabapentin microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP and elicited NAc dopamine release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on WDR neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous gabapentin-induced CPP and NAc dopamine release but failed to block its inhibition of tactile allodynia. Gabapentin therefore can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from non-opioid analgesics, gabapentin requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of gabapentin’s analgesic effects in patients. PMID:28832395

Sleep Deprivation and Recovery Sleep Prior to a Noxious Inflammatory Insult Influence Characteristics and Duration of Pain.

PubMed

Vanini, Giancarlo

2016-01-01

Insufficient sleep and chronic pain are public health epidemics. Sleep loss worsens pain and predicts the development of chronic pain. Whether previous, acute sleep loss and recovery sleep determine pain levels and duration remains poorly understood. This study tested whether acute sleep deprivation and recovery sleep prior to formalin injection alter post-injection pain levels and duration. Male Sprague-Dawley rats (n = 48) underwent sleep deprivation or ad libitum sleep for 9 hours. Thereafter, rats received a subcutaneous injection of formalin or saline into a hind paw. In the recovery sleep group, rats were allowed 24 h between sleep deprivation and the injection of formalin. Mechanical and thermal nociception were assessed using the von Frey test and Hargreaves' method. Nociceptive measures were performed at 1, 3, 7, 10, 14, 17 and 21 days post-injection. Formalin caused bilateral mechanical hypersensitivity (allodynia) that persisted for up to 21 days post-injection. Sleep deprivation significantly enhanced bilateral allodynia. There was a synergistic interaction when sleep deprivation preceded a formalin injection. Rats allowed a recovery sleep period prior to formalin injection developed allodynia only in the injected limb, with higher mechanical thresholds (less allodynia) and a shorter recovery period. There were no persistent changes in thermal nociception. The data suggest that acute sleep loss preceding an inflammatory insult enhances pain and can contribute to chronic pain. The results encourage studies in a model of surgical pain to test whether enhancing sleep reduces pain levels and duration. © 2016 Associated Professional Sleep Societies, LLC.

Evaluation of the novel avocado/soybean unsaponifiable Arthrocen to alter joint pain and inflammation in a rat model of osteoarthritis.

PubMed

Goudarzi, Ramin; Reid, Allison; McDougall, Jason J

2018-01-01

Avocado/soybean unsaponifiables such as Arthrocen have been reported to reduce cartilage catabolism and chondrocytic synthesis of inflammatory mediators associated with osteoarthritis (OA). While there is some clinical evidence that avocado/soybean unsaponifiables can reduce OA pain, no preclinical studies have corroborated this observation. The present study determined whether addition of an avocado/soybean unsaponifiable (Arthrocen) to the drinking water of OA rats reduced direct and referred joint pain. OA was induced in male Wistar rats by intra-articular injection of sodium monoiodoacetate (MIA: 0.3mg) and animals were allowed to recover for 14 days. Arthrocen was added to the drinking water which was available to animals ad libitum. On day 30, joint pain was assessed by dynamic incapacitance while referred pain was determined by von Frey hair algesiometry. The joint damage induced by MIA injection was severe and was consistent with end-stage OA. Arthrocen consumption (approximately 35 mg/day) attenuated the joint oedema associated with MIA injection. Hindlimb weight bearing also significantly improved in Arthrocen-treated rats (P<0.05); however, von Frey hair mechanosensitivity was unaffected by this treatment. These data indicate that Arthrocen has the potential to reduce joint inflammation and pain associated with end-stage OA.

Effects of electroacupuncture on orphanin FQ immunoreactivity and preproorphanin FQ mRNA in nucleus of raphe magnus in the neuropathic pain rats.

PubMed

Ma, Fei; Xie, Hong; Dong, Zhi-Qiang; Wang, Yan-Qing; Wu, Gen-Cheng

2004-07-15

Orphanin FQ (OFQ) is an endogenous ligand for opioid receptor-like-1 (ORL1) receptor. Previous studies have shown that both OFQ immunoreactivity and preproorphanin FQ (ppOFQ) mRNA expression could be observed in the brain regions involved in pain modulation, e.g., nucleus of raphe magnus (NRM), dorsal raphe nucleus (DRN), and ventrolateral periaqueductal gray (vlPAG). It was reported that electroacupuncture (EA) has analgesic effect on neuropathic pain, and the analgesic effect was mediated by the endogenous opioid peptides. In the present study, we investigated the effects of EA on the changes of OFQ in the neuropathic pain rats. In the sciatic nerve chronic constriction injury (CCI) model, we investigated the changes of ppOFQ mRNA and OFQ immunoreactivity in NRM after EA by in situ hybridization (ISH) and immunohistochemistry methods, respectively. Then, the ppOFQ mRNA-positive and OFQ immunoreactive cells were counted under a computerized image analysis system. The results showed that expression of ppOFQ mRNA decreased and OFQ immunoreactivity increased after EA treatment in the neuropathic pain rats. These results indicated that EA modulated OFQ synthesis and OFQ peptide level in NRM of the neuropathic pain rats. Copyright 2004 Elsevier Inc.

Sensitization of TRPV1 receptors by TNF-α orchestrates the development of vincristine-induced pain.

PubMed

Wang, Ying; Feng, Chenyang; He, Haoying; He, Jinjin; Wang, Jun; Li, Xiaomin; Wang, Shasha; Li, Wei; Hou, Jiuzhou; Liu, Tong; Fang, Dong; Xie, Song-Qiang

2018-04-01

Vincristine is one of the most common anticancer drugs clinically employed in the treatment of various malignancies. A major side effect associated with vincristine is the development of neuropathic pain, which is not readily relieved by available analgesics. Although efforts have been made to identify the pathogenesis of vincristine-induced neuropathic pain, the mechanisms underlying its pathogenesis have not been fully elucidated. In the present study, a neuropathic pain model was established in Sprague-Dawley rats by intraperitoneal injection of vincristine sulfate. The results demonstrated that vincristine administration induced the upregulation of transient receptor potential cation channel subfamily V member 1 (TRPV1) protein expression and current density in dorsal root ganglion (DRG) nociceptive neurons. Consistently, inhibition of TRPV1 with capsazepine alleviated vincristine-induced mechanical allodynia and thermal hyperalgesia in rats. Furthermore, vincristine administration induced the upregulation of tumor necrosis factor (TNF)-α production in DRGs, and inhibition of TNF-α synthesis with thalidomide in vivo reversed TRPV1 protein expression, as well as pain hypersensitivity induced by vincristine in rats. The present results suggested that TNF-α could sensitize TRPV1 by promoting its expression, thus leading to mechanical allodynia and thermal hyperalgesia in vincristine-treated rats. Taken together, these findings may enhance our understanding of the pathophysiological mechanisms underlying vincristine-induced pain.

Evaluation of the novel avocado/soybean unsaponifiable Arthrocen to alter joint pain and inflammation in a rat model of osteoarthritis

PubMed Central

Goudarzi, Ramin; Reid, Allison

2018-01-01

Background Avocado/soybean unsaponifiables such as Arthrocen have been reported to reduce cartilage catabolism and chondrocytic synthesis of inflammatory mediators associated with osteoarthritis (OA). While there is some clinical evidence that avocado/soybean unsaponifiables can reduce OA pain, no preclinical studies have corroborated this observation. The present study determined whether addition of an avocado/soybean unsaponifiable (Arthrocen) to the drinking water of OA rats reduced direct and referred joint pain. Methods OA was induced in male Wistar rats by intra-articular injection of sodium monoiodoacetate (MIA: 0.3mg) and animals were allowed to recover for 14 days. Arthrocen was added to the drinking water which was available to animals ad libitum. On day 30, joint pain was assessed by dynamic incapacitance while referred pain was determined by von Frey hair algesiometry. Results The joint damage induced by MIA injection was severe and was consistent with end-stage OA. Arthrocen consumption (approximately 35 mg/day) attenuated the joint oedema associated with MIA injection. Hindlimb weight bearing also significantly improved in Arthrocen-treated rats (P<0.05); however, von Frey hair mechanosensitivity was unaffected by this treatment. Conclusions These data indicate that Arthrocen has the potential to reduce joint inflammation and pain associated with end-stage OA. PMID:29489828

Magnesium sulfate reduces formalin-induced orofacial pain in rats with normal magnesium serum levels.

PubMed

Srebro, Dragana P; Vučković, Sonja M; Dožić, Ivan S; Dožić, Branko S; Savić Vujović, Katarina R; Milovanović, Aleksandar P; Karadžić, Branislav V; Prostran, Milica Š

2018-02-01

In humans, orofacial pain has a high prevalence and is often difficult to treat. Magnesium is an essential element in biological a system which controls the activity of many ion channels, neurotransmitters and enzymes. Magnesium produces an antinociceptive effect in neuropathic pain, while in inflammatory pain results are not consistent. We examined the effects of magnesium sulfate using the rat orofacial formalin test, a model of trigeminal pain. Male Wistar rats were injected with 1.5% formalin into the perinasal area, and the total time spent in pain-related behavior (face rubbing) was quantified. We also spectrophotometrically determined the concentration of magnesium and creatine kinase activity in blood serum. Magnesium sulfate administered subcutaneously (0.005-45mg/kg) produced significant antinociception in the second phase of the orofacial formalin test in rats at physiological serum concentration of magnesium. The effect was not dose-dependent. The maximum antinociceptive effect of magnesium sulfate was about 50% and was achieved at doses of 15 and 45mg/kg. Magnesium did not affect increase the levels of serum creatine kinase activity. Preemptive systemic administration of magnesium sulfate as the only drug can be used to prevent inflammatory pain in the orofacial region. Its analgesic effect is not associated with magnesium deficiency. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Ketamine differentially restores diverse alterations of neuroligins in brain regions in a rat model of neuropathic pain-induced depression.

PubMed

Pan, Wei; Zhang, Guang-Fen; Li, Hui-Hui; Ji, Mu-Huo; Zhou, Zhi-Qiang; Li, Kuan-Yu; Yang, Jian-Jun

2018-07-04

Depression is present in a large proportion of patients suffering from chronic pain, and yet the underlying mechanisms remain to be elucidated. Neuroligins (NLs), as a family of cell-adhesion proteins, are involved in synaptic formation and have been linked to various neuropsychiatric disorders. Here, we studied the alterations in NL1 and NL2 in the medial prefrontal cortex (mPFC), the anterior cingulate cortex (ACC), and the hippocampus in a rat model of neuropathic pain-induced depression, and whether ketamine, a rapid and robust antidepressant, could restore these abnormalities. In the present study, we found that spared nerve injury induced significant mechanical allodynia and subsequent depressive-like symptoms, along with decreased NL1 and increased NL2 in the mPFC, decreased NL1 in the ACC, and decreased NL2 in the hippocampus. In addition, brain-derived neurotrophic factor (BDNF) was reduced in these brain regions. It is noteworthy that ketamine (10 mg/kg) relieved neuropathic pain-induced depressive behaviors and restored alterations of BDNF and NLs in the mPFC and the hippocampus at 24 h and 72 h after the administration of ketamine, but only restored BDNF in the ACC. In conclusion, NLs showed diverse changes in different brain regions in the rat model of neuropathic pain-induced depression, which could be reversed differentially by the administration of ketamine.

Behavioral, cellular and molecular maladaptations covary with exposure to pyridostigmine bromide in a rat model of gulf war illness pain.

PubMed

Cooper, B Y; Flunker, L D; Johnson, R D; Nutter, T J

2018-08-01

Many veterans of Operation Desert Storm (ODS) struggle with the chronic pain of Gulf War Illness (GWI). Exposure to insecticides and pyridostigmine bromide (PB) have been implicated in the etiology of this multisymptom disease. We examined the influence of 3 (DEET (N,N-diethyl-meta-toluamide), permethrin, chlorpyrifos) or 4 GW agents (DEET, permethrin, chlorpyrifos, pyridostigmine bromide (PB)) on the post-exposure ambulatory and resting behaviors of rats. In three independent studies, rats that were exposed to all 4 agents consistently developed both immediate and delayed ambulatory deficits that persisted at least 16 weeks after exposures had ceased. Rats exposed to a 3 agent protocol (PB excluded) did not develop any ambulatory deficits. Cellular and molecular studies on nociceptors harvested from 16WP (weeks post-exposure) rats indicated that vascular nociceptor Na v 1.9 mediated currents were chronically potentiated following the 4 agent protocol but not following the 3 agent protocol. Muscarinic linkages to muscle nociceptor TRPA1 were also potentiated in the 4 agent but not the 3 agent, PB excluded, protocol. Although K v 7 activity changes diverged from the behavioral data, a K v 7 opener, retigabine, transiently reversed ambulation deficits. We concluded that PB played a critical role in the development of pain-like signs in a GWI rat model and that shifts in Na v 1.9 and TRPA1 activity were critical to the expression of these pain behaviors. Copyright © 2018 Elsevier Inc. All rights reserved.

Sex differences in stress-induced visceral hypersensitivity following early life adversity: a two hit model.

PubMed

Prusator, D K; Greenwood-Van Meerveld, B

2016-12-01

Early life adversity (ELA) has been indicated as a risk factor for the development of stress axis dysfunction in adulthood, specifically in females. We previously showed that unpredictable ELA induces visceral hyperalgesia in adult female rats. It remains to be determined whether ELA alters visceral nociceptive responses to stress in adulthood. The current study tested the hypothesis that following ELA, exposure to an adulthood stressor, or second hit, serves as a risk factor for exaggerated stress-induced visceral hypersensitivity that is sex-specific. Following ELA, adult stress was induced via a single exposure (acute) or repetitive daily exposure, 1 h/day for 7 days (chronic), to water avoidance stress (WAS). Acute WAS increased pain behaviors in all adult female rats, however, females that experienced unpredictable ELA exhibited significantly more pain behaviors compared to those exposed to predictable ELA or controls. Following chronic WAS, all adult females exhibited increased pain responses, however, an exaggerated response was observed in rats exposed to unpredictable or predictable ELA compared to controls. Similarly, in adult male rats exposure to acute or chronic WAS increased pain behaviors, however, there were no differences in pain behaviors between ELA groups. This study highlights a novel consequence of ELA on stress-induced visceral nociception in adulthood that is sex-specific. More importantly, our study suggests that ELA not only serves as a risk factor for development of chronic pain in adulthood, but also serves as a predisposition for worsening of visceral pain following adult stress in female rats. © 2016 John Wiley & Sons Ltd.

Postoperative Analgesia Due to Sustained-Release Buprenorphine, Sustained-Release Meloxicam, and Carprofen Gel in a Model of Incisional Pain in Rats (Rattus norvegicus)

PubMed Central

Seymour, Travis L; Adams, Sean C; Felt, Stephen A; Jampachaisri, Katechan; Yeomans, David C; Pacharinsak, Cholawat

2016-01-01

Postoperative analgesia in laboratory rats is complicated by the frequent handling associated with common analgesic dosing requirements. Here, we evaluated sustained-release buprenorphine (Bup-SR), sustained-release meloxicam (Melox-SR), and carprofen gel (CG) as refinements for postoperative analgesia. The aim of this study was to investigate whether postoperative administration of Bup-SR, Melox-SR, or CG effectively controls behavioral mechanical and thermal hypersensitivity in a rat model of incisional pain. Rats were randomly assigned to 1 of 5 treatment groups: saline, 1 mL/kg SC BID; buprenorphine HCl (Bup HCl), 0.05 mg/kg SC BID; Bup-SR, 1.2 mg/kg SC once; Melox-SR, 4 mg/kg SC once; and CG, 2 oz PO daily. Mechanical and thermal hypersensitivity were tested daily from day–1 through 4. Bup HCl and Bup-SR attenuated mechanical and thermal hypersensitivity on days 1 through 4. Melox-SR and CG attenuated mechanical hypersensitivity–but not thermal hypersensitivity–on days 1 through 4. Plasma concentrations, measured by using UPLC with mass spectrometry, were consistent between both buprenorphine formulations. Gross pathologic examination revealed no signs of toxicity in any group. These findings suggest that postoperative administration of Bup HCl and Bup-SR—but not Melox-SR or CG—effectively attenuates mechanical and thermal hypersensitivity in a rat model of incisional pain. PMID:27177563

Postoperative Analgesia Due to Sustained-Release Buprenorphine, Sustained-Release Meloxicam, and Carprofen Gel in a Model of Incisional Pain in Rats (Rattus norvegicus).

PubMed

Seymour, Travis L; Adams, Sean C; Felt, Stephen A; Jampachaisri, Katechan; Yeomans, David C; Pacharinsak, Cholawat

2016-01-01

Postoperative analgesia in laboratory rats is complicated by the frequent handling associated with common analgesic dosing requirements. Here, we evaluated sustained-release buprenorphine (Bup-SR), sustained-release meloxicam (Melox-SR), and carprofen gel (CG) as refinements for postoperative analgesia. The aim of this study was to investigate whether postoperative administration of Bup-SR, Melox-SR, or CG effectively controls behavioral mechanical and thermal hypersensitivity in a rat model of incisional pain. Rats were randomly assigned to 1 of 5 treatment groups: saline, 1 mL/kg SC BID; buprenorphine HCl (Bup HCl), 0.05 mg/kg SC BID; Bup-SR, 1.2 mg/kg SC once; Melox-SR, 4 mg/kg SC once; and CG, 2 oz PO daily. Mechanical and thermal hypersensitivity were tested daily from day-1 through 4. Bup HCl and Bup-SR attenuated mechanical and thermal hypersensitivity on days 1 through 4. Melox-SR and CG attenuated mechanical hypersensitivity-but not thermal hypersensitivity-on days 1 through 4. Plasma concentrations, measured by using UPLC with mass spectrometry, were consistent between both buprenorphine formulations. Gross pathologic examination revealed no signs of toxicity in any group. These findings suggest that postoperative administration of Bup HCl and Bup-SR-but not Melox-SR or CG-effectively attenuates mechanical and thermal hypersensitivity in a rat model of incisional pain.

Proteomic identification of altered cerebral proteins in the complex regional pain syndrome animal model.

PubMed

Nahm, Francis Sahngun; Park, Zee-Yong; Nahm, Sang-Soep; Kim, Yong Chul; Lee, Pyung Bok

2014-01-01

Complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder. Although the exact pathophysiology of CRPS is not fully understood, central and peripheral mechanisms might be involved in the development of this disorder. To reveal the central mechanism of CRPS, we conducted a proteomic analysis of rat cerebrum using the chronic postischemia pain (CPIP) model, a novel experimental model of CRPS. After generating the CPIP animal model, we performed a proteomic analysis of the rat cerebrum using a multidimensional protein identification technology, and screened the proteins differentially expressed between the CPIP and control groups. Results. A total of 155 proteins were differentially expressed between the CPIP and control groups: 125 increased and 30 decreased; expressions of proteins related to cell signaling, synaptic plasticity, regulation of cell proliferation, and cytoskeletal formation were increased in the CPIP group. However, proenkephalin A, cereblon, and neuroserpin were decreased in CPIP group. Altered expression of cerebral proteins in the CPIP model indicates cerebral involvement in the pathogenesis of CRPS. Further study is required to elucidate the roles of these proteins in the development and maintenance of CRPS.

Pathological activity in mediodorsal thalamus of rats with spinal cord injury pain.

PubMed

Whitt, Jessica L; Masri, Radi; Pulimood, Nisha S; Keller, Asaf

2013-02-27

Spinal cord injury (SCI) results not only in motor deficits, but produces, in many patients, excruciating chronic pain (SCI pain). We have previously shown, in a rodent model, that SCI causes suppression of activity in the GABAergic nucleus, the zona incerta (ZI), and concomitant increased activity in one of its main targets, the posterior nucleus of the thalamus (PO); the increased PO activity is correlated with the maintenance and expression of hyperalgesia after SCI. Here, we test the hypothesis that SCI causes a similar pathological increase in other thalamic nuclei regulated by the ZI, specifically the mediodorsal thalamus (MD), which is involved in the emotional-affective aspects of pain. We recorded single and multiunit activity from MD of either anesthetized or awake rats, and compared data from rats with SCI with data from sham-operated controls (anesthetized experiments) or with data from the same animals prelesion (awake experiments). Consistent with our hypothesis, MD neurons from rats with SCI show significant increases in spontaneous firing rates and in the magnitude and duration of responses to noxious stimuli. In a subset of anesthetized animals, similar changes in activity of MD neurons were produced by pharmacologically inactivating ZI in naive rats, suggesting that the changes in the MD after SCI are related to suppressed inhibition from the ZI. These data support our hypothesis that SCI pain results, at least in part, from a loss of inhibition to thalamic nuclei associated with both the sensory-discriminative and emotional-affective components of pain.

Sleep Deprivation and Recovery Sleep Prior to a Noxious Inflammatory Insult Influence Characteristics and Duration of Pain

PubMed Central

Vanini, Giancarlo

2016-01-01

Study Objectives: Insufficient sleep and chronic pain are public health epidemics. Sleep loss worsens pain and predicts the development of chronic pain. Whether previous, acute sleep loss and recovery sleep determine pain levels and duration remains poorly understood. This study tested whether acute sleep deprivation and recovery sleep prior to formalin injection alter post-injection pain levels and duration. Methods: Male Sprague-Dawley rats (n = 48) underwent sleep deprivation or ad libitum sleep for 9 hours. Thereafter, rats received a subcutaneous injection of formalin or saline into a hind paw. In the recovery sleep group, rats were allowed 24 h between sleep deprivation and the injection of formalin. Mechanical and thermal nociception were assessed using the von Frey test and Hargreaves' method. Nociceptive measures were performed at 1, 3, 7, 10, 14, 17 and 21 days post-injection. Results: Formalin caused bilateral mechanical hypersensitivity (allodynia) that persisted for up to 21 days post-injection. Sleep deprivation significantly enhanced bilateral allodynia. There was a synergistic interaction when sleep deprivation preceded a formalin injection. Rats allowed a recovery sleep period prior to formalin injection developed allodynia only in the injected limb, with higher mechanical thresholds (less allodynia) and a shorter recovery period. There were no persistent changes in thermal nociception. Conclusion: The data suggest that acute sleep loss preceding an inflammatory insult enhances pain and can contribute to chronic pain. The results encourage studies in a model of surgical pain to test whether enhancing sleep reduces pain levels and duration. Citation: Vanini G. Sleep deprivation and recovery sleep prior to a noxious inflammatory insult influence characteristics and duration of pain. SLEEP 2016;39(1):133–142. PMID:26237772

Evaluation of analgesic and anti-inflammatory activity of a combination of tramadol-ibuprofen in experimental animals.

PubMed

Suthakaran, Chidambarann; Kayalvizhi, Muniyagounder K; Nithya, Karnam; Raja, Thozhudalangudy Ar

2017-01-01

Pain is the major concern of patients attending dental clinics, and satisfactory pain relief has always been difficult to achieve. Since the pathophysiology of pain is a complex, central and peripheral nervous system process, combined analgesic regimens with different mechanisms of action as a multimodal approach are becoming popular among the clinicians and dentists. The aim of the present study was to evaluate the analgesic and anti-inflammatory activity of ibuprofen and tramadol when used alone or in combination in animal models of pain and inflammation. The animals were divided into six groups with six animals in each group. Analgesic activity was assessed by hot plate method in rats and by acetic acid-induced writhing test in mice. Paw edema model in rats after induction with 0.1 mL of 1% carrageenan was used to assess the anti-inflammatory activity. Analysis of variance followed by Tukey's honestly significant difference post hoc test was used for statistical analysis. Combined use of tramadol and ibuprofen provided enhanced analgesic and anti-inflammatory effects in animal models of pain and inflammation.

WenTong HuoXue Cream Can Inhibit the Reduction of the Pain-Related Molecule PLC-β3 in the Dorsal Root Ganglion of a Rat Model of Diabetic Peripheral Neuropathy

PubMed Central

Feng, Chengcheng; Xu, Lijuan; Guo, Shiyun; Chen, Qian; Shen, Yuguo; Zang, Deng

2018-01-01

WenTong HuoXue Cream (WTHX-Cream) has been shown to effectively alleviate clinical symptoms of diabetic peripheral neuropathy (DPN). This study investigated the gene and protein expression of the pain-related molecule PLC-β3 in the dorsal root ganglion (DRG) of DPN rats. 88 specific pathogen-free male Wistar rats were randomly divided into placebo (10 rats) and DPN model (78 rats) groups, and the 78 model rats were used to establish the DPN model by intraperitoneal injection of streptozotocin and were then fed a high-fat diet for 8 weeks. These rats were randomly divided into the model group, the high-, medium-, and low-dose WTHX-Cream + metformin groups, the metformin group, the capsaicin cream group, and the capsaicin cream + metformin group. After 4 weeks of continuous drug administration, the blood glucose, body weight, behavioral indexes, and sciatic nerve conduction velocity were measured. The pathological structure of the DRG and the sciatic nerve were observed. PLC-β3 mRNA and protein levels in the DRG of rats were measured. Compared with the model group, the high-dose WTHX-Cream group showed increased sciatic nerve conduction velocity, improved sciatic nerve morphological changes, and increased expression of PLC-β3 mRNA and protein in the DRG. This study showed that WTHX-Cream improves hyperalgesia symptoms of DPN by inhibiting the reduction of PLC-β3 mRNA and protein expression in the diabetic DRG of DPN rats. PMID:29599806

WenTong HuoXue Cream Can Inhibit the Reduction of the Pain-Related Molecule PLC-β3 in the Dorsal Root Ganglion of a Rat Model of Diabetic Peripheral Neuropathy.

PubMed

Feng, Chengcheng; Xu, Lijuan; Guo, Shiyun; Chen, Qian; Shen, Yuguo; Zang, Deng; Ma, Li

2018-01-01

WenTong HuoXue Cream (WTHX-Cream) has been shown to effectively alleviate clinical symptoms of diabetic peripheral neuropathy (DPN). This study investigated the gene and protein expression of the pain-related molecule PLC- β 3 in the dorsal root ganglion (DRG) of DPN rats. 88 specific pathogen-free male Wistar rats were randomly divided into placebo (10 rats) and DPN model (78 rats) groups, and the 78 model rats were used to establish the DPN model by intraperitoneal injection of streptozotocin and were then fed a high-fat diet for 8 weeks. These rats were randomly divided into the model group, the high-, medium-, and low-dose WTHX-Cream + metformin groups, the metformin group, the capsaicin cream group, and the capsaicin cream + metformin group. After 4 weeks of continuous drug administration, the blood glucose, body weight, behavioral indexes, and sciatic nerve conduction velocity were measured. The pathological structure of the DRG and the sciatic nerve were observed. PLC- β 3 mRNA and protein levels in the DRG of rats were measured. Compared with the model group, the high-dose WTHX-Cream group showed increased sciatic nerve conduction velocity, improved sciatic nerve morphological changes, and increased expression of PLC- β 3 mRNA and protein in the DRG. This study showed that WTHX-Cream improves hyperalgesia symptoms of DPN by inhibiting the reduction of PLC- β 3 mRNA and protein expression in the diabetic DRG of DPN rats.

The Effect of Gabapentin and Tramadol in Cancer Pain Induced by Glioma Cell in Rat Femur.

PubMed

Corona-Ramos, Janette Nallely; Déciga-Campos, Myrna; Romero-Piña, Mario; Medina, Luis A; Martínez-Racine, Issac; Jaramillo-Morales, Osmar A; García-López, Patricia; López-Muñoz, Francisco Javier

2017-08-01

Preclinical Research The presence of pain as part of the cancer process is variable. Glioblastoma multiform (GBM) can produce bone metastasis, a condition that involves other pathological phenotypes including neuropathic and inflammatory pain. Tramadol and gabapentin are drugs used in the treatment of neuropathic pain. However, there are no studies evaluating their analgesic effects in bone metastasis. We produced a pain model induced by the inoculation of glioma cells (10 5 ) into the rat femur, by perforating the intercodiloid fossa. Painful behavior was evaluated by measuring mechanical allodynia using the Von Frey test while thermal hyperalgesia was assessed in the plantar test. Histopathological features were evaluated and antinociceptive responses were compared using tramadol and gabapentin. The inoculation of cells inside the right femur produced nociceptive behaviors. Tramadol and gabapentin produced an anti-allodynic effect in this condition, but tramadol did not produce an anti-hyperalgesic response. The development of this model will allow us to perform tests to elucidate the pathology of bone metastasis, cancer pain, and in particular the pain produced by glioma. Drug Dev Res 78 : 173-183, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Advances in cancer pain from bone metastasis.

PubMed

Zhu, Xiao-Cui; Zhang, Jia-Li; Ge, Chen-Tao; Yu, Yuan-Yang; Wang, Pan; Yuan, Ti-Fei; Fu, Cai-Yun

2015-01-01

With the technological advances in cancer diagnosis and treatment, the survival rates for patients with cancer are prolonged. The issue of figuring out how to improve the life quality of patients with cancer has become increasingly prominent. Pain, especially bone pain, is the most common symptom in malignancy patients, which seriously affects the life quality of patients with cancer. The research of cancer pain has a breakthrough due to the development of the animal models of cancer pain in recent years, such as the animal models of mouse femur, humerus, calcaneus, and rat tibia. The establishment of several kinds of animal models related to cancer pain provides a new platform in vivo to investigate the molecular mechanisms of cancer pain. In this review, we focus on the advances of cancer pain from bone metastasis, the mechanisms involved in cancer pain, and the drug treatment of cancer pain in the animal models.

Investigation of the effect of traditional Chinese medicine on pain and inflammation in chronic nonbacterial prostatitis in rats.

PubMed

Liu, Y-J; Song, G-H; Liu, G T

2016-08-01

According to traditional Chinese medicine, the symptoms of chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CNP/CPPS) may be treated using a cocktail of herbs that stimulate blood circulation ('activating blood circulation formula'). We investigated the effect of three doses of this formula on a rat model of CNP/CPPS. Male Wistar rats were injected with a saline extract of male sex accessory glands on days 0 and 30 to induce prostatitis and then treated daily by gavage between days 32 and 60. Treatment with low, medium and high doses of activating blood circulation formula resulted in an almost total rescue of paw withdrawal threshold at day 60, and treatment with the highest dose also significantly decreased prostate inflammation (assessed histopathologically). We further observed elevated serum prostaglandin E2 levels in the CNP/CPPS model which decreased upon high-dose treatment, and increased Cox-2 expression in the prostate and spinal cord dorsal horn which was rescued in both tissues in the high-dose group and in the prostate in the medium-dose group. These results shed light on a possible mechanism by which activating blood circulation therapy may alleviate pain in a rat model of CNP/CPPS by downregulating Cox-2 expression in the spinal cord, thereby raising the pain threshold. Further research will be needed to fully characterise the mechanism by which activating blood circulation therapy produces this therapeutic effect. © 2016 Blackwell Verlag GmbH.

Effect of A-317491 delivered by glycolipid-like polymer micelles on endometriosis pain.

PubMed

Yuan, Ming; Ding, Shaojie; Meng, Tingting; Lu, Binbin; Shao, Shihong; Zhang, Xinmei; Yuan, Hong; Hu, Fuqiang

2017-01-01

Endometriosis is a common gynecological disease with a lack of effective clinical treatment. Current therapy often results in endometriosis pain recurrence and serious side effects. P2X 3 receptor, an adenosine triphosphate (ATP)-gated ion channel, might be implicated in endometriosis pain. In this study, chitosan oligosaccharide-g-stearic acid (CSOSA) polymer micelles-coated nanostructured lipid carriers (NLCs) were developed as a novel delivery system for A-317491, a selective P2X 3 receptor antagonist for endometriosis pain therapy. A-317491-loaded NLC (NLC/A-317491) could be coated by CSOSA micelles to form CSOSA/NLC/A-317491 nanoparticles. Pheochromocytoma PC12 cells, which highly expressed P2X 3 receptors, were used as a cell model, and the CSOSA/NLC/A-317491 partly blocked the Ca 2+ influx induced by ATP stimulation. In nude mouse and rat endometriotic models, CSOSA/NLC could accumulate into endometriotic lesions after vein injection. In endometriotic rats, CSOSA/NLC/A-317491 reversed mechanical and heat hyperalgesia with long-term efficacy, which might be attributed to the massive CSOSA/NLC/A-317491 distribution in the endometriotic lesions. In conclusion, A-317491 delivered by CSOSA/NLC nanoparticles attenuated endometriosis pain in rats, and CSOSA/NLC/A-317491 could be used as an effective treatment strategy for P2X 3 -targeted therapy in endometriosis pain.

Nociceptive neuronal Fc-gamma receptor I is involved in IgG immune complex induced pain in the rat.

PubMed

Jiang, Haowu; Shen, Xinhua; Chen, Zhiyong; Liu, Fan; Wang, Tao; Xie, Yikuan; Ma, Chao

2017-05-01

Antigen-specific immune diseases such as rheumatoid arthritis are often accompanied by pain and hyperalgesia. Our previous studies have demonstrated that Fc-gamma-receptor type I (FcγRI) is expressed in a subpopulation of rat dorsal root ganglion (DRG) neurons and can be directly activated by IgG immune complex (IgG-IC). In this study we investigated whether neuronal FcγRI contributes to antigen-specific pain in the naïve and rheumatoid arthritis model rats. In vitro calcium imaging and whole-cell patch clamp recordings in dissociated DRG neurons revealed that only the small-, but not medium- or large-sized DRG neurons responded to IgG-IC. Accordingly, in vivo electrophysiological recordings showed that intradermal injection of IgG-IC into the peripheral receptive field could sensitize only the C- (but not A-) type sensory neurons and evoke action potential discharges. Pain-related behavioral tests showed that intradermal injection of IgG-IC dose-dependently produced mechanical and thermal hyperalgesia in the hindpaw of rats. These behavioral effects could be alleviated by localized administration of non-specific IgG or an FcγRI antibody, but not by mast cell stabilizer or histamine antagonist. In a rat model of antigen-induced arthritis (AIA) produced by methylated bovine serum albumin, FcγRI were found upregulated exclusively in the small-sized DRG neurons. In vitro calcium imaging revealed that significantly more small-sized DRG neurons responded to IgG-IC in the AIA rats, although there was no significant difference between the AIA and control rats in the magnitude of calcium changes in the DRG neurons. Moreover, in vivo electrophysiological recordings showed that C-nociceptive neurons in the AIA rats exhibited a greater incidence of action potential discharges and stronger responses to mechanical stimuli after IgG-IC was injected to the receptive fields. These results suggest that FcγRI expressed in the peripheral nociceptors might be directly activated by IgG-IC and contribute to antigen-specific pain in pathological conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

Antinociceptive and pronociceptive effect of levetiracetam in tonic pain model.

PubMed

Cortes-Altamirano, José Luis; Reyes-Long, Samuel; Olmos-Hernández, Adriana; Bonilla-Jaime, Herlinda; Carrillo-Mora, Paul; Bandala, Cindy; Alfaro-Rodriguez, Alfonso

2018-04-01

Levetiracetam (LEV) is a novel anticonvulsant with proven antinociceptive properties. However, the antinociceptive and pronociceptive effect of this drug has not yet been fully elucidated in a tonic pain model. Thirty-six male rats (Wistar) were randomized into six groups and underwent the formalin test as follows: rats in the control group were administered 50μL of 1% formalin in the paw; sham-group rats were administered 50μL of saline in the paw to mimick the application of formalin; the four experimental groups were administered LEV intragastrically (ig) (50, 100, 200 and 300mg/kg), and 40min later 50μL of 1% formalin was injected in the paw. LEV exhibited antinociceptive effect in the 300mg/kg LEV group (p<0.05) and a pronociceptive effect in the 100mg/kg LEV group (p<0.05) and in the 50mg/kg LEV group (p<0.001). The antinociceptive and pronociceptive effect of LEV in a tonic pain model is dose-dependent. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – neurokinin-1 antagonist peptidomimetics

PubMed Central

Guillemyn, Karel; Kleczkowska, Patrycia; Lesniak, Anna; Dyniewicz, Jolanta; Van der Poorten, Olivier; Van den Eynde, Isabelle; Keresztes, Attila; Varga, Eva; Lai, Josephine; Porreca, Frank; Chung, Nga N.; Lemieux, Carole; Mika, Joanna; Rojewska, Ewelina; Makuch, Wioletta; Van Duppen, Joost; Przewlocka, Barbara; Broeck, Jozef Vanden; Lipkowski, Andrzej W.; Schiller, Peter W.; Tourwé, Dirk; Ballet, Steven

2014-01-01

A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3’,5’-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioral assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat. PMID:25544687

Towards Development of a Dermal Pain Model: In Vitro Activation of Rat and Human Transient Receptor Potential Ankyrin Repeat 1 and Safe Dermal Injection of o-Chlorobenzylidene Malononitrile to Rat.

PubMed

Annas, Anita; Berg, Anna-Lena; Nyman, Eva; Meijer, Thomas; Lundgren, Viveka; Franzén, Bo; Ståhle, Lars

2015-12-01

During clinical development of analgesics, it is important to have access to pharmacologically specific human pain models. o-Chlorobenzylidene malononitrile (CS) is a selective and potent agonist of the transient receptor potential ankyrin repeat 1 (TRPA1), which is a transducer molecule in nociceptors sensing reactive chemical species. While CS has been subject to extensive toxicological investigations in animals and human beings, its effects on intradermal or subcutaneous injection have not previously been reported. We have investigated the potential of CS to be used as an agonist on TRPA1 in human experimental pain studies. A calcium influx assay was used to confirm the capacity of CS to activate TRPA1 with >100,000 times the selectivity over the transient receptor potential vanilloid receptor 1. CS dose-dependently (EC50 0.9 μM) released calcitonin gene-related peptide in rat dorsal root ganglion cultures, supporting involvement in pain signalling. In a local tolerance study, injection of a single intradermal dose of 20 mM CS to rats resulted in superficial, circular crusts at the injection sites after approximately 4 days. The histopathology evaluation revealed a mild, acute inflammatory reaction in the epidermis and dermis at the intradermal CS injection site 1 day after administration. After 14 days, the epidermal epithelium was fully restored. The symptoms were not considered to be adverse, and it is suggested that doses up to 20 μL of 20 mM CS can be safely administered to human beings. In conclusion, our data support development of a CS human dermal pain model. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Photobiomodulation therapy by NIR laser in persistent pain: an analytical study in the rat.

PubMed

Micheli, Laura; Di Cesare Mannelli, Lorenzo; Lucarini, Elena; Cialdai, Francesca; Vignali, Leonardo; Ghelardini, Carla; Monici, Monica

2017-11-01

Over the past three decades, physicians have used laser sources for the management of different pain conditions obtaining controversial results that call for further investigations. In order to evaluate the pain relieving possibilities of photobiomodulation therapy (PBMT), we tested two near infrared (NIR) laser systems, with different power, against various kinds of persistent hyperalgesia animal models. In rats, articular pain was reproduced by the intra-articular injection of sodium monoiodoacetate (MIA) and complete Freund's adjuvant (CFA), while compressive neuropathy was modelled by the chronic constriction injury of the sciatic nerve (CCI). In MIA and CFA models, (NIR) laser (MLS-Mphi, ASA S.r.l., Vicenza, Italy) application was started 14 days after injury and was performed once a day for a total of 13 applications. In MIA-treated animals, the anti-hyperalgesic effect of laser began 5 min after treatment and vanished after 60 min. The subsequent applications evoked similar effects. In CFA-treated rats, laser efficacy started 5 min after treatment and disappeared after 180 min. In rats that underwent CCI, two treatment protocols with similar fluence but different power output were tested using a new experimental device called Multiwave Locked System laser (MLS-HPP). Treatments began 7 days after injury and were performed during 3 weeks for a total of 10 applications. Both protocols reduced mechanical hyperalgesia and hindlimb weight bearing alterations until 60 min after treatment with a higher efficacy recorded for the animals treated using the higher power output. In conclusion, this study supports laser therapy as a potential treatment for immediate relief of chronic articular or neuropathic pain.

Central and peripheral anti-hyperalgesic effects of diosmin in a neuropathic pain model in rats.

PubMed

Carballo-Villalobos, Azucena Ibeth; González-Trujano, María Eva; Pellicer, Francisco; Alvarado-Vásquez, Noé; López-Muñoz, Francisco Javier

2018-01-01

Flavonoids are natural compounds showing anti-hyperalgesic activity in models of pain. Diosmin is a compound poorly studied in the treatment of neuropathic pain. This study evaluates the anti-hyperalgesic actions of diosmin and possible mechanisms of action involved by using a neuropathic pain model in rats. Experimental neuropathic pain was induced by chronic constriction injury (CCI) in male Wistar rats, then aesthesiometric index and plantar tests were assessed to evaluate mechanical and thermal hyperalgesia, respectively, in order to explore the analgesic effects of acute and sub-chronic treatment with diosmin. The GABA A , 5-HT 1A , D 2 -like and opioid receptors participation, as well as levels of TNF-α, IL-1β and IL-6, were evaluated in the spinal cord and sciatic nerve tissues after acute and subchronic diosmin administration. In addition, the presence of diosmin on cerebral samples was determined by UHPLC-MS analysis. Acute and sub-chronic treatment with diosmin significantly diminished the mechanical and thermal hyperalgesia induced by CCI in rats. This anti-hyperalgesic effects of diosmin were modified in the presence of naloxone (1mg/kg, i.p.) and haloperidol (0.1mg/kg, i.p.), but not by GABA A and 5-HT 1A receptor antagonists. The anti-hyperalgesic effects of diosmin were also linked with reduced levels of TNF-α, IL-1β and IL-6. The presence of diosmin in the cerebral samples was confirmed by chromatographic analysis. In conclusion, our results provide evidence that diosmin produces significant anti-hyperalgesic effects acting at central level by an opioid and D 2 dopaminergic receptors participation, and at peripheral level by reducing proinflammatory cytokines. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

AMPAkines have novel analgesic properties in rat models of persistent neuropathic and inflammatory pain.

PubMed

Le, Alexander M; Lee, Michelle; Su, Chen; Zou, Anthony; Wang, Jing

2014-11-01

Novel analgesics that do not suppress the respiratory drive are urgently needed. Glutamate signaling through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors plays important roles in central pain circuits. AMPAkines augment AMPA receptor function and have been shown to stimulate the respiratory drive to oppose opioid-induced hypoventilation. However, their role in chronic pain states remains unknown. The authors studied AMPAkines (CX546 and CX516) in rat spared nerve injury (SNI) model of neuropathic pain and Complete Freund's Adjuvant (CFA) model of inflammatory pain. They measured the effect of AMPAkines on mechanical and cold allodynia. They also evaluated their effect on depressive symptoms of pain using the forced swim test, as time of immobility on this test has been used as a measure for behavioral despair, a feature of depression. The authors found that CX546, compared with dimethyl sulfoxide (DMSO) control, reduced both mechanical and sensory allodynia in SNI (DMSO group, n = 9; CX546 group, n = 11) and CFA models (both DMSO and CX546 groups, n = 9). They found that CX546, compared with control, also reduced depressive symptoms of pain by decreasing immobility on the forced swim test in both SNI (both DMSO and CX546 groups, n = 8) and CFA models (both DMSO and CX546 groups, n = 10). Finally, they found that CX516, compared with control, also reduced mechanical and cold allodynia in the SNI model (both DMSO and CX516 groups, n = 10). AMPAkines alleviate pain hypersensitivity as well as depression-like behavior associated with long-lasting nerve injury and inflammatory insult.

Anti-allodynic effect of NW-1029, a novel Na(+) channel blocker, in experimental animal models of inflammatory and neuropathic pain.

PubMed

Veneroni, O; Maj, R; Calabresi, M; Faravelli, L; Fariello, R G; Salvati, P

2003-03-01

NW-1029, a benzylamino propanamide derivative, was selected among several molecules of this chemical class on the basis of its affinity for the [(3)H]batracotoxin ligand displacement of the Na(+) channel complex and also on the basis of its voltage and use-dependent inhibitory action on the Na(+) currents of the rat DRG (dorsal root ganglia) sensory neuron. This study evaluated the analgesic activity of NW-1029 in animal models of inflammatory and neuropathic pain (formalin test in mice, complete Freund's adjuvant and chronic constriction injury in rats) as well as in acute pain test (hot-plate and tail-flick in rats). Orally administered NW-1029 dose-dependently reduced cumulative licking time in the early and late phase of the formalin test (ED(50)=10.1 mg/kg in the late phase). In the CFA model, NW-1029 reversed mechanical allodynia (von Frey test) after both i.p. and p.o. administration (ED(50)=0.57 and 0.53 mg/kg), respectively. Similarly, NW-1029 reversed mechanical allodynia in the CCI model after both i.p. and p.o. administration yielding an ED(50) of 0.89 and 0.67 mg/kg, respectively. No effects were observed in the hot-plate and tail-flick tests up to 30 mg/kg p.o. The compound orally administered (0.1-10 mg/kg) was well tolerated, without signs of neurological impairment up to high doses (ED(50)=470 and 245 mg/kg in rat and mice Rotarod test, respectively). These results indicate that NW-1029 has anti-nociceptive properties in models of inflammatory and neuropathic pain.

miR-155 modulates the progression of neuropathic pain through targeting SGK3

PubMed Central

Liu, Shaoxing; Zhu, Bo; Sun, Yan; Xie, Xianfeng

2015-01-01

This study aimed to illustrate the potential effects of miR-155 in neuropathic pain and its potential mechanism. Spragure-Dawley (SD) rats were used for neuropathic pain model of bilateral chronic constriction injury (bCCI) construction. Effects of miR-155 expression on pain threshold of mechanical stimuli (MWT), paw withdrawal threshold latency (PMTL) and cold threshold were analyzed. Target for miR-155 was analyzed using bioinformatics methods. Moreover, effects of miR-155 target gene expression on pain thresholds were also assessed. Compared with the controls and sham group, miR-155 was overexpressed in neuropathic pain rats (P<0.05), but miR-155 slicing could significantly decreased the pain thresholds (P<0.05). Serum and glucocorticoid regulated protein kinase 3 (SGK3) was predicted as the target gene for miR-155, and miR-155 expression was negatively correlated to SGK3 expression. Furthermore, SGK3 overexpression could significantly decreased the pain thresholds which was the same as miR-155 (P<0.05). Moreover, miR-155 slicing and SGK3 overexpression could significantly decrease the painthreshold. The data presented in this study suggested that miR-155 slicing could excellently alleviate neuropathic pain in rats through targeting SGK3 expression. miR-155 may be a potential therapeutic target for neuropathic pain treatment. PMID:26823753

MiR-155 modulates the progression of neuropathic pain through targeting SGK3.

PubMed

Liu, Shaoxing; Zhu, Bo; Sun, Yan; Xie, Xianfeng

2015-01-01

This study aimed to illustrate the potential effects of miR-155 in neuropathic pain and its potential mechanism. Spragure-Dawley (SD) rats were used for neuropathic pain model of bilateral chronic constriction injury (bCCI) construction. Effects of miR-155 expression on pain threshold of mechanical stimuli (MWT), paw withdrawal threshold latency (PMTL) and cold threshold were analyzed. Target for miR-155 was analyzed using bioinformatics methods. Moreover, effects of miR-155 target gene expression on pain thresholds were also assessed. Compared with the controls and sham group, miR-155 was overexpressed in neuropathic pain rats (P<0.05), but miR-155 slicing could significantly decreased the pain thresholds (P<0.05). Serum and glucocorticoid regulated protein kinase 3 (SGK3) was predicted as the target gene for miR-155, and miR-155 expression was negatively correlated to SGK3 expression. Furthermore, SGK3 overexpression could significantly decreased the pain thresholds which was the same as miR-155 (P<0.05). Moreover, miR-155 slicing and SGK3 overexpression could significantly decrease the painthreshold. The data presented in this study suggested that miR-155 slicing could excellently alleviate neuropathic pain in rats through targeting SGK3 expression. miR-155 may be a potential therapeutic target for neuropathic pain treatment.

Increased thermal pain sensitivity in animals exposed to chronic high dose Vicodin but not pure hydrocodone.

PubMed

O'Connell, Thomas F; Carpenter, Patrick S; Caballero, Nadia; Putnam, Andrew J; Steere, Joshua T; Matz, Gregory J; Foecking, Eileen M

2014-01-01

Vicodin, the combination drug of acetaminophen and the opioid hydrocodone, is one of the most prescribed drugs on the market today. Opioids have demonstrated the ability to paradoxically cause increased pain sensitivity to users in a phenomena called opioid-induced hyperalgesia (OIH). While selected opioids have been shown to produce OIH symptoms in an animal model, hydrocodone and the combination drug Vicodin have yet to be studied. The purpose of this study was to explore the effect of exposure to chronic high dose Vicodin or its components on the sensitivity to both thermal and mechanical pain. Animals were randomly divided into 4 groups, Vicodin, acetaminophen, hydrocodone, or vehicle control, and administered the drug daily for 120 days. Rats were subsequently tested for thermal and mechanical sensitivity. The rats in the Vicodin group displayed a significant decrease in withdrawal time to thermal pain. The rats receiving acetaminophen, hydrocodone, and vehicle showed no statistically significant hypersensitivity in thermal testing. None of the groups demonstrated statistically significant hypersensitivity to mechanical testing. The data suggests Vicodin produces signs of OIH in a rodent model. However, increased pain sensitivity was only noted in the thermal pathway and the hypersensitivity was only seen with the opioid combination drug, not the opioid alone. The results of this study both support the results of previous rodent opioid studies while generating further questions about the specific properties of Vicodin that contribute to pain hypersensitivity. The growing use of Vicodin to treat chronic pain necessitates further research looking into this paradoxical pain response.

Expression profiling of genes modulated by minocycline in a rat model of neuropathic pain

PubMed Central

2014-01-01

Background The molecular mechanisms underlying neuropathic pain are constantly being studied to create new opportunities to prevent or alleviate neuropathic pain. The aim of our study was to determine the gene expression changes induced by sciatic nerve chronic constriction injury (CCI) that are modulated by minocycline, which can effectively diminish neuropathic pain in animal studies. The genes associated with minocycline efficacy in neuropathic pain should provide insight into the etiology of neuropathic pain and identify novel therapeutic targets. Results We screened the ipsilateral dorsal part of the lumbar spinal cord of the rat CCI model for differentially expressed genes. Out of 22,500 studied transcripts, the abundance levels of 93 transcripts were altered following sciatic nerve ligation. Percentage analysis revealed that 54 transcripts were not affected by the repeated administration of minocycline (30 mg/kg, i.p.), but the levels of 39 transcripts were modulated following minocycline treatment. We then selected two gene expression patterns, B1 and B2. The first transcription pattern, B1, consisted of 10 mRNA transcripts that increased in abundance after injury, and minocycline treatment reversed or inhibited the effect of the injury; the B2 transcription pattern consisted of 7 mRNA transcripts whose abundance decreased following sciatic nerve ligation, and minocycline treatment reversed the effect of the injury. Based on the literature, we selected seven genes for further analysis: Cd40, Clec7a, Apobec3b, Slc7a7, and Fam22f from pattern B1 and Rwdd3 and Gimap5 from pattern B2. Additionally, these genes were analyzed using quantitative PCR to determine the transcriptional changes strongly related to the development of neuropathic pain; the ipsilateral DRGs (L4-L6) were also collected and analyzed in these rats using qPCR. Conclusion In this work, we confirmed gene expression alterations previously identified by microarray analysis in the spinal cord and analyzed the expression of selected genes in the DRG. Moreover, we reviewed the literature to illustrate the relevance of these findings for neuropathic pain development and therapy. Further studies are needed to elucidate the roles of the individual genes in neuropathic pain and to determine the therapeutic role of minocycline in the rat neuropathic pain model. PMID:25038616

Morus alba L. Stem Extract Attenuates Pain and Articular Cartilage Damage in the Anterior Cruciate Ligament Transection-Induced Rat Model of Osteoarthritis.

PubMed

Khunakornvichaya, Arada; Lekmeechai, Sujinna; Pham, Phi Phuong; Himakoun, Wanwisa; Pitaksuteepong, Tasana; Morales, Noppawan Phumala; Hemstapat, Warinkarn

2016-01-01

This study was designed to investigate the anti-nociceptive effect of Morus alba stem extract as well as its cartilage protective effect in the anterior cruciate ligament transection (ACLT)-induced rat model of osteoarthritis (OA). The anti-nociceptive effect of this plant extract was determined by measuring hind limb weight bearing, while the severity of cartilage damage to the knee joints was evaluated using the modified Mankin grading system. Oral administration of M. alba stem extract (56 and 560 mg/kg) significantly attenuated joint pain as indicated by a significant (p < 0.05) increase in the values of percent weight borne on the operated hind limb for the OA-induced groups that received M. alba stem extract at 56 and 560 mg/kg when compared to those of the vehicle-treated OA-induced group. In addition, a significant improvement in the Mankin score was also observed in rats treated with 560 mg/kg M. alba stem extract, which was in agreement with its pain-relieving effect. The results showed that M. alba stem extract exhibited an anti-nociceptive effect as well as cartilage protection in the ACLT-induced rat model of OA, supporting its potential use as a therapeutic treatment for OA. © 2016 S. Karger AG, Basel.

Evaluation of a novel biodegradable thermosensitive keto-hydrogel for improving postoperative pain in a rat model.

PubMed

Wu, Meng-Huang; Shih, Ming-Hung; Hsu, Wei-Bin; Dubey, Navneet Kumar; Lee, Wen-Fu; Lin, Tsai-Yu; Hsieh, Meng-Yow; Chen, Chin-Fu; Peng, Kuo-Ti; Huang, Tsung-Jen; Shi, Chung-Sheng; Guo, Ren-Shyang; Cai, Chang-Jhih; Chung, Chiu-Yen; Wong, Chung-Hang

2017-01-01

This study evaluates the sustained analgesic effect of ketorolac-eluting thermosensitive biodegradable hydrogel in the plantar incisional pain model of the rat hind-paw. A ketorolac-embedded 2, 2'-Bis (2-oxazolin) (BOX) linking methoxy-poly(ethylene glycol) and poly(lactide-co-glycolide) (mPEG-PLGA) diblock copolymer (BOX copolymer) was synthesized as keto-hydrogel based on optimal sol-gel phase transition and in vitro drug release profile. The effect of keto-hydrogel on postoperative pain (POP) was assessed using the established plantar incisional pain model in hind-paw of rats and compared to that of ketorolac solution. Pain and sensory threshold, as well as pain scoring, were evaluated with behavioral tests by means of anesthesiometer and incapacitance apparatus, respectively. Pro-inflammatory cytokine levels (TNF-α, IL-6, VEGF, and IL-1β) around incisional wounds were measured by ELISA. Tissue histology was assessed using hematoxylin and eosin and Masson's trichrome staining. Ten mg/mL (25 wt%) keto-hydrogel showed a sol-gel transition at 26.4°C with a 10-day sustained drug release profile in vitro. Compared to ketorolac solution group, the concentration of ketorolac in tissue fluid was higher in the keto-hydrogel group during the first 18 h of application. Keto-hydrogel elevated pain and sensory threshold, increased weight-bearing capacity, and significantly reduced the levels of TNF-α, IL-6, and IL-1β while enhanced VEGF in tissue fluid. Histologic analysis reveals greater epithelialization and collagen deposition around wound treated with keto-hydrogel. In conclusion, our study suggests that keto-hydrogel is an ideal compound to treat POP with a secondary gain of improved incisional wound healing.

The inhibition of nitric oxide-activated poly(ADP-ribose) synthetase attenuates transsynaptic alteration of spinal cord dorsal horn neurons and neuropathic pain in the rat.

PubMed

Mao, J; Price, D D; Zhu, J; Lu, J; Mayer, D J

1997-09-01

Transsynaptic alteration of spinal cord dorsal horn neurons characterized by hyperchromatosis of cytoplasm and nucleoplasm (so-called 'dark' neurons) occurs in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the common sciatic nerve. The incidence of dark neurons in CCI rats has been proposed to be mediated by glutamate-induced neurotoxicity. In the present study, we examined whether the inhibition of the nitric oxide (NO)-activated poly(ADP-ribose) synthetase (PARS), a nuclear enzyme critical to glutamate-induced neurotoxicity, would both reduce the incidence of dark neurons and attenuate behavioral manifestations of neuropathic pain in CCI rats. Dark neurons were observed bilaterally (with ipsilateral predominance) within the spinal cord dorsal horn, particularly in laminae I-II, of rats 8 days after unilateral sciatic nerve ligation as compared to sham operated rats. The number of dark neurons in the dorsal horn was dose-dependently reduced in CCI rats receiving once daily intrathecal (i.t.) treatment with the PARS inhibitor benzamide (200 or 400 nmol, but not 100 nmol benzamide or saline) for 7 days. Consistent with the histological improvement, thermal hyperalgesia, mechanical hyperalgesia, and low threshold mechano-allodynia also were reliably reduced in CCI rats treated with either 200 or 400 nmol benzamide. Neither dark neurons nor neuropathic pain behaviors were reliably affected by i.t. administration of either 800 nmol novobiocin (a mono(ADP-ribose) synthetase) or 800 nmol benzoic acid (the backbone structure of benzamide), indicating a selective effect of benzamide. Intrathecal treatment with an NO synthase inhibitor NG-nitro-L-arginine methyl ester (40 nmol, but not its inactive D-isomer) utilizing the same benzamide treatment regimen resulted in similar reductions of both dark neurons and neuropathic pain behaviors in CCI rats. These results provide, for the first time, in vivo evidence indicating that benzamide is neuroprotective and that the PARS-mediated transsynaptic alteration of spinal cord dorsal horn neurons contributes to behavioral manifestations of neuropathic pain in CCI rats. These observations may have general implications beyond treatment of neuropathic pain in that PARS-mediated neuronal alterations may play a significant role in glutamate-mediated neurotoxicity under many other circumstances.

Neuroprotective and antinociceptive effects of rosemary (Rosmarinus officinalis L.) extract in rats with painful diabetic neuropathy.

PubMed

Rasoulian, Bahram; Hajializadeh, Zahra; Esmaeili-Mahani, Saeed; Rashidipour, Marzieh; Fatemi, Iman; Kaeidi, Ayat

2018-05-12

Diabetes mellitus is associated with the development of neuronal tissue damage in different central and peripheral nervous system regions. A common complication of diabetes is painful diabetic peripheral neuropathy. We have explored the antihyperalgesic and neuroprotective properties of Rosmarinus officinalis L. extract (RE) in a rat model of streptozotocin (STZ)-induced diabetes. The nociceptive threshold and motor coordination of these diabetic rats was assessed using the tail-flick and rotarod treadmill tests, respectively. Activated caspase-3 and the Bax:Bcl-2 ratio, both biochemical indicators of apoptosis, were assessed in the dorsal half of the lumbar spinal cord tissue by western blotting. Treatment of the diabetic rats with RE improved hyperglycemia, hyperalgesia and motor deficit, suppressed caspase-3 activation and reduced the Bax:Bcl-2 ratio, suggesting that the RE has antihyperalgesic and neuroprotective effects in this rat model of STZ-induced diabetes. Cellular mechanisms underlying the observed effects may, at least partially, be related to the inhibition of neuronal apoptosis.

A Single Sub-anesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats

PubMed Central

Wang, Jing; Goffer, Yossef; Xu, Duo; Tukey, David S.; Shamir, D. B.; Eberle, Sarah E.; Zou, Anthony H.; Blanck, Thomas J.J.; Ziff, Edward B.

2011-01-01

Background Chronic pain is associated with depression. In rodents, pain is often assessed by sensory hypersensitivity, which does not sufficiently measure affective responses. Low-dose ketamine has been used to treat both pain and depression, but it is not clear whether ketamine can relieve depression associated with chronic pain and whether this antidepressant effect depends on its anti-nociceptive properties. Methods We examined whether the spared nerve injury (SNI) model of neuropathic pain induces depressive behavior in rats, using sucrose preference test and forced swim test, and tested whether a subanesthetic dose of ketamine treats SNI-induced depression. Results SNI-treated rats, compared with control, showed decreased sucrose preference (0.719 ± 0.068 (mean ± SEM) vs. 0.946 ± 0.010) and enhanced immobility in the forced swim test (107.3 ± 14.6s vs. 56.2 ± 12.5s). Further, sham-operated rats demonstrated depressive behaviors in the acute postoperative period (0.790 ± 0.062 on postoperative day 2). A single subanesthetic dose of ketamine (10mg/kg) did not alter SNI-induced hypersensitivity; however, it treated SNI-associated depression-like behaviors (0.896 ± 0.020 for ketamine vs. 0.663 ± 0.080 for control 1 day after administration; 0.858 ± 0.017 for ketamine vs. 0.683 ± 0.077 for control 5 days after administration). Conclusions Chronic neuropathic pain leads to depression-like behaviors. The postoperative period also confers vulnerability to depression, possibly due to acute pain. Sucrose preference test and forced swim test may be used to compliment sensory tests for assessment of pain in animal studies. Low-dose ketamine can treat depression-like behaviors induced by chronic neuropathic pain. PMID:21934410

Sleep deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion.

PubMed

Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

2014-09-01

Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. © 2014 Associated Professional Sleep Societies, LLC.

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis.

PubMed

Sagar, Devi Rani; Ashraf, Sadaf; Xu, Luting; Burston, James J; Menhinick, Matthew R; Poulter, Caroline L; Bennett, Andrew J; Walsh, David A; Chapman, Victoria

2014-08-01

Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA). To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain. Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group. Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage. Our data suggest that early targeting of osteoclasts may reduce pain associated with OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

[The changes of monocarboxylate transporter-2 in spinal cord horn in a rat model of chronic inflammatory pain].

PubMed

He, Jian-hua; Xu, Li; Shen, Yu; Kong, Ming-jian; Shi, Lin-yu; Ma, Zheng-liang

2015-01-01

To investigate the changes in the levels of monocarboxylate transporter-2 in spinal cord horn in a rat model of chronic inflammatory pain. Male SD rats weighting 180 - 220 g were randomly divided into two groups(n = 48): normal saline group (NS group), complete Freund's adjuvant group (CFA group). Rats were given injections of CFA 100 µl in left hind paw in group CFA, and an equal volume of saline was given injection in group NS. Mechanical withdraw threshold(MWT) and thermal withdraw latency(TWL) were measured at before injection(T0 and 3 h, 1 d, 3 d, 7 d, 14 d, and 21 d after injection(T1-7). Four rats were chosen from each group at T0-7 and sacrificed, and L4-5 segments of the spinal cord horn were removed for measurement of the expression of monocarboxylate transporter-2 by Western blot analysis. In CFA group, mechanical hyperalgesia and allodynia appeared on the 3 h after CFA injection, then until the day 14. The expression of monocarboxylate transporter-2 in the spinal dorsal horn of rats in CFA group was significantly higher than that in normal control group at T1-6(P <0.05). The protein level of monocarboxylate transporter-2 was apparently correlated with MWT and TWL(P <0.01 and P <0.05) in CFA group. The level of monocarboxylate transporter-2 in spinal dorsal horn is significantly increased in a rat model of chronic inflammatory pain and the change may involve in the formation and maintenance of central sensitization in spinal cord of chronic inflammatory uain.

Radiotherapy Suppresses Bone Cancer Pain through Inhibiting Activation of cAMP Signaling in Rat Dorsal Root Ganglion and Spinal Cord.

PubMed

Zhu, Guiqin; Dong, Yanbin; He, Xueming; Zhao, Ping; Yang, Aixing; Zhou, Rubing; Ma, Jianhua; Xie, Zhong; Song, Xue-Jun

2016-01-01

Radiotherapy is one of the major clinical approaches for treatment of bone cancer pain. Activation of cAMP-PKA signaling pathway plays important roles in bone cancer pain. Here, we examined the effects of radiotherapy on bone cancer pain and accompanying abnormal activation of cAMP-PKA signaling. Female Sprague-Dawley rats were used and received tumor cell implantation (TCI) in rat tibia (TCI cancer pain model). Some of the rats that previously received TCI treatment were treated with X-ray radiation (radiotherapy). Thermal hyperalgesia and mechanical allodynia were measured and used for evaluating level of pain caused by TCI treatment. PKA mRNA expression in dorsal root ganglion (DRG) was detected by RT-PCR. Concentrations of cAMP, IL-1β, and TNF-α as well as PKA activity in DRG and the spinal cord were measured by ELISA. The results showed that radiotherapy significantly suppressed TCI-induced thermal hyperalgesia and mechanical allodynia. The level of PKA mRNA in DRG, cAMP concentration and PKA activity in DRG and in the spinal cord, and concentrations of IL-1β and TNF-α in the spinal cord were significantly reduced by radiotherapy. In addition, radiotherapy also reduced TCI-induced bone loss. These findings suggest that radiotherapy may suppress bone cancer pain through inhibition of activation of cAMP-PKA signaling pathway in DRG and the spinal cord.

Long non-coding RNA CCAT1 modulates neuropathic pain progression through sponging miR-155.

PubMed

Dou, Lidong; Lin, Hongqi; Wang, Kaiwei; Zhu, Guosong; Zou, Xuli; Chang, Enqiang; Zhu, Yongfeng

2017-10-27

Neuropathic pain is caused by dysfunction or primary injury of the somatosensory nervous system. Long noncoding RNAs (lncRNAs) play important roles in the development of neuropathic pain. However, the effects of lncRNA colon cancer associated transcript-1 (CCAT1) in neuropathic pain have not been reported. The model of bilateral sciatic nerve chronic constriction injuries (bCCI) is regarded as long-lasting mechanical hypersensitivity and cold allodynia, which is the representative symptom in the human subjects suffering from the neuropathic pain. In this study, we found that CCAT1 expression was decreased in the spinal dorsal horn, dorsal root ganglion (DRG), hippocampus, and anterior cingulate cortex (ACC) of rats with bCCI. The rats of bCCI presented the cold allodynia after the 14 th day of postoperation. We furtherly showed that lncRNA CCAT1 decreased miR-155 expression and enhanced Serum and glucocorticoid regulated protein kinase 3 (SGK3) expression in the NGF-differentiated PC12 cell. We found that miR-155 expression was increased in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. However, SGK3 expression was downregulated in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. Moreover, lncRNA CCAT1 overexpression could alleviate the pain thresholds and inhibited expression of SGK3 could rescue this effect. In conclusion, these results suggested the crucial roles of CCAT1 and SGK3 in the neuropathic pain.

Long non-coding RNA CCAT1 modulates neuropathic pain progression through sponging miR-155

PubMed Central

Dou, Lidong; Lin, Hongqi; Wang, Kaiwei; Zhu, Guosong; Zou, Xuli; Chang, Enqiang; Zhu, Yongfeng

2017-01-01

Neuropathic pain is caused by dysfunction or primary injury of the somatosensory nervous system. Long noncoding RNAs (lncRNAs) play important roles in the development of neuropathic pain. However, the effects of lncRNA colon cancer associated transcript-1 (CCAT1) in neuropathic pain have not been reported. The model of bilateral sciatic nerve chronic constriction injuries (bCCI) is regarded as long-lasting mechanical hypersensitivity and cold allodynia, which is the representative symptom in the human subjects suffering from the neuropathic pain. In this study, we found that CCAT1 expression was decreased in the spinal dorsal horn, dorsal root ganglion (DRG), hippocampus, and anterior cingulate cortex (ACC) of rats with bCCI. The rats of bCCI presented the cold allodynia after the 14th day of postoperation. We furtherly showed that lncRNA CCAT1 decreased miR-155 expression and enhanced Serum and glucocorticoid regulated protein kinase 3 (SGK3) expression in the NGF-differentiated PC12 cell. We found that miR-155 expression was increased in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. However, SGK3 expression was downregulated in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. Moreover, lncRNA CCAT1 overexpression could alleviate the pain thresholds and inhibited expression of SGK3 could rescue this effect. In conclusion, these results suggested the crucial roles of CCAT1 and SGK3 in the neuropathic pain. PMID:29163801

Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wang, X-J; Xia, L-L; Xu, T-Y; Zhang, X-H; Zhu, Z-W; Zhang, M-G; Liu, Y; Xu, C; Zhong, S; Shen, Z-J

2016-04-01

There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle-to-collagen ratio and alpha-smooth muscle actin expression and an increase in transforming growth factor-beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats. © 2015 Blackwell Verlag GmbH.

Effects of fluoxetine on changes of pain sensitivity in chronic stress model rats.

PubMed

Lian, Yan-Na; Chang, Jin-Long; Lu, Qi; Wang, Yi; Zhang, Ying; Zhang, Feng-Min

2017-06-09

Exposure to stress could facilitate or inhibit pain responses (stress-induced hyperalgesia or hypoalgesia, respectively). Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor antidepressant. There have been contradictory reports on whether fluoxetine produces antinociceptive effects. The purpose of this study was to elucidate changes in pain sensitivity after chronic stress exposure, and the effects of fluoxetine on these changes. We measured thermal, mechanical, and formalin-induced acute and inflammatory pain by using the tail-flick, von Frey, and formalin tests respectively. The results showed that rats exposed to chronic stress exhibited thermal and formalin-induced acute and inflammatory hypoalgesia and transient mechanical hyperalgesia. Furthermore, fluoxetine promoted hypoalgesia in thermal and inflammatory pain and induced mechanical hyperalgesia. Our results indicate that the 5-HT system could be involved in hypoalgesia of thermal and inflammatory pain and induce transient mechanical hyperalgesia after stress exposure. Copyright © 2017 Elsevier B.V. All rights reserved.

Nutmeg oil alleviates chronic inflammatory pain through inhibition of COX-2 expression and substance P release in vivo.

PubMed

Zhang, Wei Kevin; Tao, Shan-Shan; Li, Ting-Ting; Li, Yu-Sang; Li, Xiao-Jun; Tang, He-Bin; Cong, Ren-Huai; Ma, Fang-Li; Wan, Chu-Jun

2016-01-01

Chronic pain, or sometimes referred to as persistent pain, reduces the life quality of patients who are suffering from chronic diseases such as inflammatory diseases, cancer and diabetes. Hence, herbal medicines draw many attentions and have been shown effective in the treatment or relief of pain. Here in this study, we used the CFA-injected rats as a sustainable pain model to test the anti-inflammatory and analgesic effect of nutmeg oil, a spice flavor additive to beverages and baked goods produced from the seed of Myristica fragrans tree. We have demonstrated that nutmeg oil could potentially alleviate the CFA-injection induced joint swelling, mechanical allodynia and heat hyperanalgesia of rats through inhibition of COX-2 expression and blood substance P level, which made it possible for nutmeg oil to be a potential chronic pain reliever.

Up-regulation of CXCR4 expression contributes to persistent abdominal pain in rats with chronic pancreatitis.

PubMed

Zhu, Hong-Yan; Liu, Xuelian; Miao, Xiuhua; Li, Di; Wang, Shusheng; Xu, Guang-Yin

2017-01-01

Background Pain in patients with chronic pancreatitis is critical hallmark that accompanied inflammation, fibrosis, and destruction of glandular pancreas. Many researchers have demonstrated that stromal cell-derived factor 1 (also named as CXCL12) and its cognate receptor C-X-C chemokine receptor type 4 (CXCR4) involved in mediating neuropathic and bone cancer pain. However, their roles in chronic pancreatic pain remain largely unclear. Methods Chronic pancreatitis was induced by intraductal injection of trinitrobenzene sulfonic acid to the pancreas. Von Frey filament tests were conducted to evaluate pancreas hypersensitivity of rat. Expression of CXCL12, CXCR4, NaV1.8, and pERK in rat dorsal root ganglion was detected by Western blot analyses. Dorsal root ganglion neuronal excitability was assessed by electrophysiological recordings. Results We showed that both CXCL12 and CXCR4 were dramatically up-regulated in the dorsal root ganglion in trinitrobenzene sulfonic acid-induced chronic pancreatitis pain model. Intrathecal application with AMD3100, a potent and selective CXCR4 inhibitor, reversed the hyperexcitability of dorsal root ganglion neurons innervating the pancreas of rats following trinitrobenzene sulfonic acid injection. Furthermore, trinitrobenzene sulfonic acid-induced extracellular signal-regulated kinase activation and Nav1.8 up-regulation in dorsal root ganglias were reversed by intrathecal application with AMD3100 as well as by blockade of extracellular signal-regulated kinase activation by intrathecal U0126. More importantly, the trinitrobenzene sulfonic acid-induced persistent pain was significantly suppressed by CXCR4 and extracellular signal-regulated kinase inhibitors. Conclusions The present results suggest that the activation of CXCL12-CXCR4 signaling might contribute to pancreatic pain and that extracellular signal-regulated kinase-dependent Nav1.8 up-regulation might lead to hyperexcitability of the primary nociceptor neurons in rats with chronic pancreatitis.

Effects of acute chemotherapy-induced mucositis on spontaneous behaviour and the grimace scale in laboratory rats.

PubMed

Whittaker, A L; Leach, M C; Preston, F L; Lymn, K A; Howarth, G S

2016-04-01

Intestinal mucositis is a frequent side-effect of chemotherapy treatment. Many oncological research programs aim to identify novel treatments for this distressing condition, and these programs frequently use rat models. Little is known about the presence and progression of pain in these models and how this can best be treated by analgesic therapy. We used a number of behaviour-based methods of pain assessment to determine which tools were best suited for pain identification. Baseline measures for behavioural assessment, rat grimace score and sociability were determined through analysis of continuously recorded video data and an applied social interaction test (n = 16). Mucositis was then induced by intraperitoneal injection of 5-fluorouracil (150 mg/kg) and further behavioural analyses undertaken. An assessment of enrichment interaction was also made by determining the mass of a plastic chew toy gnawed both pre- and post-chemotherapy injection. Behavioural scoring was performed 1, 6, 12, 24 and 48 h after injection, with facial expression being scored at the 12, 24 and 48 h time-points. Sociability testing was performed once during the post-injection period. No significant differences were found in grimace scores between baseline and later daily measures. Behaviours similar to those previously reported post-laparotomy were observed. Writhing, twitching and back-arching behaviours were most evident in rats affected by mucositis and were increased in frequency (respective P values: 0.002, 0.004 and 0.008) 48 h after chemotherapy injection compared with baseline, implying that pain onset occurred around this time-point. Social investigatory behaviour was also increased (P = 0.002) following disease onset. Each day, rats post-5FU injection gnawed a greater percentage of their Nylabone enrichment by weight than the saline-injected control rats (P = 0.046). These data suggest that, of the tools tested, behavioural assessment scoring may find greatest utility in rodent models of intestinal mucositis and should be investigated further. © The Author(s) 2015.

Different patterns of morphological changes in the hippocampus and dentate gyrus accompany the differential expression of disability following nerve injury.

PubMed

Kalman, Eszter; Keay, Kevin A

2014-12-01

Physical and psychological trauma which results in mood disorders and the disruption of complex behaviours is associated with reductions in hippocampal volume. Clinical evaluation of neuropathic pain reveals mood and behavioural change in a significant number of patients. A rat model of neuropathic injury results in complex behavioural changes in a subpopulation (~30%) of injured rats; these changes are co-morbid with a range of other 'disabilities'. The specific objective of this study was to determine in rats the morphology of the hippocampus and dentate gyrus in individuals with and without complex behavioural disruptions following a constriction injury of the sciatic nerve, and to determine whether rats that develop disabilities following nerve injury have a reduced hippocampal volume compared with injured rats with no disabilities. The social behaviours of nerve-injured rats were evaluated before and after nerve injury. The morphology of the hippocampus of rats with and without behavioural disruptions was compared in serial histological sections. Single-housing and repeated social-interaction testing had no effect on the morphology of either the hippocampus or the dentate gyrus. Rats with transient or ongoing disability identified by behavioural disruption following sciatic nerve injury, show bilateral reductions in hippocampal volume, and lateralised reduction in the dentate gyrus (left side). Disabled rats display a combination of behavioural and physiological changes, which resemble many of the criteria used clinically to diagnose mood disorders. They also show reductions in the volume of the hippocampus similar to people with clinically diagnosed mood disorders. The sciatic nerve injury model reveals a similarity to the human neuropathic pain presentation presenting an anatomically specific focus for the investigation of the neural mechanisms underpinning the co-morbidity of chronic pain and mood disorder. © 2014 Anatomical Society.

Rubus occidentalis analgesic effect in a rat model of incisional pain.

PubMed

Choi, Geun Joo; Kang, Hyun; Kim, Won Joong; Kwon, Ji Wung; Kim, Beom Gyu; Choi, Yoo Shin; Cha, Young Joo; Ko, Jin Soo

2016-11-01

The purpose of this study was to evaluate the analgesic effect of Rubus occidentalis extract (ROE) in a rat model of incisional pain. The involved mechanisms and proinflammatory cytokine response were also examined. To investigate the analgesic effect, rats were intraperitoneally administered with normal saline or various doses of ROE before or after a plantar incision. To evaluate the involved mechanism, rats were intraperitoneally administered yohimbine, dexmedetomidine, prazosin, naloxone, atropine, or mecamylamine after a plantar incision; ROE was then administered intraperitoneally. The mechanical withdrawal threshold (MWT) was tested with von Frey filaments at various time points. To determine the inflammatory response, serum levels of interleukin (IL)-1β or IL-6 were measured. The MWTs significantly increased at 15 min after postincisional administration of 300 mg/kg ROE when compared with those in the control group. This elevation was observed for up to 45 min. Overall, MWTs increased in proportion to ROE dosage; however, ROEs administered before the incision produced no significant change in the MWT. The analgesic effect of ROE was significantly antagonized by mecamylamine, naloxone, and yohimbine, and agonized by dexmedetomidine. Administration of ROE inhibited the postincisional increase in serum IL-1β and IL-6. Intraperitoneal administration of ROE after surgery induces antinociceptive effects in a rat model of postoperative pain, and its effects on mechanical hyperalgesia may be associated with α 2 -adrenergic, nicotinic cholinergic, and opioid receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of Psychological Stress on Pain Perception in an Animal Model of Endometriosis.

PubMed

Hernandez, Siomara; Cruz, Myrella L; Seguinot, Inevy I; Torres-Reveron, Annelyn; Appleyard, Caroline B

2017-10-01

Pain in patients with endometriosis is considered a significant source of stress but does not always correlate with severity of the condition. We have demonstrated that stress can worsen endometriosis in an animal model. Here, we tested the impact of a psychological stress protocol on pain thresholds and pain receptors. Endometriosis was induced in female rats by suturing uterine horn tissue next to the intestinal mesentery. Sham rats had sutures only. Rats were exposed to water avoidance stress for 7 consecutive days or handled for 5 minutes (no stress). Fecal pellets and serum corticosterone (CORT) levels were measured as an index of anxiety. Pain perception was assessed using hot plate and Von Frey tests. Substance P, enkephalin, endomorphin-2, Mu opioid receptor (MOR), and neurokinin-1 receptor expression in the spinal cord were measured by immunohistochemistry. Fecal pellets and CORT were significantly higher in the endo-stress (ES) group than endo-no stress (ENS; P < .01) and sham-no stress groups (SNS; P < .01). The ES rats had more colonic damage ( P < .001 vs SNS; P < .05 vs ENS), vesicle mast cell infiltration ( P < .01 vs ENS), and more severe vesicles than ENS. The ES developed significant hyperalgesia ( P < .05) but stress reversed the allodynic effect caused by endo ( P < .001). The MOR expression was significantly reduced in ENS versus SNS ( P < .05) and more enkephalin expression was found in endo groups. Animals subjected to stress develop more severe symptoms but interestingly stress seems to have beneficial effects on abdominal allodynia, which could be a consequence of the stress-induced analgesia phenomenon.

Synergistic interactions between paracetamol and oxcarbazepine in somatic and visceral pain models in rodents.

PubMed

Tomić, Maja A; Vucković, Sonja M; Stepanović-Petrović, Radica M; Ugresić, Nenad D; Prostran, Milica S; Bosković, Bogdan

2010-04-01

Combination therapy is a valid approach in pain treatment, in which a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of coadministered paracetamol, a widely used non-opioid analgesic, and oxcarbazepine, a relatively novel anticonvulsant with analgesic properties, in a rat model of paw inflammatory hyperalgesia and in a mice model of visceral pain and determined the type of interaction between components. The effects of paracetamol, oxcarbazepine, and their combinations were examined in carrageenan-induced (0.1 mL, 1%) paw inflammatory hyperalgesia in rats and in an acetic acid-induced (10 mg/kg, 0.75%) writhing test in mice. In both models, drugs were coadministered in fixed-dose fractions of the 50% effective dose (ED(50)), and type of interaction was determined by isobolographic analysis. Paracetamol (50-200 mg/kg peroral), oxcarbazepine (40-160 mg/kg peroral), and their combination (1/8, 1/4, 1/3, and 1/2 of a single drug ED(50)) produced a significant, dose-dependent antihyperalgesia in carrageenan-injected rats. In the writhing test in mice, paracetamol (60-180 mg/kg peroral), oxcarbazepine (20-80 mg/kg peroral), and their combination (1/16, 1/8, 1/4, and 1/2 of a single drug ED(50)) significantly and dose dependently reduced the number of writhes. In both models, isobolographic analysis revealed a significant synergistic interaction between paracetamol and oxcarbazepine, with a >4-fold reduction of doses of both drugs in combination, compared with single drugs ED(50). The synergistic interaction between paracetamol and oxcarbazepine provides new information about combination pain treatment and should be explored further in patients, especially with somatic and/or visceral pain.

Sleep Deprivation Aggravates Median Nerve Injury-Induced Neuropathic Pain and Enhances Microglial Activation by Suppressing Melatonin Secretion

PubMed Central

Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

2014-01-01

Study Objectives: Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. Design: Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. Participants: Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. Measurements: Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. Results: In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. Conclusions: Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. Citation: Huang CT, Chiang RP, Chen CL, Tsai YJ. Sleep deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion. SLEEP 2014;37(9):1513-1523. PMID:25142572

Naringenin regulates production of matrix metalloproteinases in the knee-joint and primary cultured articular chondrocytes and alleviates pain in rat osteoarthritis model.

PubMed

Wang, C C; Guo, L; Tian, F D; An, N; Luo, L; Hao, R H; Wang, B; Zhou, Z H

2017-03-23

Inflammation of cartilage is a primary symptom for knee-joint osteoarthritis. Matrix metalloproteinases (MMPs) are known to play an important role in the articular cartilage destruction related to osteoarthritis. Naringenin is a plant-derived flavonoid known for its anti-inflammatory properties. We studied the effect of naringenin on the transcriptional expression, secretion and enzymatic activity of MMP-3 in vivo in the murine monosodium iodoacetate (MIA) osteoarthritis model. The assessment of pain behavior was also performed in the MIA rats. The destruction of knee-joint tissues was analyzed microscopically. Moreover, the effect of naringenin was also studied in vitro in IL-1β activated articular chondrocytes. The transcriptional expression of MMP-3, MMP-1, MMP-13, thrombospondin motifs (ADAMTS-4) and ADAMTS-5 was also studied in primary cultured chondrocytes of rats. Naringenin caused significant reduction in pain behavior and showed marked improvement in the tissue morphology of MIA rats. Moreover, a significant inhibition of MMP-3 expression in MIA rats was observed upon treatment with naringenin. In the in vitro tests, naringenin caused a significant reduction in the transcriptional expression, secretion and enzymatic activity of the studied degradative enzymes. The NF-κB pathway was also found to be inhibited upon treatment with naringenin in vitro. Overall, the study suggests that naringenin alleviated pain and regulated the production of matrix-metalloproteinases via regulation of NF-κB pathway. Thus, naringenin could be a potent therapeutic option for the treatment of osteoarthritis.

The local effect of octreotide on mechanical pain sensitivity is more sensitive in DA rats than DA.1U rats.

PubMed

Yao, Fan-Rong; Wang, Hui-Sheng; Guo, Yuan; Zhao, Yan

2016-02-01

A recent study by the authors indicated that major histocompatibility complex (MHC) genes are associated with the differences in basal pain sensitivity and in formalin model between Dark-Agouti (DA) and novel congenic DA.1U rats, which have the same genetic background as DA rats except for the u alleles of MHC. The objective of the present study is to investigate whether there is a difference in the pristane-induced arthritis (PIA) model and local analgesic effect of octreotide (OCT) between DA and DA.1U rats. The hindpaw mechanical withdrawal threshold (MWT) and heat withdrawal latency (HWL) were observed. The C unit firings of the tibial nerve evoked by non-noxious and noxious toe movements were recorded by electrophysiological methods in normal and PIA models in DA and DA.1U rats before and after local OCT administration. The expression of somatostatin receptor 2A (SSTR2A) was observed by immunohistochemistry. The results demonstrate that DA rats have a higher mechanical sensitivity than DA.1U rats after PIA. Local OCT administration significantly elevated MWT in DA rats under normal and PIA sate, but not in DA.1U rats. The electrophysiological experiments showed OCT significantly attenuated the firings of C units evoked by non-noxious and noxious stimulation in DA rats more than those in DA.1U rats both in normal and PIA states. In addition, the expression of SSTR2A in the dorsal horn of the spinal cord was significantly higher in DA than in DA.1U rats. All of the findings suggest a higher local analgesic effect of OCT in DA rats than DA.1U rats, which might be associated with the MHC genes. © 2016 John Wiley & Sons Australia, Ltd.

Efficacy of Common Analgesics for Postsurgical Pain in Rats

PubMed Central

Waite, Megan E; Tomkovich, Ashleigh; Quinn, Tammie L; Schumann, Alan P; Dewberry, L Savannah; Totsch, Stacie K; Sorge, Robert E

2015-01-01

Each year, millions of rats undergo surgery for research purposes and receive analgesics to alleviate pain. We sought to evaluate the efficacy of common analgesics in tests of hot-plate nociception and postsurgical pain by using the Rat Grimace Scale. Rats received a single dose of one of several drug–dose combinations and were tested by using the hot-plate test (acute pain) or after laparotomy (with either prophylactic or intraoperative analgesic). The efficacy of analgesics for hot-plate pain was generally not predictive of efficacy for surgical pain. Carprofen and ketoprofen were rarely effective in any of the conditions tested. With the exception of the opioid buprenorphine, several of the drugs we tested required higher-than-recommended doses to alleviate pain. Taken together, our data suggest that current analgesic use frequently is insufficient, and many rats may experience significant postsurgical pain even when analgesics are used in commonly recommended doses. PMID:26224443

DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain.

PubMed

Li, Yan; North, Robert Y; Rhines, Laurence D; Tatsui, Claudio Esteves; Rao, Ganesh; Edwards, Denaya D; Cassidy, Ryan M; Harrison, Daniel S; Johansson, Caj A; Zhang, Hongmei; Dougherty, Patrick M

2018-01-31

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Na v 1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Na v 1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Na v 1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Na v 1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Na v 1.7 associated with spontaneous activity. Na v 1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Na v 1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain. SIGNIFICANCE STATEMENT This work demonstrates that the expression and function of the voltage-gated sodium channel Na v 1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Na v 1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Na v 1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class. Copyright © 2018 the authors 0270-6474/18/381124-13$15.00/0.

Melatonin Alters the Mechanical and Thermal Hyperalgesia Induced by Orofacial Pain Model in Rats.

PubMed

Scarabelot, Vanessa Leal; Medeiros, Liciane Fernandes; de Oliveira, Carla; Adachi, Lauren Naomi Spezia; de Macedo, Isabel Cristina; Cioato, Stefania Giotti; de Freitas, Joice S; de Souza, Andressa; Quevedo, Alexandre; Caumo, Wolnei; Torres, Iraci Lucena da Silva

2016-10-01

Melatonin is a neuroendocrine hormone that presents a wide range of physiological functions including regulating circadian rhythms and sleep, enhancing immune function, sleep improvement, and antioxidant effects. In addition, melatonin has received special attention in pain treatment since it is effective and presents few adverse effects. In this study, we evaluated the effect of acute dose of melatonin upon hyperalgesia induced by complete Freund's adjuvant in a chronic orofacial pain model in Sprague-Dawley rats. Nociceptive behavior was assessed by facial Von Frey and the hot plate tests at baseline and thereafter 30, 60, and 120 min, 24 h, and 7 days after melatonin treatment. We demonstrated that acute melatonin administration alters mechanical and thermal hyperalgesia induced by an orofacial pain model (TMD), highlighting that the melatonin effect upon mechanical hyperalgesia remained until 7 days after its administration. Besides, we observed specific tissue profiles of neuroimmunomodulators linked to pain conditions and/or melatonin effect (brain-derived neurotrophic factor, nerve growth factor, and interleukins 6 and 10) in the brainstem levels, and its effects were state-dependent of the baseline of these animals.

MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain

PubMed Central

He, Shao-Qiu; Li, Zhe; Chu, Yu-Xia; Han, Liang; Xu, Qian; Li, Man; Yang, Fei; Liu, Qin; Tang, Zongxiang; Wang, Yun; Hin, Niyada; Tsukamoto, Takashi; Slusher, Barbara; Tiwari, Vinod; Shechter, Ronen; Wei, Feng; Raja, Srinivasa N; Dong, Xinzhong; Guan, Yun

2014-01-01

Chronic neuropathic pain is often refractory to current pharmacotherapies. The rodent Mas-related G-protein-coupled receptor subtype C (MrgC) shares substantial homogeneity with its human homolog, MrgX1, and is located specifically in small-diameter dorsal root ganglion (DRG) neurons. However, evidence regarding the role of MrgC in chronic pain conditions has been disparate and inconsistent. Accordingly, the therapeutic value of MrgX1 as a target for pain treatment in humans remains uncertain. Here, we found that intrathecal injection of BAM8-22 (a 15-amino acid peptide MrgC agonist) and JHU58 (a novel dipeptide MrgC agonist) inhibited both mechanical and heat hypersensitivity in rats after an L5 spinal nerve ligation (SNL). Intrathecal JHU58-induced pain inhibition was dose-dependent in SNL rats. Importantly, drug efficacy was lost in Mrg-cluster gene knockout (Mrg KO) mice and was blocked by gene silencing with intrathecal MrgC siRNA and by a selective MrgC receptor antagonist in SNL rats, suggesting that the drug action is MrgC-dependent. Further, in a mouse model of trigeminal neuropathic pain, microinjection of JHU58 into ipsilateral subnucleus caudalis inhibited mechanical hypersensitivity in wild-type but not Mrg KO mice. Finally, JHU58 attenuated the mEPSC frequency both in medullary dorsal horn neurons of mice after trigeminal nerve injury and in lumbar spinal dorsal horn of mice after SNL. We provide multiple lines of evidence that MrgC agonism at spinal but not peripheral sites may constitute a novel pain inhibitory mechanism that involves inhibition of peripheral excitatory inputs onto postsynaptic dorsal horn neurons in different rodent models of neuropathic pain. PMID:24333779

Parameter Optimization Analysis of Prolonged Analgesia Effect of tDCS on Neuropathic Pain Rats

PubMed Central

Wen, Hui-Zhong; Gao, Shi-Hao; Zhao, Yan-Dong; He, Wen-Juan; Tian, Xue-Long; Ruan, Huai-Zhen

2017-01-01

Background: Transcranial direct current stimulation (tDCS) is widely used to treat human nerve disorders and neuropathic pain by modulating the excitability of cortex. The effectiveness of tDCS is influenced by its stimulation parameters, but there have been no systematic studies to help guide the selection of different parameters. Objective: This study aims to assess the effects of tDCS of primary motor cortex (M1) on chronic neuropathic pain in rats and to test for the optimal parameter combinations for analgesia. Methods: Using the chronic neuropathic pain models of chronic constriction injury (CCI), we measured pain thresholds before and after anodal-tDCS (A-tDCS) using different parameter conditions, including stimulation intensity, stimulation time, intervention time and electrode located (ipsilateral or contralateral M1 of the ligated paw on male/female CCI models). Results: Following the application of A-tDCS over M1, we observed that the antinociceptive effects were depended on different parameters. First, we found that repetitive A-tDCS had a longer analgesic effect than single stimulus, and both ipsilateral-tDCS (ip-tDCS) and contralateral-tDCS (con-tDCS) produce a long-lasting analgesic effect on neuropathic pain. Second, the antinociceptive effects were intensity-dependent and time-dependent, high intensities worked better than low intensities and long stimulus durations worked better than short stimulus durations. Third, timing of the intervention after injury affected the stimulation outcome, early use of tDCS was an effective method to prevent the development of pain, and more frequent intervention induced more analgesia in CCI rats, finally, similar antinociceptive effects of con- and ip-tDCS were observed in both sexes of CCI rats. Conclusion: Optimized protocols of tDCS for treating antinociceptive effects were developed. These findings should be taken into consideration when using tDCS to produce analgesic effects in clinical applications. PMID:28659772

The effects of pressure on arthritic knees in a rat model of CFA-induced arthritis.

PubMed

Koo, Sung Tae; Lee, Chang-Hyung; Choi, Hyeunseok; Shin, Yong Il; Ha, Ki Tae; Ye, Hanna; Shim, Hyun Bo

2013-01-01

Pain is influenced by weather changes under certain circumstances, and inflammatory pain in animal models is ameliorated by pressure, but the underlying mechanism of atmospheric pressure has not been clearly elucidated. To examine the effect of pressure on pain in an arthritic animal model. Controlled animal study. Laboratory animal study. Following an injection of complete Freund's adjuvant (CFA) into one side of a knee joint, 32 rats were assigned randomly to 2 groups and either placed under 1 or 2.5 atmospheres absolute (ATA) in a hyperbaric chamber for 5 hours. The pain levels were assessed daily for up to 2 weeks post-injection to determine the changes in weight bearing (WB) of the affected limbs. In addition, the levels of gelatinase, MMP-2, and MMP-9 expression in the synovial fluids of the knees were analyzed. After arthritis induction, the rats in the 1 ATA group showed reduced WB of the affected limbs (< 10% of normal limbs). This reduction in WB peaked at 2 days after the injection and then decreased spontaneously. Nevertheless, the pain behavior lasted for more than 2 weeks. In the 2.5 ATA group, the WB was significantly better during the experiment.  The MMP-9/MMP-2 ratio increased at 7 and 14 days after the CFA injection in the 1 ATA group. However, repetitive exposure to 2.5 ATA significantly reduced this ratio in the 2.5 ATA group. Although a sufficient number of samples were used to support the hypothesis that high atmospheric pressure improves a painful condition in this study, an additional larger-scale study will be needed to confirm these findings. Exposure to elevated pressures appears to relieve arthritic pain for extended periods by reducing the inflammatory process and should be considered as a possible alternative pain-reducing therapy.

Genome-Wide Transcriptional Profiling of Skin and Dorsal Root Ganglia after Ultraviolet-B-Induced Inflammation

PubMed Central

Paterson, Kathryn J.; Sisignano, Marco; Schmid, Ramona; Rust, Werner; Hildebrandt, Tobias; Geisslinger, Gerd; Orengo, Christine; Bennett, David L.; McMahon, Stephen B.

2014-01-01

Ultraviolet-B (UVB)-induced inflammation produces a dose-dependent mechanical and thermal hyperalgesia in both humans and rats, most likely via inflammatory mediators acting at the site of injury. Previous work has shown that the gene expression of cytokines and chemokines is positively correlated between species and that these factors can contribute to UVB-induced pain. In order to investigate other potential pain mediators in this model we used RNA-seq to perform genome-wide transcriptional profiling in both human and rat skin at the peak of hyperalgesia. In addition we have also measured transcriptional changes in the L4 and L5 DRG of the rat model. Our data show that UVB irradiation produces a large number of transcriptional changes in the skin: 2186 and 3888 genes are significantly dysregulated in human and rat skin, respectively. The most highly up-regulated genes in human skin feature those encoding cytokines (IL6 and IL24), chemokines (CCL3, CCL20, CXCL1, CXCL2, CXCL3 and CXCL5), the prostanoid synthesising enzyme COX-2 and members of the keratin gene family. Overall there was a strong positive and significant correlation in gene expression between the human and rat (R = 0.8022). In contrast to the skin, only 39 genes were significantly dysregulated in the rat L4 and L5 DRGs, the majority of which had small fold change values. Amongst the most up-regulated genes in DRG were REG3B, CCL2 and VGF. Overall, our data shows that numerous genes were up-regulated in UVB irradiated skin at the peak of hyperalgesia in both human and rats. Many of the top up-regulated genes were cytokines and chemokines, highlighting again their potential as pain mediators. However many other genes were also up-regulated and might play a role in UVB-induced hyperalgesia. In addition, the strong gene expression correlation between species re-emphasises the value of the UVB model as translational tool to study inflammatory pain. PMID:24732968

Increased expression of CaV3.2 T-type calcium channels in damaged DRG neurons contributes to neuropathic pain in rats with spared nerve injury.

PubMed

Kang, Xue-Jing; Chi, Ye-Nan; Chen, Wen; Liu, Feng-Yu; Cui, Shuang; Liao, Fei-Fei; Cai, Jie; Wan, You

2018-01-01

Ion channels are very important in the peripheral sensitization in neuropathic pain. Our present study aims to investigate the possible contribution of Ca V 3.2 T-type calcium channels in damaged dorsal root ganglion neurons in neuropathic pain. We established a neuropathic pain model of rats with spared nerve injury. In these model rats, it was easy to distinguish damaged dorsal root ganglion neurons (of tibial nerve and common peroneal nerve) from intact dorsal root ganglion neurons (of sural nerves). Our results showed that Ca V 3.2 protein expression increased in medium-sized neurons from the damaged dorsal root ganglions but not in the intact ones. With whole cell patch clamp recording technique, it was found that after-depolarizing amplitudes of the damaged medium-sized dorsal root ganglion neurons increased significantly at membrane potentials of -85 mV and -95 mV. These results indicate a functional up-regulation of Ca V 3.2 T-type calcium channels in the damaged medium-sized neurons after spared nerve injury. Behaviorally, blockade of Ca V 3.2 with antisense oligodeoxynucleotides could significantly reverse mechanical allodynia. These results suggest that Ca V 3.2 T-type calcium channels in damaged medium-sized dorsal root ganglion neurons might contribute to neuropathic pain after peripheral nerve injury.

Anti-allodynic effect of mangiferin in neuropathic rats: Involvement of nitric oxide-cyclic GMP-ATP sensitive K+ channels pathway and serotoninergic system.

PubMed

de Los Monteros-Zuñiga, Antonio Espinosa; Izquierdo, Teresa; Quiñonez-Bastidas, Geovanna Nallely; Rocha-González, Héctor Isaac; Godínez-Chaparro, Beatriz

The neurobiology of neuropathic pain is caused by injury in the central or peripheral nervous system. Recent evidence points out that mangiferin shows anti-nociceptive effect in inflammatory pain. However, its role in inflammatory and neuropathic pain and the possible mechanisms of action are not yet established. The purpose of this study was to determine the possible anti-allodynic effect of mangiferin in rats with spinal nerve ligation (SNL). Furthermore, we sought to investigate the possible mechanisms of action that contribute to these effects. Mechanical allodynia to stimulation with the von Frey filaments was measured by the up and down method. Intrathecal administration of mangiferin prevented, in a dose-dependent fashion, SNL-induced mechanical allodynia. Mangiferin-induced anti-allodynia was prevented by the intrathecal administration of L-NAME (100μg/rat, non-selective nitric oxide synthase inhibitor), ODQ (10μg/rat, inhibitor of guanylate-cyclase) and glibenclamide (50μg/rat, channel blocker of ATP-sensitive K + channels). Moreover, methiothepin (30μg/rat, non-selective 5-HT receptor antagonist), WAY-100635 (6μg/rat, selective 5-HT 1A receptor antagonist), SB-224289 (5μg/rat, selective 5-HT 1B receptor antagonist), BRL-15572 (4μg/rat, selective 5-HT 1D receptor antagonist) and SB-659551 (6μg/rat, selective 5-HT 5A receptor antagonist), but not naloxone (50μg/rat, non-selective opioid receptor antagonist), were able to prevent mangiferin-induced anti-allodynic effect. These data suggest that the anti-allodynic effect induced by mangiferin is mediated at least in part by the serotoninergic system, involving the activation of 5-HT 1A/1B/1D/5A receptors, as well as the nitric oxide-cyclic GMP-ATP-sensitive K + channels pathway, but not by the opioidergic system, in the SNL model of neuropathic pain in rats. Copyright © 2016. Published by Elsevier Inc.

[Antihyperalgesic activity of chlorimipramine and sodium phenytoin in an induced model of neuropathic pain in rats].

PubMed

Guevara-López, Uriah; Gutiérrez-Sougarret, Bernardo; López-Pavón, Lucy; Aldrete, J Antonio; Tamayo-Valenzuela, Antonio

2004-01-01

Neuropathic pain results from injury or impairment of the nervous system manifested by pain syndrome. Experimental models have been used to study its effects and how to suppress these. Tricyclic antidepressants (TCA) and anticonvulsant (AC) have been used for treatment. To evaluate the antihyperanalgesic efficiency of intraperitoneal (IP) chlorimipramine (CIP) vs IP phenytoine (DFH) for induced neuropathic pain in an experimental animal model. After making a surgical ligature of the sciatic nerve in the right leg of 18 male rats, the time of withdrawal of both claws immersed in hot (45 degrees C) and cold water (10 degrees C) was measured during a four week period before and after IP CIP, DFH, or placebo administered in a double blind study. Significant statistical differences were observed in the time of withdrawal with CIP as compared with DFH and when both groups were compared with placebo (as tested by the paw immersion in hot water). When the thermal stimulus was cold water, an increase of the time of withdrawal was seen with DFH. These findings suggest that CIP and FS are both effective in the treatment of neuropathic pain in an animal model, as well as for the treatment of secondary hiperalgesia.

NMDA and AMPA receptors in the anterior cingulate cortex mediates visceral pain in visceral hypersensitivity rats.

PubMed

Zhou, Lin; Huang, Junjing; Gao, Jun; Zhang, Guanpo; Jiang, Jinjin

2014-02-01

Several studies have shown that N-methyl-D-aspartate (NMDA)-receptor activation in anterior cingulate cortex (ACC) neurons plays critical roles in modulating visceral pain responses in visceral hypersensitivity (VH) rats. However, there are few reports about the expressions of NMDA and α-amino-3-hydroxy-5-methyl-4-isox-azolepropionic-acid (AMPA) receptor subtypes in ACC of VH model rats at different time points. The current study was undertaken to investigate NR2A, NR2B and GluR2 expressions in ACC of VH rats that were induced by administration with 5% mustard oil. Our results indicated that NR2B, but not NR2A, was highly expressed in VH model group on day 15, 22, and 36 compared with normal group (p < 0.05). GluR2 expression was also higher in VH model group on day 15, 22, and 36 than that of normal group (p < 0.05). These findings suggested increased expression of NR2B and GluR2 might be key mechanisms for long-term synaptic plastic changes in VH rats. Copyright © 2014. Published by Elsevier Inc.

A Judgement Bias Test to Assess Affective State and Potential Therapeutics in a Rat Model of Chemotherapy-Induced Mucositis.

PubMed

George, Rebecca P; Barker, Timothy H; Lymn, Kerry A; Bigatton, Dylan A; Howarth, Gordon S; Whittaker, Alexandra L

2018-05-29

Chemotherapy-induced mucositis is an extremely painful condition that occurs in 40-60% of patients undergoing chemotherapy. As mucositis currently has no effective treatment, and due to the self-limiting nature of the condition, the major treatment aims are to manage symptoms and limit pain with significance placed on improving patient quality of life. Rodent models are frequently used in mucositis research. These investigations typically assess pathological outcomes, yet fail to include a measure of affective state; the key therapeutic goal. Assessment of cognitive biases is a novel approach to determining the affective state of animals. Consequently, this study aimed to validate a cognitive bias test through a judgement bias paradigm to measure affective state in a rat model of chemotherapy-induced intestinal mucositis. Rats with intestinal mucositis demonstrated a negative affective state, which was partially ameliorated by analgesic administration, whilst healthy rats showed an optimistic response. This study concluded that the judgement bias test was able to evaluate the emotional state of rats with chemotherapy-induced mucositis. These findings provide a foundation for future refinement to the experimental design associated with the animal model that will expedite successful transitioning of novel therapeutics to clinical practice, and also improve humane endpoint implementation.

Merging the Structural Motifs of Functionalized Amino Acids and α-Aminoamides: Compounds with Significant Anticonvulsant Activities

PubMed Central

Salomé, Christophe; Salomé-Grosjean, Elise; Stables, James P.; Kohn, Harold

2010-01-01

Functional amino acids (FAAs) and α-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4′-((3″-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED50 values of 13, 14, ~10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases. PMID:20394379

Merging the structural motifs of functionalized amino acids and alpha-aminoamides: compounds with significant anticonvulsant activities.

PubMed

Salomé, Christophe; Salomé-Grosjean, Elise; Stables, James P; Kohn, Harold

2010-05-13

Functional amino acids (FAAs) and alpha-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4'-((3''-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED(50) values of 13, 14, approximately 10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.

MiR-203 involves in neuropathic pain development and represses Rap1a expression in nerve growth factor differentiated neuronal PC12 cells.

PubMed

Li, Haixia; Huang, Yuguang; Ma, Chao; Yu, Xuerong; Zhang, Zhiyong; Shen, Le

2015-01-01

Although microRNAs (miRNAs) have been shown to play a role in numerous biological processes, their function in neuropathic pain is not clear. The rat bilateral sciatic nerve chronic constriction injury (bCCI) is an established model of neuropathic pain, so we examined miRNA expression and function in the spinal dorsal horn in bCCI rats. Microarray and real-time polymerase chain reaction were used to examine the expression of miRNA in nerve system of bCCI rats, and the targets of miRNA were predicted by bioinformatic approaches. The function of specific miRNA was estimated through the methods of gene engineering. This study revealed substantially (∼10-fold) decreased miR-203 expression in the spinal dorsal horns but not the dorsal root ganglions, hippocampus, or anterior cingulate cortexes of bCCI rats. Rap1a protein expression was upregulated in bCCI rat spinal dorsal horns. We further verified that miR-203 directly targeted the 3'-untranslated region of the rap1a gene, thereby decreasing rap1a protein expression in neuron-like cells. Rap1a has diverse neuronal functions and their perturbation is responsible for several mental disorders. For example, Rap1a/MEK/ERK is involved in peripheral sensitization. These data suggest a potential role for miR-203 in regulating neuropathic pain development, and Rap1a is a validated target gene in vitro. Results from our study and others indicate the possibility that Rap1a may be involved in pain. We hope that these results can provide support for future research into miR-203 in gene therapy for neuropathic pain.

ERK-GluR1 phosphorylation in trigeminal spinal subnucleus caudalis neurons is involved in pain associated with dry tongue.

PubMed

Nakaya, Yuka; Tsuboi, Yoshiyuki; Okada-Ogawa, Akiko; Shinoda, Masamichi; Kubo, Asako; Chen, Jui Yen; Noma, Noboru; Batbold, Dulguun; Imamura, Yoshiki; Sessle, Barry J; Iwata, Koichi

2016-01-01

Dry mouth is known to cause severe pain in the intraoral structures, and many dry mouth patients have been suffering from intraoral pain. In development of an appropriate treatment, it is crucial to study the mechanisms underlying intraoral pain associated with dry mouth, yet the detailed mechanisms are not fully understood. To evaluate the mechanisms underlying pain related to dry mouth, the dry-tongue rat model was developed. Hence, the mechanical or heat nocifensive reflex, the phosphorylated extracellular signal-regulated kinase and phosphorylated GluR1-IR immunohistochemistries, and the single neuronal activity were examined in the trigeminal spinal subnucleus caudalis of dry-tongue rats. The head-withdrawal reflex threshold to mechanical, but not heat, stimulation of the tongue was significantly decreased on day 7 after tongue drying. The mechanical, but not heat, responses of trigeminal spinal subnucleus caudalis nociceptive neurons were significantly enhanced in dry-tongue rats compared to sham rats on day 7. The number of phosphorylated extracellular signal-regulated kinase-immunoreactive cells was also significantly increased in the trigeminal spinal subnucleus caudalis following noxious stimulation of the tongue in dry-tongue rats compared to sham rats on day 7. The decrement of the mechanical head-withdrawal reflex threshold (HWT) was reversed during intracisternal administration of the mitogen-activated protein kinase kinase 1 inhibitor, PD98059. The trigeminal spinal subnucleus caudalis neuronal activities and the number of phosphorylated extracellular signal-regulated kinase-immunoreactive cells following noxious mechanical stimulation of dried tongue were also significantly decreased following intracisternal administration of PD98059 compared to vehicle-administrated rats. Increased number of the phosphorylated GluR1-IR cells was observed in the trigeminal spinal subnucleus caudalis of dry-tongue rats, and the number of phosphorylated GluR1-IR cells was significantly reduced in PD98059-administrated rats compared to the vehicle-administrated tongue-dry rats. These findings suggest that the pERK-pGluR1 cascade is involved in central sensitization of trigeminal spinal subnucleus caudalis nociceptive neurons, thus resulting in tongue mechanical hyperalgesia associated with tongue drying. © The Author(s) 2016.

Nociceptive Response to L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats.

PubMed

Nascimento, G C; Bariotto-Dos-Santos, K; Leite-Panissi, C R A; Del-Bel, E A; Bortolanza, M

2018-04-02

Non-motor symptoms are increasingly identified to present clinical and diagnostic importance for Parkinson's disease (PD). The multifactorial origin of pain in PD makes this symptom of great complexity. The dopamine precursor, L-DOPA (L-3,4-dihydroxyphenylalanine), the classic therapy for PD, seems to be effective in pain threshold; however, there are no studies correlating L-DOPA-induced dyskinesia (LID) and nociception development in experimental Parkinsonism. Here, we first investigated nociceptive responses in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease to a hind paw-induced persistent inflammation. Further, the effect of L-DOPA on nociception behavior at different times of treatment was investigated. Pain threshold was determined using von Frey and Hot Plate/Tail Flick tests. Dyskinesia was measured by abnormal involuntary movements (AIMs) induced by L-DOPA administration. This data is consistent to show that 6-OHDA-lesioned rats had reduced nociceptive thresholds compared to non-lesioned rats. Additionally, when these rats were exposed to a persistent inflammatory challenge, we observed increased hypernociceptive responses, namely hyperalgesia. L-DOPA treatment alleviated pain responses on days 1 and 7 of treatment, but not on day 15. During that period, we observed an inverse relationship between LID and nociception threshold in these rats, with a high LID rate corresponding to a reduced nociception threshold. Interestingly, pain responses resulting from CFA-induced inflammation were significantly enhanced during established dyskinesia. These data suggest a pro-algesic effect of L-DOPA-induced dyskinesia, which is confirmed by the correlation founded here between AIMs and nociceptive indexes. In conclusion, our results are consistent with the notion that central dopaminergic mechanism is directly involved in nociceptive responses in Parkinsonism condition.

Sciatic endometriosis induces mechanical hypersensitivity, segmental nerve damage, and robust local inflammation in rats

PubMed Central

Chen, S.; Xie, W.; Strong, J. A.; Jiang, J.; Zhang, J.-M.

2015-01-01

Background Endometriosis is a common cause of pain including radicular pain. Ectopic endometrial tissue may directly affect peripheral nerves including the sciatic, which has not been modelled in animals. Methods We developed a rat model for sciatic endometriosis by grafting a piece of autologous uterine tissue around the sciatic nerve. Control animals underwent a similar surgery but received a graft of pelvic fat tissue. Results The uterine grafts survived and developed fluid filled cysts; the adjacent nerve showed signs of swelling and damage. Mechanical and cold hypersensitivity and allodynia of the ipsilateral hindpaw developed gradually over the first two weeks after the surgery, peaked at 2 to 5 weeks, and was almost resolved by 7 weeks. Control animals showed only minor changes in these pain behaviors. Histological signs of inflammation in the uterine graft and in the adjacent nerve were observed at 3 weeks but were resolving by 7 weeks. In vivo fiber recording showed increased spontaneous activity, especially of C fibers, in sciatic nerve proximal to the uterine graft. Several pro-inflammatory cytokines including interluekin-18, VEGF, fractalkine, and MIP-1α, were elevated in the uterine graft plus sciatic nerve samples, compared to samples from normal nerve or nerve plus fat graft. Growth associated protein 43 (GAP43), a marker of regenerating nerve fibers, was observed in the adjacent sciatic nerve as well as in the uterine graft. Conclusions This model shared many features with other rat models of endometriosis, but also had some unique features more closely related to neuropathic pain models. PMID:26688332

Antinociceptive Effect of Ghrelin in a Rat Model of Irritable Bowel Syndrome Involves TRPV1/Opioid Systems.

PubMed

Mao, Yuqing; Li, Zhengyang; Chen, Kan; Yu, Huafang; Zhang, Shaoren; Jiang, Miao; Ma, Yuanhua; Liang, Chunli; Liu, Hongyan; Li, Huanqing; Hua, Qian; Zhou, Hao; Sun, Yonghong; Fan, Xiaoming

2017-01-01

Irritable bowel syndrome (IBS), defined as recurrent abdominal pain and changes in bowel habits, seriously affects quality of life and ability to work. Ghrelin is a brain-gut hormone, which has been reported to show antinociceptive effects in peripheral pain. We investigated the effect of ghrelin on visceral hypersensitivity and pain in a rat model of IBS. Maternal deprivation (MD) was used to provide a stress-induced model of IBS in Wistar rats. Colorectal distension (CRD) was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR) scores. Rats that were confirmed to have visceral hypersensitivity after MD were injected with ghrelin (10 µg/kg) subcutaneously twice a week from weeks 7 to 8. [D-Lys3]-GHRP-6 (100 nmol/L) and naloxone (100 nmol/L) were administered subcutaneously to block growth hormone secretagogue receptor 1α (GHS-R1α) and opioid receptors, respectively. Expression of transient receptor potential vanilloid type 1 (TRPV1) and µ and κ opioid receptors (MOR and KOR) in colon, dorsal root ganglion (DRG) and cerebral cortex tissues were detected by western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical analyses and immunofluorescence. Ghrelin treatment increased expression of opioid receptors and inhibited expression of TRPV1 in colon, dorsal root ganglion (DRG) and cerebral cortex. The antinociceptive effect of ghrelin in the rat model of IBS was partly blocked by both the ghrelin antagonist [D-Lys3]-GHRP-6 and the opioid receptor antagonist naloxone. The results indicate that ghrelin exerted an antinociceptive effect, which was mediated via TRPV1/opioid systems, in IBS-induced visceral hypersensitivity. Ghrelin might potentially be used as a new treatment for IBS. © 2017 The Author(s). Published by S. Karger AG, Basel.

Use of the TRPV1 Agonist Capsaicin to Provide Long-Term Analgesia in a Rat Limb Fracture/Open Repair, Internal Fixation Model

DTIC Science & Technology

2012-10-01

W81XWH-10-2-0093 TITLE: Use of the TRPV1 Agonist Capsaicin to Provide Long-Term Analgesia in a Rat Limb Fracture/Open Repair, Internal Fixation Model...2. REPORT TYPE Final 3. DATES COVERED (From - To) 30September2010-29September2012 4. TITLE AND SUBTITLE Use of the TRPV1 Agonist Capsaicin to...capsaicin around the fracture site. 15. SUBJECT TERMS Femur fracture, Rat Model, Pain, Capsaicin, Trauma, TRPV1 16. SECURITY CLASSIFICATION OF

P2Y12 receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2',3'-dideoxycytidine.

PubMed

Yi, Zhihua; Xie, Lihui; Zhou, Congfa; Yuan, Huilong; Ouyang, Shuai; Fang, Zhi; Zhao, Shanhong; Jia, Tianyu; Zou, Lifang; Wang, Shouyu; Xue, Yun; Wu, Bing; Gao, Yun; Li, Guilin; Liu, Shuangmei; Xu, Hong; Xu, Changshui; Zhang, Chunping; Liang, Shangdong

2018-03-01

The direct neurotoxicity of HIV and neurotoxicity of combination antiretroviral therapy medications both contribute to the development of neuropathic pain. Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in mechanical and thermal hyperalgesia. The P2Y 12 receptor expressed in SGCs of the DRG is involved in pain transmission. In this study, we explored the role of the P2Y 12 receptor in neuropathic pain induced by HIV envelope glycoprotein 120 (gp120) combined with ddC (2',3'-dideoxycytidine). A rat model of gp120+ddC-induced neuropathic pain was used. Peripheral nerve exposure to HIV-gp120+ddC increased mechanical and thermal hyperalgesia in gp120+ddC-treated model rats. The gp120+ddC treatment increased expression of P2Y 12 receptor mRNA and protein in DRG SGCs. In primary cultured DRG SGCs treated with gp120+ddC, the levels of [Ca 2+ ] i activated by the P2Y 12 receptor agonist 2-(Methylthio) adenosine 5'-diphosphate trisodium salt (2-MeSADP) were significantly increased. P2Y 12 receptor shRNA treatment inhibited 2-MeSADP-induced [Ca 2+ ] i in primary cultured DRG SGCs treated with gp120+ddC. Intrathecal treatment with a shRNA against P2Y 12 receptor in DRG SGCs reduced the release of pro-inflammatory cytokines, decreased phosphorylation of p38 MAPK in the DRG of gp120+ddC-treated rats. Thus, downregulating the P2Y 12 receptor relieved mechanical and thermal hyperalgesia in gp120+ddC-treated rats.

Effect of dexmedetomidine and cold stress in a rat model of neuropathic pain: Role of interleukin-6 and tumor necrosis factor-α.

PubMed

Farghaly, Hanan Sayed M; Mahmoud, Ahmed Mostafa; Abdel-Sater, Khaled A

2016-04-05

Dexmedetomidine (Dex) is a novel Alpha 2-adrenoceptor agonist. It decreases sympathetic tone and attenuates the stress responses to anesthesia and surgery. People exposed to cold suffer unpleasant thermal pain, which is experienced as stress and causes the release of noradrenaline from the sympathetic terminals. The present study investigated the effects of cold stress and dexmedetomidine on chronic constriction injury (CCI) model of the sciatic nerve in rats. Sixty four male Wistar rats were divided into seven groups of eight rats each: repeated cold stress (RCS) group, sham RCS group, CCI group, sham CCI group, Dex-treated group received a single dose of Dex (5 μg/kg), CCI+Dex group, CCI+RCS group. Interleukin-6 (IL-6) and tumor necrosis factor- alpha (TNF-α) levels in the serum were measured by enzyme-linked immunosorbent assay. The mean body weight of CCI, RCS, CCI+RCS, CCI+Dex and RCS+Dex groups decreased significantly compared with pre-values. Dexmedetomidine and CCI caused significant changes of the systolic, diastolic and mean blood pressure. Both RCS and CCI groups showed significant decreased of reaction time in the hot plate test. The RCS and CCI groups demonstrated a significant mechanical hyperalgesia, while pain threshold was increased in the RCS+Dex group. A significant decrease of serum IL-6 and TNF-α was demonstrated in CCI+RCS and CCI+Dex groups. The therapeutic effectiveness of dexmedetomidine in neuropathic pain may be through inhibition of proinflammatory cytokines, primarily IL-6 and TNF-α. Moreover, cold stress may result in increased resistance to neuropathic pain. Copyright © 2016 Elsevier B.V. All rights reserved.

Houttuynia cordata Thunb reverses oxaliplatin-induced neuropathic pain in rat by regulating Th17/Treg balance.

PubMed

Wan, Cheng-Fu; Zheng, Li-Li; Liu, Yan; Yu, Xue

2016-01-01

Oxaliplatin is a widely used anti-advanced colorectal cancer drug, while it could induce neuropathy. Houttuynia cordata Thunb (HCT) has a wide range of biological activities, such as anti-inflammation, anti-cancer, and immune regulation. In the present study, we investigated the effect of HCT on oxaliplatin-induced neuropathy in rat models. HCT (1000 mg/kg/day) significantly decreased the number of withdrawal responses and the withdrawal latency in oxaliplatin-treated rats. HCT could down-regulated the serum levels of Interleukin-6 (IL-6) and macrophage inflammatory protein1-α (MIP-1α) in oxaliplatin-treated rats. Th17/Treg balance was reversed by HCT in oxaliplatin-treated rats by regulating PI3K/Akt/mTOR signaling pathway. The present results suggest that HCT is useful as a therapeutic drug for oxaliplatin-induced neuropathic pain.

Houttuynia cordata Thunb reverses oxaliplatin-induced neuropathic pain in rat by regulating Th17/Treg balance

PubMed Central

Wan, Cheng-Fu; Zheng, Li-Li; Liu, Yan; Yu, Xue

2016-01-01

Oxaliplatin is a widely used anti-advanced colorectal cancer drug, while it could induce neuropathy. Houttuynia cordata Thunb (HCT) has a wide range of biological activities, such as anti-inflammation, anti-cancer, and immune regulation. In the present study, we investigated the effect of HCT on oxaliplatin-induced neuropathy in rat models. HCT (1000 mg/kg/day) significantly decreased the number of withdrawal responses and the withdrawal latency in oxaliplatin-treated rats. HCT could down-regulated the serum levels of Interleukin-6 (IL-6) and macrophage inflammatory protein1-α (MIP-1α) in oxaliplatin-treated rats. Th17/Treg balance was reversed by HCT in oxaliplatin-treated rats by regulating PI3K/Akt/mTOR signaling pathway. The present results suggest that HCT is useful as a therapeutic drug for oxaliplatin-induced neuropathic pain. PMID:27186286

Use of Liposomal Bupivacaine for Postoperative Analgesia in an Incisional Pain Model in Rats (Rattus norvegicus)

PubMed Central

Kang, Stacey C; Jampachaisri, Katechan; Seymour, Travis L; Felt, Stephen A; Pacharinsak, Cholawat

2017-01-01

The local anesthetic bupivacaine is valuable for perioperative analgesia, but its use in the postoperative period is limited by its short duration of action. Here, we evaluated the application of a slow-release liposomal formulation of bupivacaine for postoperative analgesia. The aim was to assess whether liposomal bupivacaine effectively attenuates postoperative mechanical and thermal hypersensitivity in a rat model of incisional pain. Rats (n = 36) were randomly assigned to 1 of 5 treatment groups: saline, 1 mL/kg SC every 12 h for 2 d; buprenorphine HCl, 0.05 mg/kg SC every 12 h for 2 d (Bup HCl); 0.5% bupivacaine, 2 mg/kg SC local infiltration once (Bupi); liposomal bupivacaine, 1 mg/kg SC local infiltration once (Exp1); and liposomal bupivacaine, 6 mg/kg SC local infiltration once (Exp6). Mechanical and thermal hypersensitivity were evaluated daily on days –1, 0, 1, 2, 3, and 4. The saline group exhibited both hypersensitivities through all 4 evaluated postoperative days. Bup HCl attenuated mechanical hypersensitivity for 2 d and thermal hypersensitivity for 1 d. Bupi attenuated only thermal hypersensitivity for 4 d. Rats in the Exp1 group showed attenuation of both mechanical and thermal hypersensitivity for 4 d, and those in the Exp6 group had attenuation of mechanical hypersensitivity on day 0 and thermal hypersensitivity for 4 d. These data suggest that a single local infiltration of liposomal bupivacaine at a dose of 1 mg/kg SC effectively attenuates postoperative mechanical and thermal hypersensitivity for 4 d in a rat model of incisional pain. PMID:28905717

Use of Liposomal Bupivacaine for Postoperative Analgesia in an Incisional Pain Model in Rats (Rattus norvegicus).

PubMed

Kang, Stacey C; Jampachaisri, Katechan; Seymour, Travis L; Felt, Stephen A; Pacharinsak, Cholawat

2017-01-01

The local anesthetic bupivacaine is valuable for perioperative analgesia, but its use in the postoperative period is limited by its short duration of action. Here, we evaluated the application of a slow-release liposomal formulation of bupivacaine for postoperative analgesia. The aim was to assess whether liposomal bupivacaine effectively attenuates postoperative mechanical and thermal hypersensitivity in a rat model of incisional pain. Rats (n = 36) were randomly assigned to 1 of 5 treatment groups: saline, 1 mL/kg SC every 12 h for 2 d; buprenorphine HCl, 0.05 mg/kg SC every 12 h for 2 d (Bup HCl); 0.5% bupivacaine, 2 mg/kg SC local infiltration once (Bupi); liposomal bupivacaine, 1 mg/kg SC local infiltration once (Exp1); and liposomal bupivacaine, 6 mg/kg SC local infiltration once (Exp6). Mechanical and thermal hypersensitivity were evaluated daily on days -1, 0, 1, 2, 3, and 4. The saline group exhibited both hypersensitivities through all 4 evaluated postoperative days. Bup HCl attenuated mechanical hypersensitivity for 2 d and thermal hypersensitivity for 1 d. Bupi attenuated only thermal hypersensitivity for 4 d. Rats in the Exp1 group showed attenuation of both mechanical and thermal hypersensitivity for 4 d, and those in the Exp6 group had attenuation of mechanical hypersensitivity on day 0 and thermal hypersensitivity for 4 d. These data suggest that a single local infiltration of liposomal bupivacaine at a dose of 1 mg/kg SC effectively attenuates postoperative mechanical and thermal hypersensitivity for 4 d in a rat model of incisional pain.

Crocin improved locomotor function and mechanical behavior in the rat model of contused spinal cord injury through decreasing calcitonin gene related peptide (CGRP).

PubMed

Karami, Masoume; Bathaie, S Zahra; Tiraihi, Taqi; Habibi-Rezaei, Mehran; Arabkheradmand, Jalil; Faghihzadeh, Soghrat

2013-12-15

Various approaches have been offered to alleviate chronic pain resulting from spinal cord injuries (SCIs). Application of herbs and natural products, with potentially lower adverse effects, to cure diseases has been recommended in both traditional and modern medicines. Here, the effect of crocin on chronic pain induced by spinal cord contusion was investigated in an animal model. Female Wistar rats were randomly divided into five groups (5 rats in each); three groups were contused at the L1 level. One group was treated with crocin (150mg/kg) two weeks after spinal cord injury; the second group, control, was treated with vehicle only; and the third group was treated with ketoprofen. Two normal groups were also considered with or without crocin treatment. The mechanical behavioral test, the locomotor recovery test and the thermal behavioral test were applied weekly to evaluate the injury and recovery of rats. Significant improvements (p<0.05) in mechanical behavioral and locomotor recovery tests were seen in the rats treated with crocin. Thermal behavioral test did not show any significant changes due to crocin treatment. Plasma concentration of calcitonin-gene related peptide (CGRP) changed from 780.2±2.3 to 1140.3±4.5pg/ml due to SCI and reached 789.1±2.7pg/ml after crocin treatment. These changes were significant at the level of p<0.05. The present study shows the beneficial effects of crocin treatment on chronic pain induced by SCI, through decreasing CGRP as an important mediator of inflammation and pain. Copyright © 2013 Elsevier GmbH. All rights reserved.

Pregnancy suppresses neuropathic pain induced by chronic constriction injury in rats through the inhibition of TNF-α

PubMed Central

Onodera, Yoshiko; Kanao-Kanda, Megumi; Kanda, Hirotsugu; Sasakawa, Tomoki; Iwasaki, Hiroshi; Kunisawa, Takayuki

2017-01-01

Purpose Pregnancy-induced analgesia develops during late pregnancy, but it is unclear whether this analgesia is effective against neuropathic pain. The detailed molecular mechanisms underlying pregnancy-induced analgesia have not been investigated. We examined the antinociceptive effect of pregnancy-induced analgesia in a neuropathic pain model and the expression of tumor necrosis factor (TNF)-α, glial fibrillary acidic protein (GFAP), Iba-1, and c-Fos in the spinal dorsal horn just before parturition. Materials and methods Female Sprague Dawley rats (200–250 g) were randomly assigned to one of four groups (pregnant + chronic constriction injury [CCI]; pregnant + sham injury; not pregnant + CCI; and not pregnant + sham injury). Separate groups were used for the behavioral and tissue analyses. CCI of the left sciatic nerve was surgically induced 3 days after confirming pregnancy in the pregnancy group or on day 3 in the not pregnant group. The spinal cord was extracted 18 days after CCI. TNF-α, GFAP, Iba-1, and c-Fos expression levels in the spinal dorsal horn were measured by Western blot analysis. Mechanical threshold was tested using von Frey filaments. Results The lowered mechanical threshold induced by CCI was significantly attenuated within 1 day before parturition and decreased after delivery. TNF-α expression in CCI rats was decreased within 1 day before parturition. Further, GFAP, Iba-1, and c-Fos expression in the spinal dorsal horn was reduced in the pregnant rats. Serum TNF-α in all groups was below measurable limits. Conclusion Our findings indicate that pregnancy-induced analgesia suppresses neuropathic pain through reducing spinal levels of TNF-α, GFAP, Iba-1, and c-Fos in a rat model of CCI. PMID:28331359

The effects of pre-emptive low-dose X-ray irradiation on MIA induced inflammatory pain in rats

NASA Astrophysics Data System (ADS)

Hahm, Suk-Chan; Lee, Go-Eun; Kim, Eun-Hye; Kim, Junesun; Lee, Taewoong; Lee, Wonho

2013-07-01

This study was performed to determine the effect of pre-emptive low-dose irradiation on the development of inflammatory pain and to characterize the potential mechanisms underlying this effect in osteoarthritis (OA) animal model. Whole-body X-irradiations with 0.1, 0.5, 1 Gy or sham irradiations were performed for 3 days before the induction of ostearthritis with monosodium iodoacetate (MIA) (40 µl, in saline) into the right knee joint in male Sprague Dawley rats. Behavioral tests for arthritic pain including evoked and non-evoked pain were conducted before and after MIA injection and inducible nitric-oxide synthase (iNOS) expression level was measured by western blot. Low-dose radiation significantly prevented the development of mechanical allodynia and thermal hyperalgesia and reduction in weight bearing that is regarded as a behavioral signs of non-evoked pain following MIA injection. Low-dose radiation significantly inhibited the increase in iNOS expression after MIA injection in spinal L3-5 segments in rat. These data suggest that low-dose X-irradiation is able to prevent the development of arthritic pain through modulation of iNOS expression in the spinal cord dorsal horn. Thus, low-dose radiotherapy could be substituted in part for treatment with drugs for patients with chronic inflammatory disease in clinical setting.

St. John's Wort seed and feverfew flower extracts relieve painful diabetic neuropathy in a rat model of diabetes.

PubMed

Galeotti, Nicoletta; Maidecchi, Anna; Mattoli, Luisa; Burico, Michela; Ghelardini, Carla

2014-01-01

Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes and the few approved therapies for the management of pain have limited efficacy and side effects. With the aim to explore and develop new pharmacological treatments, we investigated the antihyperalgesic properties of St. John's Wort (SJW) and feverfew in streptozotocin (STZ)-diabetic rats. Acute administration of a SJW seed extract reversed mechanical hyperalgesia with a prolonged effect. A SJW extract obtained from the aerial portion of the plant and a feverfew flower extract partially relieved neuropathic pain whereas a feverfew leaf extract was ineffective. The antihyperalgesic efficacy of these herbal drugs was comparable to that of clinically used antihyperalgesic drugs (carbamazepine, lamotrigine, l-acetyl-levocarnitine). Further examinations of SJW and feverfew composition revealed that hyperforin and hypericin might be responsible for the antihyperalgesic properties of SJW whereas the efficacy of feverfew seems to be related to the presence of parthenolide. Rats undergoing treatment with SJW and feverfew did not show any behavioral side effect or sign of altered locomotor activity. Our results suggest that SJW and feverfew extracts may become new therapeutic perspectives for painful DPN. © 2013.

The Study of Different Approaches of Parecoxib Sodium Pretreatment on the Behavior of Rats with Neuropathic Pain.

PubMed

Cui, Wenyao; Yu, Xue; Zhang, Huiqian

2015-05-01

Our objective is to analyze and observe the different administration routes of parecoxib sodium pretreatment on the behavioral improvement of rats with neuropathic pain to provide the preclinical data of parecoxib sodium on neuropathic pain treatment. 30 SD rats were randomly divided into five groups, including model group, sham operation group, intrathecal injection group (IT group), intraperitoneal injection group (IP group), and perineural infiltration group (PI group). The rats in model group and three parecoxib sodium pretreatment groups received spinal nerve ligation (SNL). Heat pain test and 50 % paw mechanical withdrawal threshold test (50 % PMWT) were use to assess the responses after parecoxib sodium pretreatment. 50 % PMWT results of right foot in five groups had no statistical difference (P > 0.05); 50 % PMWT results of left and right feet in three parecoxib sodium pretreatment groups were obviously higher than SNL group at different time points, which was statistically different (P < 0.05); in comparison with three pretreatment groups, the data of left foot in IT group were obviously higher than PI group and IP group, and the comparison among three groups had significant difference (P < 0.05). However, the data of right foot had no significant difference among three groups (P > 0.05). Paw thermal withdrawal latency (PTWL) results of left and right feet in five groups had no significant difference before surgery (P > 0.05); after the establishment of neuropathic model, PTWL results in five groups were significantly decreased; however, PTWL results of left and right feet at 3 days after surgery in IT group were significantly higher than the two other pretreatment groups (P < 0.05); PTWL results of left and right feet at 7 and 14 days after surgery had no significant difference. Parecoxib sodium pretreatment can effectively improve the behaviors caused by neuropathic pain, and intrathecal injection is the most effective route of administration.

Electrical peripheral nerve stimulation relieves bone cancer pain by inducing Arc protein expression in the spinal cord dorsal horn

PubMed Central

Sun, Ke-fu; Feng, Wan-wen; Liu, Yue-peng; Dong, Yan-bin; Gao, Li; Yang, Hui-lin

2018-01-01

Objective The analgesic effect on chronic pain of peripheral nerve stimulation (PNS) has been proven, but its underlying mechanism remains unknown. Therefore, this study aimed to assess the analgesic effect of PNS on bone cancer pain in a rat model and to explore the underlying mechanism. Materials and methods PNS on sciatic nerves with bipolar electrode was performed in both naïve and bone cancer pain model rats. Then, the protein levels of activity-regulated cytoskeleton-associated protein (Arc), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptor 1 (GluA1), and phosphate N-methyl-d-aspartic acid-type glutamate receptor subunit 2B (pGluNR2B) in spinal cord were evaluated by immunohistochemistry and Western blotting. Thermal paw withdraw latency and mechanical paw withdraw threshold were used to estimate the analgesic effect of PNS on bone cancer pain. Intrathecal administration of Arc shRNA was used to inhibit Arc expression in the spinal cord. Results PNS at 60 and 120 Hz for 20 min overtly induced Arc expression in the spinal cord, increased thermal pain thresholds in naïve rats, and relieved bone cancer pain; meanwhile, 10 Hz PNS did not achieve those results. In addition, PNS at 60 and 120 Hz also reduced the expression of GluA1, but not pGluNR2B, in the spinal cord. Finally, the anti-nociceptive effect and GluA1 downregulation induced by PNS were inhibited by intrathecal administration of Arc shRNA. Conclusion PNS (60 Hz, 0.3 mA) can relieve bone-cancer-induced allodynia and hyperalgesia by upregulating Arc protein expression and then by decreasing GluA1 transcription in the spinal cord dorsal horn. PMID:29606887

Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain.

PubMed

Goudet, Cyril; Chapuy, Eric; Alloui, Abdelkrim; Acher, Francine; Pin, Jean-Philippe; Eschalier, Alain

2008-07-01

Glutamate plays a key role in modulation of nociceptive processing. This excitatory amino acid exerts its action through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluRs). Eight mGluRs have been identified and divided in three groups based on their sequence similarity, pharmacology and G-protein coupling. While the role of group I and II mGluRs is now well established, little is known about the part played by group III mGluRs in pain. In this work, we studied comparatively the involvement of spinal group III mGluR in modulation of acute, inflammatory and neuropathic pain. While intrathecal injection of ACPT-I, a selective group III mGluR agonist, failed to induce any change in vocalization thresholds of healthy animals submitted to mechanical or thermal stimuli, it dose-dependently inhibited the nociceptive behavior of rats submitted to the formalin test and the mechanical hyperalgesia associated with different animal models of inflammatory (carrageenan-treated and monoarthritic rats) or neuropathic pain (mononeuropathic and vincristine-treated rats). Similar effects were also observed following intrathecal injection of PHCCC, a positive allosteric modulator of mGlu4. Antihyperalgesia induced by ACPT-I was blocked either by LY341495, a nonselective antagonist of mGluR, by MAP4, a selective group III antagonist. This study provide new evidences supporting the role of spinal group III mGluRs in the modulation of pain perception in different pathological pain states of various etiologies but not in normal conditions. It more particularly highlights the specific involvement of mGlu4 in this process and may be a useful therapeutic approach to chronic pain treatment.

Chronic sciatic neuropathy in rat reduces voluntary wheel running activity with concurrent chronic mechanical allodynia

PubMed Central

Whitehead, RA; Lam, NL; Sun, MS; Sanchez, JJ; Noor, S; Vanderwall, AG; Petersen, TR; Martin, HB

2016-01-01

BACKGROUND Animal models of peripheral neuropathy produced by a number of manipulations are assessed for the presence of pathological pain states such as allodynia. While stimulus-induced behavioral assays are frequently used and important to examine allodynia (i.e. sensitivity to light mechanical touch; von Frey fiber test) other measures of behavior that reflect overall function are not only complementary to stimulus-induced responsive measures, but are also critical to gain a complete understanding of the effects of the pain model on quality of life, a clinically relevant aspect of pain on general function. Voluntary wheel running activity in rodent models of inflammatory and muscle pain is emerging as a reliable index of general function that extends beyond stimulus-induced behavioral assays. Clinically, reports of increased pain intensity occur at night, a period typically characterized with reduced activity during the diurnal cycle. We therefore examined in rats whether alterations in wheel running activity were more robust during the inactive phase compared to the active phase of their diurnal cycle in a widely used rodent model of chronic peripheral neuropathic pain, the sciatic nerve chronic constriction injury (CCI) model. METHODS In adult male Sprague Dawley rats, baseline (BL) hindpaw threshold responses to light mechanical touch were assessed using the von Frey test prior to measuring BL activity levels using freely accessible running wheels (1 hr/day for 7 sequential days) to quantify distance traveled. Running wheel activity BL values are expressed as total distance traveled (m). The overall experimental design was: following BL measures, rats underwent either sham or CCI surgery followed by repeated behavioral re-assessment of hindpaw thresholds and wheel running activity levels for up to 18 days after surgery. Specifically, separate groups of rats were assessed for wheel running activity levels (1 hr total/trial) during the onset (within first 2 hrs) of either the (1) inactive (n=8/gp) or (2) active (n = 8/gp) phase of the diurnal cycle. An additional group of CCI-treated rats (n = 8/gp) were exposed to a locked running wheel to control for the potential effects of wheel running exercise on allodynia. The 1-hr running wheel trial period was further examined at discrete 20-min intervals to identify possible pattern differences in activity during the first, middle and last portion of the 1-hr trial. The effect of neuropathy on activity levels were assessed by measuring the change from their respective BLs to distance traveled in the running wheels. RESULTS While wheel running distances between groups were not different at BL from rats examined during either the inactive phase of the diurnal cycle or active phase of the diurnal cycle, sciatic nerve CCI reduced running wheel activity levels compared to sham-operated controls during the inactive phase. Additionally, compared to sham controls, bilateral low threshold mechanical allodynia was observed at all time-points after surgical induction of neuropathy in rats with free-wheel and locked-wheel access. Allodynia in CCI compared to shams was replicated in rats whose running wheel activity was examined during the active phase of the diurnal cycle. Conversely, no significant reduction in wheel running activity was observed in CCI-treated rats compared to sham controls at any timepoint when activity levels were examined during the active diurnal phase. Lastly, running wheel activity patterns within the 1 hr trial period during the inactive phase of the diurnal cycle were relatively consistent throughout each 20 min phase. CONCLUSIONS Compared to non-neuropathic sham controls, a profound and stable reduction of running wheel activity was observed in CCI rats during the inactive phase of the diurnal cycle. A concurrent robust allodynia persisted in all rats regardless of when wheel running activity was examined or whether they ran on wheels, suggesting that acute wheel running activity does not alter chronic low intensity mechanical allodynia as measured using the von Frey fiber test. Overall, these data support that acute wheel running exercise with limited repeated exposures does not itself alter allodynia and offers a behavioral assay complementary to stimulus-induced measures of neuropathic pain. PMID:27782944

Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome

PubMed Central

Buckley, Maria M; O'Halloran, Ken D; Rae, Mark G; Dinan, Timothy G; O'Malley, Dervla

2014-01-01

Abstract The search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5 mg kg−1 i.p) with or without the CRFR1 antagonist antalarmin (10 mg kg−1 i.p). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P < 0.01) and visceral pain sensitivity (P < 0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain-associated T-type calcium channel CaV3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL-6 and CRF1 receptors is effective in alleviating IBS-like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation. PMID:25260633

Interactive effects of acupuncture on pain and distress in major burns: An experiment with rats.

PubMed

Abali, Ayse Ebru; Cabioglu, Tugrul; Ozdemir, Handan; Haberal, Mehmet

2015-06-01

This study sought to investigate the interactive effects of acupuncture on pain and distress and the local progress in the burn wound in an experimental major burn model. Forty-eight male Sprague-Dawley rats were divided into six groups: S group (sham/observation during 7 days after injury); SA group (sham/acupuncture/observation during 7 days after injury); B1 group (burns/observation during 1h after injury); BA1 group (burns/acupuncture/observation during 1 h after injury); B7 group (burns/observation during 7 days after injury); and BA7 group (burns/acupuncture/observation during 7 days after injury). Pain and distress scores were evaluated throughout the study. The amounts of neutrophils and mononuclear cells were evaluated semiquantitatively, and the number of microvessels was evaluated quantitatively. Our data indicated that the average pain score of BA7 group was significantly lower than the other study groups. Histopathologic investigations indicate that the amounts of neutrophil and mononuclear cell and numbers of microvessels in the unburned skin were higher in acupuncture-applied groups. The number of microvessels in burn wounds of BA7 group was significantly higher than that of the other groups. Our data suggest that acupuncture provides low pain and distress scores in experimental rat model, and it contributes to wound healing with an enhanced angiogenesis during the acute phase of burns. Future clinical and experimental studies should be conducted to discern the benefits from acupuncture in pain management of burn patients. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

Chronic pain impairs cognitive flexibility and engages novel learning strategies in rats.

PubMed

Cowen, Stephen L; Phelps, Caroline E; Navratilova, Edita; McKinzie, David L; Okun, Alec; Husain, Omar; Gleason, Scott D; Witkin, Jeffrey M; Porreca, Frank

2018-03-22

Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical for survival. The prefrontal cortex is a key site of cognitive control and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (SNL model). Naïve, sham-operated, and SNL rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared to naïve and sham-operated animals. Following extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (i.e., less profitable) behavioral choice. Our data suggest, that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.

Local Infiltration of Analgesics at Surgical Wound to Reduce Postoperative Pain After Laparotomy in Rats.

PubMed

Kroin, Jeffrey S; Li, Jinyuan; Moric, Mario; Birmingham, Brian W; Tuman, Kenneth J; Buvanendran, Asokumar

There is an increasing use of local infiltration analgesia (LIA) to reduce postoperative pain. Despite widespread use of LIA, wide variations in drug combinations and concomitant use of systemic analgesics have made it difficult to determine the optimal drug combinations for LIA. Using a previously validated rat laparotomy model, the optimal LIA combination of medications to reduce postoperative pain was determined. Laparotomy was performed in an adult rat model under isoflurane anesthesia. During surgery, combinations of bupivacaine, ketorolac, and dexamethasone were injected over the sutured muscle wound before skin closing, and compared to saline (placebo). The same medications were injected systemically as controls. Postoperative pain was assessed by measuring spontaneous rearing activity. A high-dose 3-drug LIA combination (50 μL of bupivacaine 0.75%, ketorolac 6.0 mg/mL, and dexamethasone 2.0 mg/mL) increased rearing (decreased pain) at 2 hours (P = 0.0032) postsurgery compared to saline. However, the same 3 drugs injected systemically had a similar analgesic effect (P = 0.0002). Bupivacaine 0.75% alone was not effective for LIA. When low-dose (9-fold reduction) 3-drug LIA combination was used, LIA increased rearing (P = 0.0034) whereas the same 3 drugs injected systemically had no effect. Low-dose LIA ketorolac/dexamethasone (2-drug combination) also increased rearing (P = 0.0393). Our animal study suggests that clinical trials with low-dose LIA combinations of local anesthetic, nonsteroidal anti-inflammatory drug, and corticosteroid may be useful for reducing postoperative pain after laparotomy.

DAMGO in the central amygdala alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia.

PubMed

Zhang, R-X; Zhang, M; Li, A; Pan, L; Berman, B M; Ren, K; Lao, L

2013-11-12

Pain has sensory-discriminative and emotional-affective dimensions. Recent studies show that the affective component can be assessed with a conditioned place avoidance (CPA) test. We hypothesized that systemic morphine before a post-conditioning test would more potently attenuate the affective aspect compared to the sensory component and that [d-Ala2-N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), a μ-selective opioid receptor agonist, injected into the central nucleus of the amygdala (CeA) would reduce established CPA. A rat model of inflammatory pain, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a CPA test. Three experiments were performed on adult male Sprague-Dawley rats. Systemic morphine (0.5 or 1.0mg/kg) in Experiment 1, intrathecal (i.t.) morphine (2.5 μg/rat) in Experiment 2, and intra-CeA DAMGO (7.7-15.4 ng/0.4 μl) in Experiment 3 were given to CFA-injected rats (n=6-8/group) prior to a post-conditioning test. Saline-injected rats were used as control. Time spent in a pain-paired compartment was recorded twice, before conditioning and after a post-conditioning test. Paw withdrawal latency (PWL) to a noxious thermal stimulus was measured before experiment at day-1 and after the post-conditioning test; hyperalgesia was defined as a decrease in PWL. The data showed that CFA-injected rats had significantly negative CPA compared to those of saline-injected rats (P<0.05). Low-dosage systemic morphine significantly (P<0.05) reduced CFA-induced CPA but had no effect on PWL. I.t. morphine did not inhibit the display of CPA but significantly increased PWL, suppressing hyperalgesia (P<0.05). Intra-CeA DAMGO significantly inhibited the display of CPA compared to saline (P<0.05) but had no effect on PWL. The data demonstrate that morphine attenuates the affective component more powerfully than it does the sensory and suggests that the sensory and the emotional-affective dimensions are underpinned by different mechanisms. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Bisphosphonates inhibit pain, bone loss, and inflammation in a rat tibia fracture model of complex regional pain syndrome

PubMed Central

Wang, Liping; Guo, Tian-Zhi; Wei, Tzuping; Li, Wen-wu; Shi, Xiaoyou; Clark, J David; Kingery, Wade S

2016-01-01

BACKGROUND Bisphosphonates are used to prevent the bone loss and fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenis deformans. Distal limb fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into complex regional pain syndrome (CRPS). Clinical trials have reported that anti-resorptive bisphosphonates can prevent fracture-induced bone loss, inhibit serum inflammatory cytokine levels, and alleviate CRPS pain. Previously we observed that the inhibition of inflammatory cytokines or adaptive immune responses attenuated the development of pain behavior in a rat fracture model of CRPS and we hypothesized that bisphosphonates could prevent pain behavior, trabecular bone loss, post-fracture cutaneous cytokine up-regulation, and adaptive immune responses in this CRPS model. METHODS Rats underwent tibia fracture and cast immobilization for 4 weeks and were chronically administered either subcutaneously perfused alendronate or oral zoledronate. Behavioral measurements included hindpaw von Frey allodynia, unweighting, warmth, and edema. Bone microarchitecture was measured by uCT and bone cellular activity was evaluated by static and dynamic histomorphometry. Spinal cord Fos immunostaining was performed and skin cytokine (TNF, IL-1, IL-6) and nerve growth factor (NGF) levels were determined by EIA. Skin and sciatic nerve immunoglobulin levels were determined by EIA. RESULTS Tibia fracture rats developed hindpaw allodynia, unweighting, warmth, and edema, increased spinal Fos expression, trabecular bone loss in the lumbar vertebra and bilateral distal femurs as measured by uCT, increased trabecular bone resorption and osteoclast surface with decreased bone formation rates, increased cutaneous inflammatory cytokine and NGF expression and elevated immunocomplex deposition in skin and nerve. Alendronate (60 μg/kg/day s.c.) or zoledronate (3 mg/kg/day p.o.) treatment for 28 days, started at the time of fracture, completely inhibited the development of hindpaw allodynia and reduced hindpaw unweighting by 44 ± 13% and 58 ± 5%, respectively. Orally administered zoledronate (3 mg/kg/day for 21 days) treatment also completely reversed established allodynia and unweighting when started at 4-weeks post-fracture. Histomorphometric and uCT analysis demonstrated that both the 3 and 60 μg/kg/day alendronate treatments reversed trabecular bone loss (a 88 ± 25% and 188 ± 39% increase in the ipsilateral distal femur BV/TV, respectively) and blocked the increase in osteoclast numbers and erosion surface observed in bilateral distal femurs and in L5 vertebra of the fracture rats. Alendronate treatment inhibited fracture-induced increases in hindpaw inflammatory mediators, reducing post-fracture levels of TNF by 43 ± 9%, IL-1 by 60 ± 9%, IL-6 by 56 ± 14%, and NGF by 37 ± 14%, but had no effect on increased spinal cord Fos expression, or skin and sciatic nerve immunocomplex deposition. CONCLUSIONS Collectively, these results indicate that bisphosphonate therapy inhibits pain, osteoclast activation, trabecular bone loss, and cutaneous inflammation in the rat fracture model of CRPS, data supporting the hypothesis that bisphosphonate therapy can provide effective multimodal treatment for CRPS. PMID:27636578

Effects of sevoflurane on carrageenan- and fentanyl-induced pain hypersensitivity in Sprague-Dawley rats.

PubMed

Richebé, Philippe; Rivalan, Bertrand; Rivat, Cyril; Laulin, Jean-Paul; Janvier, Gérard; Maurette, Pierre; Simonnet, Guy

2009-02-01

Opioids are widely used for anesthesia but paradoxically induce postoperative pain hypersensitivity via N-methyl-D: -aspartate (NMDA) receptor modulation. Sevoflurane effects on opioid-induced hyperalgesia have not been yet evaluated in vivo. Nevertheless, some experimental in vitro studies reported anti-NMDA receptor properties for sevoflurane. The aim of this study was to evaluate sevoflurane effects on fentanyl-induced hyperalgesia in opioid-naive rats and in rats with inflammatory pain. Sevoflurane effects on hyperalgesia were evaluated in Sprague-Dawley rats: opioid-naive rats, rats treated with fentanyl (4 x 60 microg kg(-1)) and rats with inflammatory pain (carrageenan) treated with fentanyl (4 x 60 microg kg(-1)). On day zero, subcutaneous fentanyl injections were administered and inflammatory pain was induced with one carrageenan injection in one hind paw. Rats were exposed to low concentrations of sevoflurane (1.0 or 1.5%) on day zero prior to fentanyl injections and inflammatory pain induction, and for the duration of the fentanyl analgesic effect. The nociceptive threshold (Randall-Selitto test) was evaluated daily for 7 days. On day seven, naloxone was injected and the nociceptive threshold was assessed 5 min later. In rats without inflammatory pain but treated with fentanyl on day zero, sevoflurane 1.0% reversed the early (day zero) and long-lasting (day zero to day three) hyperalgesia classically described after high-doses of fentanyl (P < 0.05). This sevoflurane concentration antagonized the hyperalgesia induced by naloxone on day seven (P = 0.33). In a second experiment in rats with inflammatory pain, exposure to low concentrations of sevoflurane (1.0 and 1.5%) did not reduce fentanyl-induced hyperalgesia (P > 0.05), but nevertheless antagonized the naloxone induced hyperalgesia on day seven (P = 0.061). Relatively low sevoflurane concentrations (1.0%) reverse fentanyl-induced hyperalgesia in rats without inflammatory pain. Nevertheless, the lack of effect of sevoflurane concentrations of 1.0% and 1.5% to oppose hyperalgesia following high-dose fentanyl and inflammatory pain suggests that sevoflurane anti-hyperalgesic properties are weak.

Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) isolated from Boesenbergia rotunda (L.) Mansf. inhibits CFA-induced rheumatoid arthritis in rats.

PubMed

Voon, Fui-Ling; Sulaiman, Mohd Roslan; Akhtar, Muhammad Nadeem; Idris, Mohamad Fauzi; Akira, Ahmad; Perimal, Enoch Kumar; Israf, Daud Ahmad; Ming-Tatt, Lee

2017-01-05

Boesenbergia rotunda (L.) Mansf. had been traditionally used as herbs to treat pain and rheumatism. Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) is a compound isolated from Boesenbergia rotunda (L.) Mansf.. Previous study had shown the potential of cardamonin in inhibiting the release of pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in vitro. Thus, the possible therapeutic effect of cardamonin in the rheumatoid arthritis (RA) joints is postulated. This study was performed to investigate the anti-arthritic properties of cardamonin in rat model of induced RA, particularly on the inflammatory and pain response of RA. Rheumatoid arthritis paw inflammation was induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA) in Sprague Dawley rats. Using four doses of cardamonin (0.625, 1.25, 2.5, and 5.0mg/kg), anti-arthritic activity was evaluated through the paw edema, mechanical allodynia and thermal hyperalgesia responses. Enzyme-linked immunosorbent assay (ELISA) was carried out to evaluate the plasma level of TNF-α, IL-1β, and IL-6. Histological slides were prepared from the harvested rat paws to observe the arthritic changes in the joints. Behavioral, biochemical, and histological studies showed that cardamonin demonstrated significant inhibition on RA-induced inflammatory and pain responses as well as progression of joint destruction in rats. ELISA results showed that there was significant inhibition in TNF-α, IL-1β, and IL-6 levels in plasma of the cardamonin-treated RA rats. Overall, cardamonin possesses potential anti-arthritic properties in CFA-induced RA rat model. Copyright © 2016 Elsevier B.V. All rights reserved.

Endogenous opioids released during non-nociceptive environmental stress induce latent pain sensitization Via a NMDA-dependent process.

PubMed

Le Roy, Chloé; Laboureyras, Emilie; Gavello-Baudy, Stéphanie; Chateauraynaud, Jérémy; Laulin, Jean-Paul; Simonnet, Guy

2011-10-01

Although stress induces analgesia, there is evidence that stressful events may exacerbate pain syndromes. Here, we studied the effects of 1 to 3 prestressful events (days 0, 2, and 7), such as non-nociceptive environmental stress, on inflammatory hyperalgesia induced by a carrageenan injection (day 14) in 1 rat hind paw. Changes in nociceptive threshold were evaluated by the paw pressure vocalization test. The higher the number of stress sessions presented to the rats, the greater was the inflammatory hyperalgesia. Blockade of opioid receptors by naltrexone before each stress inhibited stress-induced analgesia and suppressed the exaggerated inflammatory hyperalgesia. Stressed versus nonstressed animals could be discriminated by their response to a fentanyl ultra-low dose (fULD), that produced hyperalgesia or analgesia, respectively. This pharmacological test permitted the prediction of the pain vulnerability level of prestressed rats because fULD analgesic or hyperalgesic indices were positively correlated with inflammatory hyperalgesic indices (r(2) = .84). In prestressed rats, fULD-induced hyperalgesia and the exaggerated inflammatory hyperalgesia were prevented NMDA receptor antagonists. This study provides some preclinical evidence that pain intensity is not only the result of nociceptive input level but is also dependent on the individual history, especially prior life stress events associated with endogenous opioid release. Based on these preclinical data, it would be of clinical interest to evaluate whether prior stressful events may also affect further pain sensation in humans. Moreover, this preclinical model could be a good tool for evaluating new therapeutic strategies for relieving pain hypersensitivity. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

Magnesium attenuates chronic hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat model of diabetic neuropathic pain

PubMed Central

Rondón, L J; Privat, A M; Daulhac, L; Davin, N; Mazur, A; Fialip, J; Eschalier, A; Courteix, C

2010-01-01

Neuropathic pain is a common diabetic complication affecting 8–16% of diabetic patients. It is characterized by aberrant symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. Magnesium (Mg) deficiency has been proposed as a factor in the pathogenesis of diabetes-related complications, including neuropathy. In the central nervous system, Mg is also a voltage-dependant blocker of the N-methyl-d-aspartate receptor channels involved in abnormal processing of sensory information. We hypothesized that Mg deficiency might contribute to the development of neuropathic pain and the worsening of clinical and biological signs of diabetes and consequently, that Mg administration could prevent or improve its complications. We examined the effects of oral Mg supplementation (296 mg l−1 in drinking water for 3 weeks) on the development of neuropathic pain and on biological and clinical parameters of diabetes in streptozocin (STZ)-induced diabetic rats. STZ administration induced typical symptoms of type 1 diabetes. The diabetic rats also displayed mechanical hypersensitivity and tactile and thermal allodynia. The level of phosphorylated NMDA receptor NR1 subunit (pNR1) was higher in the spinal dorsal horn of diabetic hyperalgesic/allodynic rats. Magnesium supplementation failed to reduce hyperglycaemia, polyphagia and hypermagnesiuria, or to restore intracellular Mg levels and body growth, but increased insulinaemia and reduced polydipsia. Moreover, it abolished thermal and tactile allodynia, delayed the development of mechanical hypersensitivity, and prevented the increase in spinal cord dorsal horn pNR1. Thus, neuropathic pain symptoms can be attenuated by targeting the Mg-mediated blockade of NMDA receptors, offering new therapeutic opportunities for the management of chronic neuropathic pain. PMID:20837644

Intrathecal administration of AYX2 DNA decoy produces a long-term pain treatment in rat models of chronic pain by inhibiting the KLF6, KLF9, and KLF15 transcription factors

PubMed Central

Klukinov, Michael; Harris, Scott; Manning, Donald C; Xie, Simon; Pascual, Conrado; Taylor, Bradley K; Donahue, Renee R; Yeomans, David C

2017-01-01

Background Nociception is maintained by genome-wide regulation of transcription in the dorsal root ganglia—spinal cord network. Hence, transcription factors constitute a promising class of targets for breakthrough pharmacological interventions to treat chronic pain. DNA decoys are oligonucleotides and specific inhibitors of transcription factor activities. A methodological series of in vivo–in vitro screening cycles was performed with decoy/transcription factor couples to identify targets capable of producing a robust and long-lasting inhibition of established chronic pain. Decoys were injected intrathecally and their efficacy was tested in the spared nerve injury and chronic constriction injury models of chronic pain in rats using repetitive von Frey testing. Results Results demonstrated that a one-time administration of decoys binding to the Kruppel-like transcription factors (KLFs) 6, 9, and 15 produces a significant and weeks–month long reduction in mechanical hypersensitivity compared to controls. In the spared nerve injury model, decoy efficacy was correlated to its capacity to bind KLF15 and KLF9 at a specific ratio, while in the chronic constriction injury model, efficacy was correlated to the combined binding capacity to KLF6 and KLF9. AYX2, an 18-bp DNA decoy binding KLF6, KLF9, and KLF15, was optimized for clinical development, and it demonstrated significant efficacy in these models. Conclusions These data highlight KLF6, KLF9, and KLF15 as transcription factors required for the maintenance of chronic pain and illustrate the potential therapeutic benefits of AYX2 for the treatment of chronic pain. PMID:28814144

Analgesic effects of intrathecally-administered 3 alpha-hydroxy-5 alpha-pregnan-20-one in a rat mechanical visceral pain model.

PubMed

Winfree, C J; Coombs, D W; DeLeo, J A; Colburn, R W

1992-01-01

Recent studies in animals have demonstrated that the steroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3A5P), is a potent analgesic when given intracerebroventricularly. Several studies in humans report that spinal steroids are effective in the treatment of chronic low-back pain when given in combination with morphine. The spinal antinociceptive effect of steroids, in particular a progesterone metabolite has not been studied in a visceral pain model. The experiments in the following study were designed to test, first, if the intrathecally-administered (i.t.) steroid, 3A5P, has analgesic properties in a mechanical visceral nociceptive assay, and second, if the intrathecal coadministration of this steroid and morphine is more effective than either therapy alone. Our mechanical visceral pain model (VPM) consists of a chronic indwelling duodenal balloon catheter implanted in the rat. The balloon is inflated to elicit a writhing response. Protection values are defined as the percentage of rats in each group which did not writhe. In this model, 3A5P was found to provide a dose-independent, though significant (p less than 0.01), antinociception when administered alone (33-67% protection vs. 0-25% for controls). Yet, protection offered by the coadministration of 3A5P and morphine (79%) was not significantly greater than that offered by morphine alone (85%). Unlike a dose and time-dependent response observed in a thermal cutaneous nociceptive assay, the antinociception of 3A5P was not dose-dependent when challenged with a mechanical visceral noxious stimulus.

Histopathological classification criteria of rat model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wang, Xianjin; Zhong, Shan; Xu, Tianyuan; Xia, Leilei; Zhang, Xiaohua; Zhu, Zhaowei; Zhang, Minguang; Shen, Zhoujun

2015-02-01

A variety of murine models of experimental prostatitis that mimic the phenotype of human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been developed. However, there is still a lack of explicit diagnosis criteria about those animal model. Our study is to establish histopathological classification criteria, which will be conducive to evaluate the animal models. We firstly established a rat model of experimental autoimmune prostatitis that is considered a valid model for CP/CPPS. For modelling, male Sprague-Dawley rats were immunized with autologous prostate tissue homogenate supernatant emulsified with complete Freund's adjuvant by subcutaneous injection into abdominal flank and simultaneously immunized with pertussis-diphtheria-tetanus vaccine by intraperitoneal injection. Three immunizations were administered semimonthly. At the 45th day, animals were killed, and prostate tissues were examined for morphology. Histologically, the prostate tissues were characterized by lymphoproliferation, atrophy of acini, and chronic inflammatory cells infiltration in the stromal connective tissue around the acini or ducts. Finally, we built histopathological classification criteria incorporating inflammation locations (mesenchyme, glands, periglandular tissues), ranges (focal, multifocal, diffuse), and grades (grade I-IV). To verify the effectiveness and practicability of the histopathological classification criteria, we conducted the treatment study with one of the alpha blockers, tamsulosin. The histopathological classification criteria of rat model of CP/CPPS will serve for further research of the pathogenesis and treatment strategies of the disease.

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes

PubMed Central

Song, Zhen-peng; Xiong, Bing-rui; Guan, Xue-hai; Cao, Fei; Manyande, Anne; Zhou, Ya-qun; Zheng, Hua; Tian, Yu-ke

2016-01-01

Aim: To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats. Methods: A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 μg, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-κB activation were also examined in primary rat astrocytes stimulated with IL-1β in vitro. Results: BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 μg) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-κB, p-IKKα and IκBα in spinal cord. In IL-1β-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 μmol/L) significantly inhibited the translocation of NF-κB to nucleus. Conclusion: Minocycline effectively alleviates BCP by inhibiting the NF-κB signaling pathway in spinal astrocytes. PMID:27157092

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes.

PubMed

Song, Zhen-Peng; Xiong, Bing-Rui; Guan, Xue-Hai; Cao, Fei; Manyande, Anne; Zhou, Ya-Qun; Zheng, Hua; Tian, Yu-Ke

2016-06-01

To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats. A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 μg, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-κB activation were also examined in primary rat astrocytes stimulated with IL-1β in vitro. BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 μg) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-κB, p-IKKα and IκBα in spinal cord. In IL-1β-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 μmol/L) significantly inhibited the translocation of NF-κB to nucleus. Minocycline effectively alleviates BCP by inhibiting the NF-κB signaling pathway in spinal astrocytes.

High-frequency electroacupuncture versus carprofen in an incisional pain model in rats.

PubMed

Teixeira, F M; Castro, L L; Ferreira, R T; Pires, P A; Vanderlinde, F A; Medeiros, M A

2012-12-01

The objective of the present study was to compare the effect of electroacupuncture (EA) and carprofen (CP) on postoperative incisional pain using the plantar incision (PI) model in rats. A 1-cm longitudinal incision was made through skin, fascia and muscles of a hind paw of male Wistar rats and the development of mechanical and thermal hypersensitivity was determined over 4 days using the von Frey and Hargreaves methods, respectively. Based on the experimental treatments received on the third postoperative day, the animals were divided into the following groups: PI+CP (CP, 2 mg/kg, po); PI+EAST36 (100-Hz EA applied bilaterally at the Zusanli point (ST36)); PI+EANP (EA applied to a non-acupoint region); PI+IMMO (immobilization only); PI (vehicle). In the von Frey test, the PI+EAST36 group had higher withdrawal force thresholds in response to mechanical stimuli than the PI, PI+IMMO and PI+EANP groups at several times studied. Furthermore, the PI+EAST36 group showed paw withdrawal thresholds in response to mechanical stimuli that were similar to those of the PI+CP group. In the Hargreaves test, all groups had latencies higher than those observed with PI. The PI+EAST36 group was similar to the PI+IMMO, PI+EANP and PI+CP groups. We conclude that 100-Hz EA at the ST36 point, but not at non-acupoints, can reduce mechanical nociception in the rat model of incisional pain, and its effectiveness is comparable to that of carprofen.

Comparison of dorsal root ganglion gene expression in rat models of traumatic and HIV-associated neuropathic pain

PubMed Central

Maratou, Klio; Wallace, Victoria C.J.; Hasnie, Fauzia S.; Okuse, Kenji; Hosseini, Ramine; Jina, Nipurna; Blackbeard, Julie; Pheby, Timothy; Orengo, Christine; Dickenson, Anthony H.; McMahon, Stephen B.; Rice, Andrew S.C.

2009-01-01

To elucidate the mechanisms underlying peripheral neuropathic pain in the context of HIV infection and antiretroviral therapy, we measured gene expression in dorsal root ganglia (DRG) of rats subjected to systemic treatment with the anti-retroviral agent, ddC (Zalcitabine) and concomitant delivery of HIV-gp120 to the rat sciatic nerve. L4 and L5 DRGs were collected at day 14 (time of peak behavioural change) and changes in gene expression were measured using Affymetrix whole genome rat arrays. Conventional analysis of this data set and Gene Set Enrichment Analysis (GSEA) was performed to discover biological processes altered in this model. Transcripts associated with G protein coupled receptor signalling and cell adhesion were enriched in the treated animals, while ribosomal proteins and proteasome pathways were associated with gene down-regulation. To identify genes that are directly relevant to neuropathic mechanical hypersensitivity, as opposed to epiphenomena associated with other aspects of the response to a sciatic nerve lesion, we compared the gp120 + ddC-evoked gene expression with that observed in a model of traumatic neuropathic pain (L5 spinal nerve transection), where hypersensitivity to a static mechanical stimulus is also observed. We identified 39 genes/expressed sequence tags that are differentially expressed in the same direction in both models. Most of these have not previously been implicated in mechanical hypersensitivity and may represent novel targets for therapeutic intervention. As an external control, the RNA expression of three genes was examined by RT-PCR, while the protein levels of two were studied using western blot analysis. PMID:18606552

Automated assessment of pain in rats using a voluntarily accessed static weight-bearing test.

PubMed

Kim, Hung Tae; Uchimoto, Kazuhiro; Duellman, Tyler; Yang, Jay

2015-11-01

The weight-bearing test is one method to assess pain in rodent animal models; however, the acceptance of this convenient method is limited by the low throughput data acquisition and necessity of confining the rodents to a small chamber. We developed novel data acquisition hardware and software, data analysis software, and a conditioning protocol for an automated high throughput static weight-bearing assessment of pain. With this device, the rats voluntarily enter the weighing chamber, precluding the necessity to restrain the animals and thereby removing the potential stress-induced confounds as well as operator selection bias during data collection. We name this device the Voluntarily Accessed Static Incapacitance Chamber (VASIC). Control rats subjected to the VASIC device provided hundreds of weight-bearing data points in a single behavioral assay. Chronic constriction injury (CCI) surgery and paw pad injection of complete Freund's adjuvant (CFA) or carrageenan in rats generated hundreds of weight-bearing data during a 30 minute recording session. Rats subjected to CCI, CFA, or carrageenan demonstrated the expected bias in weight distribution favoring the un-operated leg, and the analgesic effect of i.p. morphine was demonstrated. In comparison with existing methods, brief water restriction encouraged the rats to enter the weighing chamber to access water, and an infrared detector confirmed the rat position with feet properly positioned on the footplates, triggering data collection. This allowed hands-off measurement of weight distribution data reducing operator selection bias. The VASIC device should enhance the hands-free parallel collection of unbiased weight-bearing data in a high throughput manner, allowing further testing of this behavioral measure as an effective assessment of pain in rodents. Copyright © 2015. Published by Elsevier Inc.

Automated assessment of pain in rats using a voluntarily accessed static weight-bearing test

PubMed Central

Kim, Hung Tae; Uchimoto, Kazuhiro; Duellman, Tyler; Yang, Jay

2015-01-01

The weight-bearing test is one method to assess pain in rodent animal models; however, the acceptance of this convenient method is limited by the low throughput data acquisition and necessity of confining the rodents to a small chamber. New methods We developed novel data acquisition hardware and software, data analysis software, and a conditioning protocol for an automated high throughput static weight-bearing assessment of pain. With this device, the rats voluntarily enter the weighing chamber, precluding the necessity to restrain the animals and thereby removing the potential stress-induced confounds as well as operator selection bias during data collection. We name this device the Voluntarily Accessed Static Incapacitance Chamber (VASIC). Results Control rats subjected to the VASIC device provided hundreds of weight-bearing data points in a single behavioral assay. Chronic constriction injury (CCI) surgery and paw pad injection of complete Freund's adjuvant (CFA) or carrageenan in rats generated hundreds of weight-bearing data during a 30 minute recording session. Rats subjected to CCI, CFA, or carrageenan demonstrated the expected bias in weight distribution favoring the un-operated leg, and the analgesic effect of i.p. morphine was demonstrated. In comparison with existing methods, brief water restriction encouraged the rats to enter the weighing chamber to access water, and an infrared detector confirmed the rat position with feet properly positioned on the footplates, triggering data collection. This allowed hands-off measurement of weight distribution data reducing operator selection bias. Conclusion The VASIC device should enhance the hands-free parallel collection of unbiased weight-bearing data in a high throughput manner, allowing further testing of this behavioral measure as an effective assessment of pain in rodents. PMID:26143745

Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor.

PubMed

Cao, Xue-Hong; Byun, Hee-Sun; Chen, Shao-Rui; Cai, You-Qing; Pan, Hui-Lin

2010-09-01

Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced approximately 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.

Distinct alterations in colonic morphology and physiology in two rat models of enhanced stress-induced anxiety and depression-like behaviour.

PubMed

O'Malley, Dervla; Julio-Pieper, Marcela; Gibney, Sinead M; Dinan, Timothy G; Cryan, John F

2010-03-01

Stress and anxiety are important causal and exacerbating factors in functional gastro-intestinal (GI) disorders such as irritable bowel syndrome. Stress affects GI motility, faecal transit and visceral pain sensitivity. Additionally, permeability and function of the gut epithelium, which acts as a barrier between the external environment and the body's internal milieu is altered by stress. However, the effects of an enhanced stress response on colonic morphology require further investigation. We have used two animal models of stress and anxiety, the maternally separated (MS) and Wistar Kyoto (WKY) rats to examine colonic morphology. These rats exhibit increased anxiety behaviours, visceral hypersensitivity and increased stress-induced defecation in the open field arena. At a morphological level, increased mucus secretion and an associated elevation in the number of mucosal goblet cells was observed in the high anxiety rats. Additionally, the mucosal layer was flattened in MS and WKY rats, a finding indicative of mild mucosal damage. Furthermore, the muscular layer of the distal colon in these animals was thickened, an observation that may have implications for faecal transit and visceral pain perception. This study provides evidence of altered colonic function and morphology in two animal models with a heightened response to stress.

5-HT2C Receptor Knockdown in the Amygdala Inhibits Neuropathic-Pain-Related Plasticity and Behaviors.

PubMed

Ji, Guangchen; Zhang, Wei; Mahimainathan, Lenin; Narasimhan, Madhusudhanan; Kiritoshi, Takaki; Fan, Xiuzhen; Wang, Jigong; Green, Thomas A; Neugebauer, Volker

2017-02-08

Neuroplasticity in the amygdala drives pain-related behaviors. The central nucleus (CeA) serves major amygdala output functions and can generate emotional-affective behaviors and modulate nocifensive responses. The CeA receives excitatory and inhibitory inputs from the basolateral nucleus (BLA) and serotonin receptor subtype 5-HT 2C R in the BLA, but not CeA, has been implicated anxiogenic behaviors and anxiety disorders. Here, we tested the hypothesis that 5-HT 2C R in the BLA plays a critical role in CeA plasticity and neuropathic pain behaviors in the rat spinal nerve ligation (SNL) model. Local 5-HT 2C R knockdown in the BLA with stereotaxic injection of 5-HT 2C R shRNA AAV vector decreased vocalizations and anxiety- and depression-like behaviors and increased sensory thresholds of SNL rats, but had no effect in sham controls. Extracellular single-unit recordings of CeA neurons in anesthetized rats showed that 5-HT 2C R knockdown blocked the increase in neuronal activity (increased responsiveness, irregular spike firing, and increased burst activity) in SNL rats. At the synaptic level, 5-HT 2C R knockdown blocked the increase in excitatory transmission from BLA to CeA recorded in brain slices from SNL rats using whole-cell patch-clamp conditions. Inhibitory transmission was decreased by 5-HT 2C R knockdown in control and SNL conditions to a similar degree. The findings can be explained by immunohistochemical data showing increased expression of 5-HT 2C R in non-GABAergic BLA cells in SNL rats. The results suggest that increased 5-HT 2C R in the BLA contributes to neuropathic-pain-related amygdala plasticity by driving synaptic excitation of CeA neurons. As a rescue strategy, 5-HT 2C R knockdown in the BLA inhibits neuropathic-pain-related behaviors. SIGNIFICANCE STATEMENT Neuroplasticity in the amygdala has emerged as an important pain mechanism. This study identifies a novel target and rescue strategy to control abnormally enhanced amygdala activity in an animal model of neuropathic pain. Specifically, an integrative approach of gene transfer, systems and brain slice electrophysiology, behavior, and immunohistochemistry was used to advance the novel concept that serotonin receptor subtype 5-HT 2C contributes critically to the imbalance between excitatory and inhibitory drive of amygdala output neurons. Local viral vector-mediated 5-HT 2C R knockdown in the amygdala normalizes the imbalance, decreases neuronal activity, and inhibits neuropathic-pain-related behaviors. The study provides valuable insight into serotonin receptor (dys)function in a limbic brain area. Copyright © 2017 the authors 0270-6474/17/371378-16$15.00/0.

The role of trigeminal nucleus caudalis orexin 1 receptors in orofacial pain transmission and in orofacial pain-induced learning and memory impairment in rats.

PubMed

Kooshki, Razieh; Abbasnejad, Mehdi; Esmaeili-Mahani, Saeed; Raoof, Maryam

2016-04-01

It is widely accepted that the spinal trigeminal nuclear complex, especially the subnucleus caudalis (Vc), receives input from orofacial structures. The neuropeptides orexin-A and -B are expressed in multiple neuronal systems. Orexin signaling has been implicated in pain-modulating system as well as learning and memory processes. Orexin 1 receptor (OX1R) has been reported in trigeminal nucleus caudalis. However, its roles in trigeminal pain modulation have not been elucidated so far. This study was designed to investigate the role of Vc OX1R in the modulation of orofacial pain as well as pain-induced learning and memory deficits. Orofacial pain was induced by subcutaneous injection of capsaicin in the right upper lip of the rats. OX1R agonist (orexin-A) and antagonist (SB-334867-A) were microinjected into Vc prior capsaicin administration. After recording nociceptive times, learning and memory was investigated using Morris water maze (MWM) test. The results indicated that, orexin-A (150 pM/rat) significantly reduced the nociceptive times, while SB334867-A (80 nM/rat) exaggerated nociceptive behavior in response to capsaicin injection. In MWM test, capsaicin-treated rats showed a significant learning and memory impairment. Moreover, SB-334867-A (80 nM/rat) significantly exaggerated learning and memory impairment in capsaicin-treated rats. However, administration of orexin-A (100 pM/rat) prevented learning and memory deficits. Taken together, these results indicate that Vc OX1R was at least in part involved in orofacial pain transmission and orexin-A has also a beneficial inhibitory effect on orofacial pain-induced deficits in abilities of spatial learning and memory. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model

PubMed Central

Sumizono, Megumi; Otsuka, Shotaro; Terashi, Takuto; Nakanishi, Kazuki; Ueda, Koki; Takada, Seiya; Kikuchi, Kiyoshi

2018-01-01

Background Exercise regimens are established methods that can relieve neuropathic pain. However, the relationship between frequency and intensity of exercise and multiple cellular responses of exercise-induced alleviation of neuropathic pain is still unclear. We examined the influence of exercise frequency on neuropathic pain and the intracellular responses in a sciatic nerve chronic constriction injury (CCI) model. Materials and methods Rats were assigned to four groups as follows: CCI and high-frequency exercise (HFE group), CCI and low-frequency exercise (LFE group), CCI and no exercise (No-Ex group), and naive animals (control group). Rats ran on a treadmill, at a speed of 20 m/min, for 30 min, for 5 (HFE) or 3 (LFE) days a week, for a total of 5 weeks. The 50% withdrawal threshold was evaluated for mechanical sensitivity. The activation of glial cells (microglia and astrocytes), expression of brain-derived neurotrophic factor (BDNF) and μ-opioid receptor in the spinal dorsal horn and endogenous opioid in the midbrain were examined using immunohistochemistry. Opioid receptor antagonists (naloxone) were administered using intraperitoneal injection. Results The development of neuropathic pain was related to the activation of glial cells, increased BDNF expression, and downregulation of the μ-opioid receptor in the ipsilateral spinal dorsal horn. In the No-Ex group, neuropathic pain showed the highest level of mechanical hypersensitivity at 2 weeks, which improved slightly until 5 weeks after CCI. In both exercise groups, the alleviation of neuropathic pain was accelerated through the regulation of glial activation, BDNF expression, and the endogenous opioid system. The expression of BDNF and endogenous opioid in relation to exercise-induced alleviation of neuropathic pain differed in the HFE and LFE groups. The effects of exercise-induced alleviation of mechanical hypersensitivity were reversed by the administration of naloxone. Conclusion The LFE and HFE program reduced neuropathic pain. Our findings indicated that aerobic exercise-induced alleviated neuropathic pain through the regulation of glial cell activation, expression of BDNF in the ipsilateral spinal dorsal horn, and the endogenous opioid system. PMID:29445295

STAT3 inhibitor WP1066 as a novel therapeutic agent for bCCI neuropathic pain rats.

PubMed

Xue, Zhao-Jing; Shen, Le; Wang, Zhi-Yao; Hui, Shang-Yi; Huang, Yu-Guang; Ma, Chao

2014-10-02

Activation of signal transducer and activator of transcription-3 (STAT3) is suggested to be critically involved in the development of chronic pain, but the complex regulation of STAT3-dependent pathway and the functional significance of inhibiting this pathway during the development of neuropathic pain remain elusive. To evaluate the contribution of the JAK2/STAT3 pathway to neuropathic pain and the potentiality of this pathway as a novel therapeutic target, we examined the effects of the STAT3 inhibitor WP1066 by intrathecal administration in a rat model of bilateral chronic constriction injury (bCCI). The pain behavior tests were performed before the surgery and on postoperative day 3, 7, 14 and 21. L4-L6 dorsal spinal cord were harvested at each time point. Both RT-PCR and Western blot were performed to evaluate the activation of JAK2/STAT3 pathway. To observe the influence of WP1066 on neuropathic pain and its molecular mechanism, WP1066 (10 μl, 10 mmol/L in DMSO) or the same capacity of DMSO as the control were applied through the intrathecal tube on the day before bCCI surgery, and on the postoperative day 3 and 5. Behavioral tests were performed to observe the therapeutic effect on mechanical, thermal and cold hyperalgesia. L4-L6 dorsal spinal cord was harvested on postoperative day fourteen, followed by RT-PCR and Western blot evaluation of the JAK2/STAT3 pathway activation. The mechanical, thermal and cold hyperalgesia of the bCCI rats were significantly decreased when compared with the Sham or the Naïve group at each postoperative time point (P<0.05). JAK2 mRNA and STAT3 mRNA were significantly increased in the bCCI rats, accompanied by SOCS3 mRNA with a similar tendency. Western blot analysis showed that JAK2 and phosphorylated STAT3 increased significantly since 3 days after bCCI. JAK2 peaked on postoperative day 14 while phosphorylated STAT3 peaked on postoperative day 7 and gradually decreased thereafter and SOCS3׳s peak level on postoperative day 3. When WP1066 were administered intrathecally, the pain behaviors of the bCCI rats were significantly improved (P<0.05). WP1066 also inhibited the mRNA level of JAK2, STAT3 and SOCS3 in bCCI rats significantly, together with the protein level of JAK2, phosphorylated STAT3 and SOCS3 on postoperative day 14 as well. Our results found that the JAK2/STAT3 pathway in the spinal cord dorsal horn was significantly activated in the bCCI neuropathic pain rats. WP1066, which inhibited the STAT3 pathway specifically, could partially alleviate the pain behavior of the bCCI rats. So it may serve as a novel therapeutic strategy against neuropathic pain. Copyright © 2014 Elsevier B.V. All rights reserved.

Glycinergic dysfunction in a subpopulation of dorsal horn interneurons in a rat model of neuropathic pain

PubMed Central

Imlach, Wendy L.; Bhola, Rebecca F.; Mohammadi, Sarasa A.; Christie, Macdonald J.

2016-01-01

The development of neuropathic pain involves persistent changes in signalling within pain pathways. Reduced inhibitory signalling in the spinal cord following nerve-injury has been used to explain sensory signs of neuropathic pain but specific circuits that lose inhibitory input have not been identified. This study shows a specific population of spinal cord interneurons, radial neurons, lose glycinergic inhibitory input in a rat partial sciatic nerve ligation (PNL) model of neuropathic pain. Radial neurons are excitatory neurons located in lamina II of the dorsal horn, and are readily identified by their morphology. The amplitude of electrically-evoked glycinergic inhibitory post-synaptic currents (eIPSCs) was greatly reduced in radial neurons following nerve-injury associated with increased paired-pulse ratio. There was also a reduction in frequency of spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSC) in radial neurons without significantly affecting mIPSC amplitude. A subtype selective receptor antagonist and western blots established reversion to expression of the immature glycine receptor subunit GlyRα2 in radial neurons after PNL, consistent with slowed decay times of IPSCs. This study has important implications as it identifies a glycinergic synaptic connection in a specific population of dorsal horn neurons where loss of inhibitory signalling may contribute to signs of neuropathic pain. PMID:27841371

Neuropathic Pain-like Alterations in Muscle Nociceptor Function Associated with Vibration-induced Muscle Pain

PubMed Central

Chen, Xiaojie; Green, Paul G.; Levine, Jon D.

2010-01-01

We recently developed a rodent model of the painful muscle disorders induced by occupational exposure to vibration. In the present study we used this model to evaluate the function of sensory neurons innervating the vibration-exposed gastrocnemius muscle. Activity of 74 vibration-exposed and 40 control nociceptors, with mechanical receptive fields in the gastrocnemius muscle, were recorded. In vibration-exposed rats ~15% of nociceptors demonstrated an intense and long-lasting barrage of action potentials in response to sustained suprathreshold mechanical stimulation (average of 2635 action potentials with frequency of ~44 Hz during a 1 minute suprathreshold stimulus) much greater than has been reported to be produced even by potent inflammatory mediators. While these high-firing nociceptors had lower mechanical thresholds than the remaining nociceptors, exposure to vibration had no effect on conduction velocity and did not induce spontaneous activity. Hyperactivity was not observed in any of 19 neurons from vibration exposed rats pretreated with intrathecal antisense for the IL-6 receptor subunit gp130. Since vibration can injure peripheral nerves, and IL-6 has been implicated in painful peripheral neuropathies, we suggest that the dramatic change in sensory neuron function and development of muscles pain, induced by exposure to vibration, reflects a neuropathic muscle pain syndrome. PMID:20800357

The effects of opioid receptor antagonists on electroacupuncture-produced anti-allodynia/hyperalgesia in rats with paclitaxel-evoked peripheral neuropathy.

PubMed

Meng, Xianze; Zhang, Yu; Li, Aihui; Xin, Jiajia; Lao, Lixing; Ren, Ke; Berman, Brian M; Tan, Ming; Zhang, Rui-Xin

2011-09-26

Research supports the effectiveness of acupuncture for conditions such as chronic low back and knee pain. In a five-patient pilot study the modality also improved the symptoms of chemotherapy-induced neuropathic pain. Using an established rat model of paclitaxel-induced peripheral neuropathy, we evaluated the effect of electroacupuncture (EA) on paclitaxel-induced hyperalgesia and allodynia that has not been studied in an animal model. We hypothesize that EA would relieve the paclitaxel-induced mechanical allodynia and hyperalgesia, which was assessed 30 min after EA using von Frey filaments. Beginning on day 13, the response frequency to von Frey filaments (4-15 g) was significantly increased in paclitaxel-injected rats compared to those injected with vehicle. EA at 10 Hz significantly (P<0.05) decreased response frequency at 4-15 g compared to sham EA; EA at 100 Hz only decreased response frequency at 15 g stimulation. Compared to sham EA plus vehicle, EA at 10 Hz plus either a μ, δ, or κ opioid receptor antagonist did not significantly decrease mechanical response frequency, indicating that all three antagonists blocked EA inhibition of allodynia and hyperalgesia. Since we previously demonstrated that μ and δ but not κ opioid receptors affect EA anti-hyperalgesia in an inflammatory pain model, these data show that EA inhibits pain through different opioid receptors under varying conditions. Our data indicate that EA at 10 Hz inhibits mechanical allodynia/hyperalgesia more potently than does EA at 100 Hz. Thus, EA significantly inhibits paclitaxel-induced allodynia/hyperalgesia through spinal opioid receptors, and EA may be a useful complementary treatment for neuropathic pain patients. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of neonatal pain, stress and their interrelation on pain sensitivity in later life in male rats.

PubMed

Butkevich, Irina P; Mikhailenko, Viktor A; Vershinina, Elena A; Aloisi, Anna Maria

2016-08-31

Neonatal pain and stress induce long-term changes in pain sensitivity. Therefore their interrelation is a topical subject of clinical and basic research. The present study investigated the effects of inflammatory peripheral pain and stress of maternal deprivation (MD)-isolation in 1-2- and 7-8-day-old Wistar rats (P1,2 and P7,8 respectively, ages comparable to preterm and full-term human babies) on basal pain and pain sensitivity in conditions of inflammatory pain (formalin test) during adolescence. The neonatal impacts were: pain (formalin injection, FOR in the paw), stress (a short 60-min MD), or pain+stress combination (FOR+MD), and appropriate controls. We found that stress of short-term maternal deprivation-isolation and inflammatory pain on P1,2 and P7,8 significantly increased the vulnerability of the nociceptive system to inflammatory pain. Maternal deprivation-isolation on P1,2 as compared with a similar impact on P7,8 had a greater effect on pain sensitivity of the adolescent rats, but the influence of early pain was independent of the injury age. Only adolescent rats with an early combination of pain and maternal deprivation-isolation showed hypoalgesia in the hot plate (HP) test. However licking duration (reflecting pain sensitivity) in these rats did not exceed licking duration in animals exposed only to maternal deprivation-isolation or pain. This study adds new data to the growing body of work demonstrating that early noxious impacts have long-term consequences for the functional activity of the nociceptive system. Our new findings may help to understand the impact of pain and maternal separation in the neonatal intensive care unit.

Bone mesenchymal stem cells attenuate radicular pain by inhibiting microglial activation in a rat noncompressive disk herniation model.

PubMed

Huang, Xiaodong; Wang, Weiheng; Liu, Xilin; Xi, Yanhai; Yu, Jiangming; Yang, Xiangqun; Ye, Xiaojian

2018-06-01

Spinal disk herniation can induce radicular pain through chemical irritation caused by proinflammatory and immune responses. Bone marrow mesenchymal stem cells (BMSCs) are a unique type of adult stem cell with the functions of suppressing inflammation and modulating immune responses. This study was undertaken to observe the effect of intrathecal BMSCs on the treatment of mechanical allodynia and the suppression of microglial activation in a rat noncompressive disk herniation model. The model was induced by the application of nucleus pulposus (NP) to the L5 dorsal root ganglion (DRG). The study found that the use of NP in the DRG can induce abnormal mechanical pain, increase the contents of the proinflammatory factors TNF-α and IL-1β, decrease the content of the anti-inflammatory cytokine TGF-β1 and activate microglia in the spinal dorsal horns (L5) (P < 0.05). BMSC administration could increase the mechanical withdrawal thresholds dramatically, decrease the contents of IL-1β and TNF-α, increase the content of TGF-β1 significantly (P < 0.05) and inhibit microglial activation in the bilateral spinal dorsal horn. Our results indicate that BMSC administration can reduce mechanical allodynia and downregulate the expression of proinflammatory cytokines by inhibiting microglial activation in the spinal dorsal horn in a rat noncompressive disk herniation model.

Coregulation of endoplasmic reticulum stress and oxidative stress in neuropathic pain and disinhibition of the spinal nociceptive circuitry.

PubMed

Ge, Yanhu; Jiao, Yingfu; Li, Peiying; Xiang, Zhenghua; Li, Zhi; Wang, Long; Li, Wenqian; Gao, Hao; Shao, Jiayun; Wen, Daxiang; Yu, Weifeng

2018-05-01

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen leads to ER stress, which is related to cellular reactive oxygen species production. Neuropathic pain may result from spinal dorsal horn (SDH) ER stress. In this study, we examined the cause-effect relationship between ER stress and neuropathic pain using the spinal nerve ligation (SNL) rat model. We showed that ER stress was mutually promotive with oxidative stress during the process. We also tested the hypothesis that spinal sensitization arose from reduced activities of GABA-ergic interneurons and that spinal sensitization was mediated by SDH ER stress. Other important findings in this study including the following: (1) nociceptive behavior was alleviated in SNL rat as long as tauroursodeoxycholic acid injections were repeated to inhibit ER stress; (2) inducing SDH ER stress in healthy rat resulted in mechanical hyperalgesia; (3) blocking protein disulfide isomerase pharmacologically reduced ER stress and nociceptive behavior in SNL rat; (4) cells in the dorsal horn with elevated ER stress were mainly neurons; and (5) whole-cell recordings made in slide preparations revealed significant inhibition of GABA-ergic interneuron activity in the dorsal horn with ER stress vs in the healthy dorsal horn. Taken together, results of the current study demonstrate that coregulation of ER stress and oxidative stress played an important role in neuropathic pain process. Inhibiting SDH ER stress could be a potential novel strategy to manage neuropathic pain.

Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons.

PubMed

Taha, Omneya; Opitz, Thoralf; Mueller, Marcus; Pitsch, Julika; Becker, Albert; Evert, Bernd Oliver; Beck, Heinz; Jeub, Monika

2017-11-01

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na + current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na + currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na + channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals. Copyright © 2017 Elsevier Inc. All rights reserved.

Muscarinic receptor activation potentiates the effect of spinal cord stimulation on pain-related behavior in rats with mononeuropathy.

PubMed

Song, Zhiyang; Meyerson, Björn A; Linderoth, Bengt

2008-05-02

Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. Our previous animal experiments performed on rat models of SCS and ensuing clinical trials have demonstrated that intrathecal (i.t.) administration of subeffective doses of certain drugs may enhance the pain relieving effect of SCS in cases with unsatisfactory SCS outcome. Recently, an augmented release of spinal acetylcholine acting on muscarinic receptors has been shown to be one of the mechanisms involved in SCS. The present study was performed to examine whether cold hypersensitivity and heat hyperalgesia in rats with partial sciatic nerve injuries can be attenuated by SCS in the same way as tactile hypersensitivity and to explore a possibly synergistic effect of SCS and a muscarinic receptor agonist, oxotremorine. Rats with signs of neuropathy were subjected to SCS applied in awake, freely moving condition. Oxotremorine was administered intrathecally. Tactile, cold and heat sensitivities were assessed by using von Frey filaments, cold spray and focused radiant heat, respectively. Oxotremorine i.t. dose-dependently suppressed the tactile hypersensitivity. SCS markedly increased withdrawal thresholds (WTs), withdrawal latencies and cold scores. When combining SCS with a subeffective dose of oxotremorine i.t., the suppressive effect of SCS on the pain-related symptoms was dramatically enhanced in rats failing to obtain a satisfactory effect with SCS alone. In conclusion, the combination of SCS and a drug with selective muscarinic receptor agonistic properties could be an optional therapy, when SCS per se has proven inefficient.

Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats.

PubMed

Sufka, Kenneth J; Staszko, Stephanie M; Johnson, Ainslee P; Davis, Morgan E; Davis, Rachel E; Smitherman, Todd A

2016-01-01

This research sought to further validate the rat nitroglycerin (NTG) migraine model by comparing the effects of single versus recurrent NTG episodes on behavioral endpoints that mirror ICHD-3 diagnostic criteria for migraine, and to determine if the altered behavioral endpoints are reduced after administration of sumatriptan. Separate cohorts of rats were administered NTG (10 mg/kg/2 ml) or saline (Experiment 1: single injection; Experiment 2: repeated injections; Experiment 3: repeated injections with sumatriptan [0.0, 0.3 and 1.0 mg/kg/ml] rescue. Behavioral endpoints were assessed 2 h after final NTG administration and included time in light/dark chambers for photophobia and activity, pain facial ratings, and cool (5 °C) and warm (46 °C) tail dip. The first two experiments demonstrated that repeated (n = 5) but not single NTG injections produced photophobia, decreased activity, and yielded less weight gain than saline injections. Experiment 3 showed that sumatriptan attenuated hypoactivity, reduced facial expressions of pain, and reversed weight alterations in a dose-dependent manner. These findings identify numerous clinical homologies of a recurrent NTG rat migraine model that may be useful for screening novel pharmacotherapies.

Intrathecal transplantation of neuroblastoma cells decreases heat hyperalgesia and cold allodynia in a rat model of neuropathic pain.

PubMed

De la Calle, J L; Mena, M A; González-Escalada, J R; Paíno, C L

2002-11-30

Intrathecal grafting of cells as biological pumps to deliver monoamines, endorphins, and/or trophic factors, has been shown to be effective in treating chronic pain both in experimental animals and in clinical trials. We have tested whether intrathecal implantation of neuroblastoma cells reduces heat hyperalgesia and cold allodynia in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Behavioral tests and cerebrospinal fluid (CSF) collection were performed before CCI, 1 week later (after which, vehicle or NB69 cells were intrathecally injected) and at 4, 7, and 14 days post-injection. Both CSF sampling and injection of the cells were performed by direct lumbar puncture. Intrathecal grafting of 4 x 10(6) NB69 neuroblastoma cells reduced to basal levels the nociceptive response to heat in nerve-injured hindpaws, while the response of control limbs remained unchanged. Similarly, the allodynic response to cold elicited by acetone evaporation decreased in the animals implanted with NB69 cells. An increase in the concentrations of dopamine and serotonin metabolites of around 150% was observed in the CSF of animals that received grafts of NB69 cells. These data suggest that the monoamines released by NB69 cells in the intrathecal space produce analgesia to neuropathic pain in rats. Copyright 2002 Elsevier Science Inc.

Further characterisation of a rat model of varicella zoster virus (VZV)-associated pain

PubMed Central

Hasnie, F. S.; Breuer, J.; Parker, S.; Wallace, V.; Blackbeard, J.; Lever, I.; Kinchington, P.R.; Dickenson, A. H.; Pheby, T.; Rice, A. S. C.

2007-01-01

Persistent herpes zoster-associated pain is a significant clinical problem and an area of largely unmet therapeutic need. Progress in elucidating the underlying pathophysiology of zoster-associated pain and related co-morbidity behaviour, in addition to appropriately targeted drug development has been hindered by the lack of an appropriate animal model. This study further characterises a recently developed rat model of zoster-associated hypersensitivity and investigates (a) response to different viral strains; (b) relationship between viral inoculum concentration (‘dose’) and mechanical hypersensitivity (‘response’); (c) attenuation of virus-associated mechanical hypersensitivity by clinically useful analgesic drugs; and (d) measurement of pain co-morbidity (anxiety-like behaviour) and pharmacological intervention in the open field paradigm (in parallel with models of traumatic peripheral nerve injury). VZV was propagated on fibroblast cells before subcutaneous injection into the glabrous footpad of the left hind limb of adult male Wistar rats. Control animals received injection of uninfected fibroblast cells. Hind-limb reflex withdrawal thresholds to mechanical, noxious thermal and cooling stimuli were recorded at specified intervals post-infection. Infection with all viral strains was associated with a dose-dependent mechanical hypersensitivity but not a thermal or cool hypersensitivity. Systemic treatment with intraperitoneal (i.p.) morphine (2.5mg/kg), amitriptyline (10mg/kg), gabapentin (30mg/kg), (S)-(+)-ibuprofen (20mg/kg) and the cannnabinoid WIN55,212-2 (2mg/kg) but not the antiviral, acyclovir (50mg/kg), was associated with a reversal of mechanical paw withdrawal thresholds. In the open field paradigm, virus-infected and nerve-injured animals demonstrated an anxiety-like pattern of ambulation (reduced entry into the central area of the open arena) which was positively correlated with mechanical hypersensitivity. This may reflect pain-related comorbidity. Further, anxiety-like behaviour was attenuated by acute i.p. administration of gabapentin (30mg/kg) in nerve-injured, but not virus-infected animals. This model will prove useful in elucidating the pathophysiology of zoster-associated pain and provide a tool for pre-clinical screening of analgesic drugs. PMID:17197105

Flurbiprofen in rapid eye movement sleep deprivation induced hyperalgesia.

PubMed

Gürel, Elif Ezgi; Ural, Keremcan; Öztürk, Gülnur; Öztürk, Levent

2014-04-10

Rapid eye movement (REM) sleep deprivation induces hyperalgesia in healthy rats. Here, we evaluated the effects of flurbiprofen, an anti-inflammatory and neuroprotective agent, on the increased thermal responses observed in REM sleep deprived rats. Forty female rats were divided into four groups following 96-hour REM sleep deprivation: intraperitoneal injections of placebo, and flurbiprofen 5 mg/kg, 15 mg/kg and 40 mg/kg were made in CONT (n=10), FBP5, FBP15 and FBP40 groups respectively. Pain threshold measurements were performed three times at baseline (0.hour), at the end of REM sleep deprivation (96.hour) and at 1 h after injections (97.hour) by hot plate and tail-flick tests. REM sleep deprivation induced a significant decrease in pain thresholds of all rats (hotplate: 0.hour vs 96.hour, 9.75±2.85 vs 5.10±2.02, p<0.001; tail flick: 0.hour vs 96.hour, 11.92±4.62 vs 7.92±5.15, p<0.001). Flurbiprofen in 15 mg/kg and 40 mg/kg doses significantly improved pain tolerance measured by tail flick test (tail flick in FBP15 and FBP40 groups: 96.hour vs 97.hour, 7.01±4.97 vs 8.34±3.61 and 5.06±1.57 vs 7.04±2.49, p<0.05 for both). 96 h of REM sleep deprivation resulted in reduced pain thresholds in both hot plate and tail flick tests. Flurbiprofen was used for the first time in a rat model of REM sleep deprivation, and it provided anti-nociceptive effects in 15 mg/kg and 40 mg/kg doses. Flurbiprofen may have the potential for treatment of painful syndromes accompanying insomnia or sleep loss. Copyright © 2014 Elsevier Inc. All rights reserved.

HDAC inhibition inhibits brachial plexus avulsion induced neuropathic pain.

PubMed

Zhao, Yingbo; Wu, Tianjian

2018-05-09

Introduction Neuropathic pain induced by brachial plexus avulsion (BPA) is a pathological condition. We hypothesized that inhibition of histone deacetylase (HDAC) could suppress BPA-induced neuropathic pain through inhibition of transient reception potential (TRP) overexpression and protein kinase B (Akt) mediated mammalian target of rapamycin (mTOR) activation. Methods We generated a rat BPA model, administered HDAC inhibitor Tricostatin A (TSA) for 7 days post-surgery and assessed the effects on HDAC expression, Akt phosphorylation, neuroinflammation and mTOR activation. Results TSA treatment alleviated BPA induced mechanical hyperalgesia, suppressed Akt phosphorylation and increased HDAC. We found suppressed pro-inflammatory cytokine levels, TRP cation channel subfamily V member 1 (TRPV1) and TRP melastatin 8 (TRPM8) expression and mTOR activity in TSA treated BPA rats. Discussion Our results suggest that altered HDAC and Akt signaling are involved in BPA-induced neuropathic pain and that inhibition of HDAC could be an effective therapeutic approach in reducing neuropathic pain. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Evaluating Intra-Articular Drug Delivery for the Treatment of Osteoarthritis in a Rat Model

PubMed Central

Allen, Kyle D.; Adams, Samuel B.

2010-01-01

Osteoarthritis (OA) is a degenerative joint disease that can result in joint pain, loss of joint function, and deleterious effects on activity levels and lifestyle habits. Current therapies for OA are largely aimed at symptomatic relief and may have limited effects on the underlying cascade of joint degradation. Local drug delivery strategies may provide for the development of more successful OA treatment outcomes that have potential to reduce local joint inflammation, reduce joint destruction, offer pain relief, and restore patient activity levels and joint function. As increasing interest turns toward intra-articular drug delivery routes, parallel interest has emerged in evaluating drug biodistribution, safety, and efficacy in preclinical models. Rodent models provide major advantages for the development of drug delivery strategies, chiefly because of lower cost, successful replication of human OA-like characteristics, rapid disease development, and small joint volumes that enable use of lower total drug amounts during protocol development. These models, however, also offer the potential to investigate the therapeutic effects of local drug therapy on animal behavior, including pain sensitivity thresholds and locomotion characteristics. Herein, we describe a translational paradigm for the evaluation of an intra-articular drug delivery strategy in a rat OA model. This model, a rat interleukin-1β overexpression model, offers the ability to evaluate anti-interleukin-1 therapeutics for drug biodistribution, activity, and safety as well as the therapeutic relief of disease symptoms. Once the action against interleukin-1 is confirmed in vivo, the newly developed anti-inflammatory drug can be evaluated for evidence of disease-modifying effects in more complex preclinical models. PMID:19943805

Low dose native type II collagen prevents pain in a rat osteoarthritis model

PubMed Central

2013-01-01

Background Osteoarthritis is the most widespread joint-affecting disease. Patients with osteoarthritis experience pain and impaired mobility resulting in marked reduction of quality of life. A progressive cartilage loss is responsible of an evolving disease difficult to treat. The characteristic of chronicity determines the need of new active disease modifying drugs. Aim of the present research is to evaluate the role of low doses of native type II collagen in the rat model of osteoarthritis induced by sodium monoiodoacetate (MIA). Methods 1, 3 and 10 mg kg-1 porcine native type II collagen were daily per os administered for 13 days starting from the day of MIA intra-articular injection. Results On day 14, collagen-treated rats showed a significant prevention of pain threshold alterations induced by MIA. Evaluation were performed on paws using mechanical noxious (Paw pressure test) or non-noxious (Electronic Von Frey test) stimuli, and a decrease of articular pain was directly measured on the damaged joint (PAM test). The efficacy of collagen in reducing pain was as higher as the dose was lowered. Moreover, a reduced postural unbalance, measured as hind limb weight bearing alterations (Incapacitance test), and a general improvement of motor activity (Animex test) were observed. Finally, the decrease of plasma and urine levels of CTX-II (Cross Linked C-Telopeptide of Type II Collagen), a biomarker of cartilage degradation, suggests a collagen-dependent decrease of structural joint damage. Conclusions These results describe the preclinical efficacy of low dosages of native type II collagen as pain reliever by a mechanism that involves a protective effect on cartilage. PMID:23915264

Development and pharmacological characterization of a model of sleep disruption-induced hypersensitivity in the rat.

PubMed

Wodarski, R; Schuh-Hofer, S; Yurek, D A; Wafford, K A; Gilmour, G; Treede, R-D; Kennedy, J D

2015-04-01

Sleep disturbance is a commonly reported co-morbidity in chronic pain patients, and conversely, disruption of sleep can cause acute and long-lasting hypersensitivity to painful stimuli. The underlying mechanisms of sleep disruption-induced pain hypersensitivity are poorly understood. Confounding factors of previous studies have been the sleep disruption protocols, such as the 'pedestal over water' or 'inverted flower pot' methods, that can cause large stress responses and therefore may significantly affect pain outcome measures. Sleep disruption was induced by placing rats for 8 h in a slowly rotating cylindrical cage causing arousal via the righting reflex. Mechanical (Von Frey filaments) and thermal (Hargreaves) nociceptive thresholds were assessed, and plasma corticosterone levels were measured (mass spectroscopy). Sleep disruption-induced hypersensitivity was pharmacologically characterized with drugs relevant for pain treatment, including gabapentin (30 mg/kg and 50 mg/kg), Ica-6p (Kv7.2/7.3 potassium channel opener; 10 mg/kg), ibuprofen (30 mg/kg and 100 mg/kg) and amitriptyline (10 mg/kg). Eight hours of sleep disruption caused robust mechanical and heat hypersensitivity in the absence of a measurable change in plasma corticosterone levels. Gabapentin had no effect on reduced nociceptive thresholds. Ibuprofen attenuated mechanical thresholds, while Ica-6p and amitriptyline attenuated only reduced thermal nociceptive thresholds. These results show that acute and low-stress sleep disruption causes mechanical and heat hypersensitivity in rats. Mechanical and heat hypersensitivity exhibited differential sensitivity to pharmacological agents, thus suggesting dissociable mechanisms for those two modalities. Ultimately, this model could help identify underlying mechanisms linking sleep disruption and hypersensitivity. © 2014 European Pain Federation - EFIC®

Orofacial inflammatory pain affects the expression of MT1 and NADPH-d in rat caudal spinal trigeminal nucleus and trigeminal ganglion

PubMed Central

Huang, Fang; He, Hongwen; Fan, Wenguo; Liu, Yongliang; Zhou, Hongyu; Cheng, Bin

2013-01-01

Very little is known about the role of melatonin in the trigeminal system, including the function of melatonin receptor 1. In the present study, adult rats were injected with formaldehyde into the right vibrissae pad to establish a model of orofacial inflammatory pain. The distribution of melatonin receptor 1 and nicotinamide adenine dinucleotide phosphate diaphorase in the caudal spinal trigeminal nucleus and trigeminal ganglion was determined with immunohistochemistry and histochemistry. The results show that there are significant differences in melatonin receptor 1 expression and nicotinamide adenine dinucleotide phosphate diaphorase expression in the trigeminal ganglia and caudal spinal nucleus during the early stage of orofacial inflammatory pain. Our findings suggest that when melatonin receptor 1 expression in the caudal spinal nucleus is significantly reduced, melatonin's regulatory effect on pain is attenuated. PMID:25206619

The Rat Grimace Scale: A partially automated method for quantifying pain in the laboratory rat via facial expressions

PubMed Central

2011-01-01

We recently demonstrated the utility of quantifying spontaneous pain in mice via the blinded coding of facial expressions. As the majority of preclinical pain research is in fact performed in the laboratory rat, we attempted to modify the scale for use in this species. We present herein the Rat Grimace Scale, and show its reliability, accuracy, and ability to quantify the time course of spontaneous pain in the intraplantar complete Freund's adjuvant, intraarticular kaolin-carrageenan, and laparotomy (post-operative pain) assays. The scale's ability to demonstrate the dose-dependent analgesic efficacy of morphine is also shown. In addition, we have developed software, Rodent Face Finder®, which successfully automates the most labor-intensive step in the process. Given the known mechanistic dissociations between spontaneous and evoked pain, and the primacy of the former as a clinical problem, we believe that widespread adoption of spontaneous pain measures such as the Rat Grimace Scale might lead to more successful translation of basic science findings into clinical application. PMID:21801409

Intrathecal [6]-gingerol administration alleviates peripherally induced neuropathic pain in male Sprague-Dawley rats.

PubMed

Gauthier, Marie-Lou; Beaudry, Francis; Vachon, Pascal

2013-08-01

[6]-Gingerol, a structural analog of capsaicin, is an agonist of the transient receptor potential vanilloid 1 channel, which is known to have therapeutic properties for the treatment of pain and inflammation. The main objective of this study was to determine the central effect of [6]-gingerol on neuropathic pain when injected intrathecally at the level of the lumbar spinal cord. [6]-Gingerol distribution was evaluated following a 40 mg/kg intraperitoneal injection, and the brain-to-plasma and spinal cord-to-plasma ratios (0.73 and 1.7, respectively) suggest that [6]-gingerol penetrates well the central nervous system of rats. Induction of pain was performed using the sciatic nerve ligation model on rats, and a 10-µg intrathecal injections of [6]-gingerol was performed to evaluate its central effect. The results suggest a significant decrease of secondary mechanical allodynia after 30 min, 2 h and 4 h (p < 0.05, p < 0.01 and p < 0.001) and thermal hyperalgesia after 30 min, 2 h and 4 h (p < 0.05, p < 0.01 and p < 0.01). These promising results illustrate that [6]-gingerol could alleviate neuropathic pain by acting centrally at the level of the spinal cord. Copyright © 2012 John Wiley & Sons, Ltd.

Inhibitory effects of aspirin-triggered resolvin D1 on spinal nociceptive processing in rat pain models.

PubMed

Meesawatsom, Pongsatorn; Burston, James; Hathway, Gareth; Bennett, Andrew; Chapman, Victoria

2016-09-02

Harnessing the actions of the resolvin pathways has the potential for the treatment of a wide range of conditions associated with overt inflammatory signalling. Aspirin-triggered resolvin D1 (AT-RvD1) has robust analgesic effects in behavioural models of pain; however, the potential underlying spinal neurophysiological mechanisms contributing to these inhibitory effects in vivo are yet to be determined. This study investigated the acute effects of spinal AT-RvD1 on evoked responses of spinal neurones in vivo in a model of acute inflammatory pain and chronic osteoarthritic (OA) pain and the relevance of alterations in spinal gene expression to these neurophysiological effects. Pain behaviour was assessed in rats with established carrageenan-induced inflammatory or monosodium iodoacetate (MIA)-induced OA pain, and changes in spinal gene expression of resolvin receptors and relevant enzymatic pathways were examined. At timepoints of established pain behaviour, responses of deep dorsal horn wide dynamic range (WDR) neurones to transcutaneous electrical stimulation of the hind paw were recorded pre- and post direct spinal administration of AT-RvD1 (15 and 150 ng/50 μl). AT-RvD1 (15 ng/50 μl) significantly inhibited WDR neurone responses to electrical stimuli at C- (29 % inhibition) and Aδ-fibre (27 % inhibition) intensities. Both wind-up (53 %) and post-discharge (46 %) responses of WDR neurones in carrageenan-treated animals were significantly inhibited by AT-RvD1, compared to pre-drug response (p < 0.05). These effects were abolished by spinal pre-administration of a formyl peptide receptor 2 (FPR2/ALX) antagonist, butoxy carbonyl-Phe-Leu-Phe-Leu-Phe (BOC-2) (50 μg/50 μl). AT-RvD1 did not alter evoked WDR neurone responses in non-inflamed or MIA-treated rats. Electrophysiological effects in carrageenan-inflamed rats were accompanied by a significant increase in messenger RNA (mRNA) for chemerin (ChemR23) receptor and 5-lipoxygenase-activating protein (FLAP) and a decrease in 15-lipoxygenase (15-LOX) mRNA in the ipsilateral spinal cord of the carrageenan group, compared to controls. Our data suggest that peripheral inflammation-mediated changes in spinal FLAP expression may contribute to the novel inhibitory effects of spinal AT-RvD1 on WDR neuronal excitability, which are mediated by FPR2/ALX receptors. Inflammatory-driven changes in this pathway may offer novel targets for inflammatory pain treatment.

Central Action of Peripherally Applied Botulinum Toxin Type A on Pain and Dural Protein Extravasation in Rat Model of Trigeminal Neuropathy

PubMed Central

Filipović, Boris; Matak, Ivica; Bach-Rojecky, Lidija; Lacković, Zdravko

2012-01-01

Background Infraorbital nerve constriction (IoNC) is an experimental model of trigeminal neuropathy. We investigated if IoNC is accompanied by dural extravasation and if botulinum toxin type A (BoNT/A) can reduce pain and dural extravasation in this model. Methodology/Principal Findings Rats which developed mechanical allodynia 14 days after the IoNC were injected with BoNT/A (3.5 U/kg) into vibrissal pad. Allodynia was tested by von Frey filaments and dural extravasation was measured as colorimetric absorbance of Evans blue - plasma protein complexes. Presence of dural extravasation was also examined in orofacial formalin-induced pain. Unilateral IoNC, as well as formalin injection, produced bilateral dural extravasation. Single unilateral BoNT/A injection bilaterally reduced IoNC induced dural extravasation, as well as allodynia (lasting more than 2 weeks). Similarly, BoNT/A reduced formalin-induced pain and dural extravasation. Effects of BoNT/A on pain and dural extravasation in IoNC model were dependent on axonal transport through sensory neurons, as evidenced by colchicine injections (5 mM, 2 µl) into the trigeminal ganglion completely preventing BoNT/A effects. Conclusions/Significance Two different types of pain, IoNC and formalin, are accompanied by dural extravasation. The lasting effect of a unilateral injection of BoNT/A in experimental animals suggests that BoNT/A might have a long-term beneficial effect in craniofacial pain associated with dural neurogenic inflammation. Bilateral effects of BoNT/A and dependence on retrograde axonal transport suggest a central site of its action. PMID:22238656

Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats.

PubMed

Merlos, Manuel; Portillo-Salido, Enrique; Brenchat, Alex; Aubel, Bertrand; Buxens, Jordi; Fisas, Angels; Codony, Xavier; Romero, Luz; Zamanillo, Daniel; Vela, José Miguel

2018-06-19

Drug combination for the treatment of pain is common clinical practice. Co-crystal of Tramadol-Celecoxib (CTC) consists of two active pharmaceutical ingredients (APIs), namely the atypical opioid tramadol and the preferential cyclooxygenase-2 inhibitor celecoxib, at a 1:1 molecular ratio. In this study, a non-formulated 'raw' form of CTC administered in suspension (referred to as ctc susp ) was compared with both tramadol and celecoxib alone in a rat plantar incision postoperative pain model. For comparison, the strong opioids morphine and oxycodone, and a tramadol plus acetaminophen combination at a molecular ratio of 1:17 were also tested. Isobolographic analyses showed that ctc susp exerted synergistic mechanical antiallodynic (experimental ED 50 =2.0±0.5mg/kg, i.p.; theoretical ED 50 =3.8±0.4mg/kg, i.p.) and thermal (experimental ED 50 =2.3±0.5mg/kg, i.p.; theoretical ED 50 =9.8±0.8mg/kg, i.p.) antihyperalgesic effects in the postoperative pain model. In contrast, the tramadol and acetaminophen combination showed antagonistic effects on both mechanical allodynia and thermal hyperalgesia. No synergies between tramadol and celecoxib on locomotor activity, motor coordination, ulceration potential and gastrointestinal transit were observed after the administration of ctc susp . Overall, rat efficacy and safety data revealed that ctc susp provided synergistic analgesic effects compared with each API alone, without enhancing adverse effects. Moreover, ctc susp showed similar efficacy but improved safety ratio (80, measured as gastrointestinal transit vs postoperative pain ED 50 ratios) compared with the strong opioids morphine (2.5) and oxycodone (5.8). The overall in vivo profile of ctc susp supports the further investigation of CTC in the clinical management of moderate-to-severe acute pain as an alternative to strong opioids. Copyright © 2018. Published by Elsevier B.V.

The Effects of Inflammatory Tooth Pain on Anxiety in Adult Male Rats

PubMed Central

Raoof, Maryam; Ebrahimnejad, Hamed; Abbasnejad, Mehdi; Amirkhosravi, Ladan; Raoof, Ramin; Esmaeili Mahani, Saeed; Ramazani, Mohsen; Shokouhinejad, Noushin; Khoshkhounejad, Mehrfam

2016-01-01

Introduction: This study aimed to examine the effects of induced inflammatory tooth pain on anxiety level in adult male rats. Methods: The mandibular incisors of 56 adult male rats were cut off and prefabricated crowns were fixed on the teeth. Formalin and capsaicin were injected intradentally to induce inflammatory tooth pain. Diazepam treated group received diazepam 30 minutes before intradental injection. The anxiety-related behavior was evaluated with elevated plus maze test. Results: Intradental application of chemical noxious stimuli, capsaicin and formalin, significantly affected nociceptive behaviors (P<0.001). Capsaicin (P<0.001) and formalin (P<0.01) significantly increased the anxiety levels in rats by decrease in the duration of time spent in open arm and increase in the duration of time spent in closed arm. Rats that received capsaicin made fewer open arm entries compared to the control animals (P<0.05). Capsaicin (P<0.001) and formalin (P<0.01) treated rats showed more stretch attend postures compared to the control and sham operated animals. In diazepampretreated rats, capsaicin induced algesic effect was prevented (P<0.001). Conclusion: Inflammatory pulpal pain has anxiogenic effect on rats, whereas diazepam premedication showed both anxiolytic and pain reducing effects. PMID:27563419

Cannabinoid receptor 2 agonist attenuates pain related behavior in rats with chronic alcohol/high fat diet induced pancreatitis.

PubMed

Zhang, Liping; Kline, Robert H; McNearney, Terry A; Johnson, Michael P; Westlund, Karin N

2014-11-17

Chronic Pancreatitis (CP) is a complex and multifactorial syndrome. Many contributing factors result in development of dysfunctional pain in a significant number of patients. Drugs developed to treat a variety of pain states fall short of providing effective analgesia for patients with chronic pancreatitis, often providing minimal to partial pain relief over time with significant side effects. Recently, availability of selective pharmacological tools has enabled great advances in our knowledge of the role of the cannabinoid receptors in pathophysiology. In particular, cannabinoid receptor 2 (CB2) has emerged as an attractive target for management of chronic pain, as demonstrated in several studies with inflammatory and neuropathic preclinical pain models. In this study, the analgesic efficacy of a novel, highly selective CB2 receptor agonist, LY3038404 HCl, is investigated in a chronic pancreatitis pain model, induced with an alcohol/high fat (AHF) diet. Rats fed the AHF diet developed visceral pain-like behaviors detectable by week 3 and reached a maximum at week 5 that persists as long as the diet is maintained. Rats with AHF induced chronic pancreatitis were treated with LY3038404 HCl (10 mg/kg, orally, twice a day for 9 days). The treated animals demonstrated significantly alleviated pain related behaviors after 3 days of dosing, including increased paw withdrawal thresholds (PWT), prolonged abdominal withdrawal latencies (ABWL), and decreased nocifensive responses to noxious 44°C hotplate stimuli. Terminal histological analysis of pancreatic tissue sections from the AHF chronic pancreatitis animals demonstrated extensive injury, including a global pancreatic gland degeneration (cellular atrophy), vacuolization (fat deposition), and fibrosis. After the LY3038404 HCl treatment, pancreatic tissue was significantly protected from severe damage and fibrosis. LY3038404 HCl affected neither open field exploratory behaviors nor dark/light box preferences as measures of higher brain and motor functions. LY3038404 HCl, a potent CB2 receptor agonist, possesses tissue protective and analgesic properties without effects on higher brain function. Thus, activation of CB2 receptors is suggested as a potential therapeutic target for visceral inflammation and pain management.

[Effect of electroacupuncture on phosphorylation of NR2B at Tyr 1742 site in the spinal dorsal horn of CFA rats].

PubMed

Liang, Yi; Fang, Jian-Qiao; Fang, Jun-Fan; Du, Jun-Ying; Qiu, Yu-Jie; Liu, Jin

2013-10-01

To observe the effect of electroacupuncture (EA) on phosphorylation of spinal NR2B at Tyr 1742 site in complete Freund's adjuvant (CFA) induced inflammatory pain rats. METHods Forty male Sprague Dawley rats were randomly divided into normal group (N group, n = 10), the model group (CFA group, n = 15), and the EA group (n = 15). The inflammatory pain model was established by subcutaneous injecting CFA (0.1 mL per rat) into the right hind paw. Paw withdrawal thresholds (PWTs) were measured before CFA injection (as the base), as well as at 24 h, 25 h, 3rd day, and 7th day after CFA injection. Phosphorylation of NR2B at Tyr 1742 site in the ispilateral spinal dorsal horn at the 3rd day post-injection were detected using immunohistochemical assay. PWTs in the CFA group were significantly lower than those of the N group at every detective time point post-injection (P < 0.01). PWTs were obviously lower in the EA group than in the N group at 24 h post-injection (P < 0.01). It showed increasing tendency, markedly higher than those of the CFA group at 25 h and 3rd day post-injection (P < 0.01). Compared with the N group, the ratio of p-NR2B positive cells in the ispilateral spinal dorsal horn of rats in the CFA group was up-regulated. Compared with the CFA group, the ratio of p-NR2B positive cells in the ispilateral spinal dorsal horn of rats showed a decreasing tendency in the EA group. EA might effectively inhibit CFA-induced inflammatory pain possibly associated with down-regulating phosphorylation of NR2B at Tyr 1742 site in the ispilateral spinal dorsal horn.

High-frequency transcutaneous electrical nerve stimulation attenuates postsurgical pain and inhibits excess substance P in rat dorsal root ganglion.

PubMed

Chen, Yu-Wen; Tzeng, Jann-Inn; Lin, Min-Fei; Hung, Ching-Hsia; Hsieh, Pei-Ling; Wang, Jhi-Joung

2014-01-01

Transcutaneous electrical nerve stimulation (TENS) is a common therapeutic modality for pain management, but its effectiveness in skin/muscle incision and retraction (SMIR)-evoked pain is unknown. We aimed to examine the effects of TENS on postoperative pain and the levels of substance P (SP), N-methyl-D-aspartate receptor 1 (NR1), and interleukin 1β (IL-1β) in rat dorsal root ganglion (DRG). High-frequency (100 Hz) TENS was administered daily beginning on postoperative day 1 (POD1) and continued until animal subjects were killed for tissues. Mechanical sensitivity to von Frey stimuli (6g and 15g) and the levels of NR1, SP, and IL-1β in DRG were assessed in the sham-operated, SMIR-operated, TENS after SMIR surgery, and placebo-TENS after SMIR surgery groups. Skin/muscle incision and retraction rats exhibited a significant hypersensitivity to von Frey stimuli on POD3. In contrast with SMIR rats, SMIR-operated rats receiving TENS therapy demonstrated a rapid recovery of mechanical hypersensitivity. The SMIR-operated rats showed an up-regulation of NR1, SP, and IL-1β in DRG on PODs 14 and 28, whereas the SMIR-operated rats after TENS administration reversed this up-regulation. By contrast, the placebo-TENS after SMIR operation did not alter postsurgical pain nor the levels of NR1, SP, and IL-1β. Our data demonstrated that TENS intervention reduced persistent postoperative pain caused by SMIR operation. Up-regulation of NR1, SP, and IL-1β in DRG, activated after SMIR surgery, is important in the development of prolonged postincisional pain. The TENS pain relief may be related to the suppression of NR1, SP, and IL-1β in DRG of SMIR rats.

Hedonic and motivational responses to food reward are unchanged in rats with neuropathic pain

PubMed Central

Okun, Alec; McKinzie, David L.; Witkin, Jeffrey M.; Remeniuk, Bethany; Husein, Omar; Gleason, Scott D.; Oyarzo, Janice; Navratilova, Edita; McElroy, Brian; Cowen, Stephen; Kennedy, Jeffrey D.; Porreca, Frank

2016-01-01

Rewards influence responses to acute painful stimuli, but the relationship of chronic pain to hedonic or motivational aspects of reward is not well understood. Here, we independently evaluated hedonic qualities of sweet or bitter tastants as well as motivation to seek food reward in rats with experimental neuropathic pain induced by L5/6 spinal nerve ligation (SNL). Hedonic response was measured by implantation of intraoral catheters to allow passive delivery of liquid solutions and “liking/disliking” responses were scored according to a facial reactivity scale. SNL rats did not differ from controls in either “liking” or “disliking” reactions to intraoral sucrose or quinine, respectively, at post-surgery day 21, suggesting no differences in perceived hedonic value of sweet or bitter tastants. To assess possible motivational deficits during acute and chronic pain, we employed fixed- and progressive-ratio response paradigms of sucrose pellet presentation in rats with transient inflammatory or chronic neuropathic pain. Assessment of response acquisition and break points under the progressive ratio schedule revealed no differences between sham and SNL rats for up to 120 days post-injury. However, rats with inflammation showed decrements in lever pressing and break points on post-CFA days 1 and 2 that normalized by day 4, consistent with transient ongoing pain. Thus, while acute, ongoing inflammatory pain may transiently reduce reward motivation, we did not detect influences of chronic neuropathic pain on hedonic or motivational responses to food rewards. Adaptations that allow normal reward responding to food regardless of chronic pain may be of evolutionary benefit to promote survival. PMID:27548047

The Effects of a Co-Application of Menthol and Capsaicin on Nociceptive Behaviors of the Rat on the Operant Orofacial Pain Assessment Device

PubMed Central

Anderson, Ethan M.; Jenkins, Alan C.; Caudle, Robert M.; Neubert, John K.

2014-01-01

Background Transient receptor potential (TRP) cation channels are involved in the perception of hot and cold pain and are targets for pain relief in humans. We hypothesized that agonists of TRPV1 and TRPM8/TRPA1, capsaicin and menthol, would alter nociceptive behaviors in the rat, but their opposite effects on temperature detection would attenuate one another if combined. Methods Rats were tested on the Orofacial Pain Assessment Device (OPAD, Stoelting Co.) at three temperatures within a 17 min behavioral session (33°C, 21°C, 45°C). Results The lick/face ratio (L/F: reward licking events divided by the number of stimulus contacts. Each time there is a licking event a contact is being made.) is a measure of nociception on the OPAD and this was equally reduced at 45°C and 21°C suggesting they are both nociceptive and/or aversive to rats. However, rats consumed (licks) equal amounts at 33°C and 21°C but less at 45°C suggesting that heat is more nociceptive than cold at these temperatures in the orofacial pain model. When menthol and capsaicin were applied alone they both induced nociceptive behaviors like lower L/F ratios and licks. When applied together though, the licks at 21°C were equal to those at 33°C and both were significantly higher than at 45°C. Conclusions This suggests that the cool temperature is less nociceptive when TRPM8/TRPA1 and TRPV1 are co-activated. These results suggest that co-activation of TRP channels can reduce certain nociceptive behaviors. These data demonstrate that the motivational aspects of nociception can be influenced selectively by TRP channel modulation and that certain aspects of pain can be dissociated and therefore targeted selectively in the clinic. PMID:24558480

A novel inhibitor of active protein kinase G attenuates chronic inflammatory and osteoarthritic pain.

PubMed

Sung, Ying-Ju; Sofoluke, Nelson; Nkamany, Mary; Deng, Shixian; Xie, Yuli; Greenwood, Jeremy; Farid, Ramy; Landry, Donald W; Ambron, Richard T

2017-05-01

Activating PKG-1α induces a long-term hyperexcitability (LTH) in nociceptive neurons. Since the LTH correlates directly with chronic pain in many animal models, we tested the hypothesis that inhibiting PKG-1α would attenuate LTH-mediated pain. We first synthesized and characterized compound N46 (N-((3R,4R)-4-(4-(2-fluoro-3-methoxy-6-propoxybenzoyl)benzamido)pyrrolidin-3-yl)-1H-indazole-5-carboxamide). N46 inhibits PKG-1α with an IC50 of 7.5 nmol, was highly selective when tested against a panel of 274 kinases, and tissue distribution studies indicate that it does not enter the CNS. To evaluate its antinociceptive potential, we used 2 animal models in which the pain involves both activated PKG-1α and LTH. Injecting complete Freund's adjuvant (CFA) into the rat hind paw causes a thermal hyperalgesia that was significantly attenuated 24 hours after a single intravenous injection of N46. Next, we used a rat model of osteoarthritic knee joint pain and found that a single intra-articular injection of N46 alleviated the pain 14 days after the pain was established and the relief lasted for 7 days. Thermal hyperalgesia and osteoarthritic pain are also associated with the activation of the capsaicin-activated transient receptor protein vanilloid-1 (TRPV1) channel. We show that capsaicin activates PKG-1α in nerves and that a subcutaneous delivery of N46 attenuated the mechanical and thermal hypersensitivity elicited by exposure to capsaicin. Thus, PKG-1α appears to be downstream of the transient receptor protein vanilloid-1. Our studies provide proof of concept in animal models that a PKG-1α antagonist has a powerful antinociceptive effect on persistent, already existing inflammatory pain. They further suggest that N46 is a valid chemotype for the further development of such antagonists.

Effects of intermedin on dorsal root ganglia in the transmission of neuropathic pain in chronic constriction injury rats.

PubMed

Xiong, Wei; Qiu, Shu-yi; Xu, Ling-yun; Zhang, Chun-ping; Yi, Yun; Wu, Qin; Huang, Li-ping; Liu, Shuang-mei; Wu, Bing; Peng, Li-chao; Song, Miao-miao; Gao, Yun; Liang, Shang-dong

2015-07-01

Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. The P2X3 receptor plays a crucial role in facilitating pain transmission. Intermedin (IMD), which is also known as adrenomedullin 2 (AMD2) is a newly discovered hormone that is a member of the calcitonin/calcitonin gene-related peptide family. The present research investigates the effects of IMD on pain transmission in neuropathic pain states as mediated by P2X3 receptors in dorsal root ganglia (DRG). Chronic constriction injury (CCI) rats were used as the neuropathic pain model. Adult male Sprague-Dawley rats were randomly assigned to five groups as follows: blank control group (Control), sham operation group (Sham), CCI rats treated with saline group (CCI+NS), CCI rats treated with IMD1-53 group (CCI+IMD1-53 ), and CCI rats treated with IMD inhibitor IMD14-47 group (CCI+IMD14-47 ). The mechanical withdrawal threshold (MWT) was tested by the von Frey method, and the thermal withdrawal latency (TWL) was tested via automatic thermal stimulus instruments. Changes in the expression of P2X3 receptors and IMD in CCI rat L4/L5 DRG were detected using immunohistochemistry, reverse transcription-polymerase chain reaction, and Western blotting. After treatment with intrathecal injection (i.t.), mechanical and thermal hyperalgesia in the CCI+IMD1-53 group was maintained, but MWT and TWL in the CCI+IMD14-47 groups increased. The expression levels of P2X3 receptors and IMD in L4/L5 DRG in the CCI+NS and CCI+IMD1-53 groups were significantly increased compared with those in the Control group or the Sham group. After application of IMD14-47 in CCI rats, there was a decrease in the expression levels of P2X3 receptors and IMD in L4/L5 DRG. The phosphorylation of p38 and ERK1/2 in L4/L5 DRG in the CCI+NS group and the CCI+IMD1-53 group was stronger than that in the Control group or the Sham group; however, the phosphorylation of p38 and ERK1/2 in the CCI+IMD14-47 group was much lower than that in the CCI+NS group or the CCI+IMD1-53 group. Our findings indicate that IMD might increase the sensitization effects of IMD on P2X3 receptors to alleviate chronic neuropathic pain injury. The IMD agonist IMD1-53 might enhance nociceptive responses mediated by P2X3 receptors in neuropathic pain, and the IMD inhibitor IMD14-47 could inhibit the sensitization of the P2X3 receptor in chronic neuropathic pain injury. © 2015 Wiley Publishing Asia Pty Ltd.

Home cage wheel running is an objective and clinically relevant method to assess inflammatory pain in male and female rats

PubMed Central

Kandasamy, Ram; Calsbeek, Jonas J.; Morgan, Michael M.

2016-01-01

Background The assessment of nociception in preclinical studies is undergoing a transformation from pain-evoked to pain-depressed tests to more closely mimic the effects of clinical pain. Many inflammatory pain-depressed behaviors (reward seeking, locomotion) have been examined, but these tests are limited because of confounds such as stress and difficulties in quantifying behavior. New Method The present study evaluates home cage wheel running as an objective method to assess the magnitude and duration of inflammatory pain in male and female rats. Results Injection of Complete Freund’s Adjuvant (CFA) into the right hindpaw to induce inflammatory pain almost completely inhibited wheel running for 2 days in males and females. Wheel running gradually returned to baseline levels within 12 days despite persistent mechanical hypersensitivity (von Frey test). Comparison with Existing Methods Continuously monitoring home cage wheel running improves on previous studies examining inflammatory pain-depressed wheel running because it is more sensitive to noxious stimuli, avoids the stress of removing the rat from its cage for testing, and provides a complete analysis of the time course for changes in nociception. Conclusions The present data indicate that home cage wheel running is a clinically relevant method to assess inflammatory pain in the rat. The decrease in activity caused by inflammatory pain and subsequent gradual recovery mimics the changes in activity caused by pain in humans. The tendency for pain-depressed wheel running to be greater in female than male rats is consistent with the tendency for women to be at greater risk of chronic pain than men. PMID:26891874

Preemptive Caffeine Administration Blocks the Increase in Postoperative Pain Caused by Previous Sleep Loss in the Rat: A Potential Role for Preoptic Adenosine A2A Receptors in Sleep-Pain Interactions.

PubMed

Hambrecht-Wiedbusch, Viviane S; Gabel, Maya; Liu, Linda J; Imperial, John P; Colmenero, Angelo V; Vanini, Giancarlo

2017-09-01

Sleep and pain are reciprocally related, but the precise mechanisms underlying this relationship are poorly understood. This study used a rat model of surgical pain to examine the effect of previous sleep loss on postoperative pain and tested the hypothesis that preoptic adenosinergic mechanisms regulate sleep-pain interactions. Relative to ad libitum sleep, 6 hours of total sleep deprivation prior to a surgical incision significantly enhanced postoperative mechanical hypersensitivity in the affected paw and prolonged the time to recovery from surgery. There were no sex-specific differences in these measures. There were also no changes in adrenocorticotropic hormone and corticosterone levels after sleep deprivation, suggesting that this effect was not mediated by the stress associated with the sleep perturbation. Systemic administration of the nonselective adenosine receptor antagonist caffeine at the onset of sleep deprivation prevented the sleep deprivation-induced increase in postoperative hypersensitivity. Microinjection of the adenosine A2A receptor antagonist ZM 241385 into the median preoptic nucleus (MnPO) blocked the increase in surgical pain levels and duration caused by prior sleep deprivation and eliminated the thermal hyperalgesia induced by sleep deprivation in a group of nonoperated (i.e., without surgical incision) rats. These data show that even a brief sleep disturbance prior to surgery worsens postoperative pain and are consistent with our hypothesis that adenosine A2A receptors in the MnPO contribute to regulate these sleep-pain interactions. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Efficacy of Various Analgesics on Shoulder Function and Rotator Cuff Tendon-to-Bone Healing in a Rat (Rattus norvegicus) Model

PubMed Central

Caro, Adam C; Tucker, Jennica J; Yannascoli, Sarah M; Dunkman, Andrew A; Thomas, Stephen J; Soslowsky, Louis J

2014-01-01

Although relief of postoperative pain is an imperative aspect of animal welfare, analgesics that do not interfere with the scientific goals of the study must be used. Here we compared the efficacy of different analgesic agents by using an established rat model of supraspinatus tendon healing and a novel gait-analysis system. We hypothesized that different analgesic agents would all provide pain relief in this model but would cause differences in tendon-to-bone healing and gait parameters. Buprenorphine, ibuprofen, tramadol–gabapentin, and acetaminophen were compared with a no-analgesia control group. Gait measures (stride length and vertical force) on the operative forelimb differed between the control group and both the buprenorphine (2 and 4 d postsurgery) and ibuprofen (2 d postsurgery) groups. Step length was different in the control group as compared with the tramadol–gabapentin (2 d after surgery), buprenorphine (2 and 4 d after surgery), and ibuprofen (2 d after surgery) groups. Regarding tendon-to-bone healing, the ibuprofen group showed less stiffness at the insertion site; no other differences in tendon-to-bone healing were detected. In summary, the analgesics evaluated were associated with differences in both animal gait and tendon-to-bone healing. This information will be useful for improving the management of postsurgical pain without adversely affecting tissue healing. Given its ability to improve gait without impeding healing, we recommend use of buprenorphine for postsurgical pain management in rats. In addition, our gait-analysis system can be used to evaluate new analgesics. PMID:24602546

Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder.

PubMed

Zhang, Y; Simpson-Durand, C D; Standifer, K M

2015-01-01

Single-prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), also induces long-lasting hyperalgesia associated with hypocortisolism and elevated nociceptin/orphanin FQ (N/OFQ) levels in serum and CSF. Here, we determined the effect of JTC-801 (N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride), a nociceptin/orphanin FQ peptide (NOP) receptor antagonist, on symptoms of pain and anxiety in rats after SPS exposure, and examined N/OFQ-NOP receptor system changes. Male Sprague Dawley rats received JTC-801 (6 mg kg(-1) i.p., once daily) during days 7-21 of SPS. The ability of JTC-801 to inhibit N/OFQ-stimulated [(35) S]-GTPγS binding was confirmed in rat brain membranes. Anxiety-like behaviour and pain sensitivity were monitored by changes in elevated plus maze performance and withdrawal responses to thermal and mechanical stimuli. Serum corticosterone and N/OFQ content in CSF, serum and brain tissues were determined by radioimmunoassay; NOP receptor protein and gene expression in amygdala, hippocampus and periaqueductal grey (PAG) were examined by immunoblotting and real-time PCR respectively. JTC-801 treatment reversed SPS-induced mechanical allodynia, thermal hyperalgesia, anxiety-like behaviour and hypocortisolism. Elevated N/OFQ levels in serum, CSF, PAG and hippocampus at day 21 of SPS were blocked by JTC-801; daily JTC-801 treatment also reversed NOP receptor protein and mRNA up-regulation in amygdala and PAG. JTC-801 reversed SPS-induced anxiety- and pain-like behaviours, and NOP receptor system up-regulation. These findings suggest that N/OFQ plays an important role in hyperalgesia and allodynia maintenance after SPS. NOP receptor antagonists may provide effective treatment for co-morbid PTSD and pain. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder

PubMed Central

Zhang, Y; Simpson-Durand, C D; Standifer, K M

2015-01-01

BACKGROUND AND PURPOSE Single-prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), also induces long-lasting hyperalgesia associated with hypocortisolism and elevated nociceptin/orphanin FQ (N/OFQ) levels in serum and CSF. Here, we determined the effect of JTC-801 (N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride), a nociceptin/orphanin FQ peptide (NOP) receptor antagonist, on symptoms of pain and anxiety in rats after SPS exposure, and examined N/OFQ-NOP receptor system changes. EXPERIMENTAL APPROACH Male Sprague Dawley rats received JTC-801 (6 mg kg−1 i.p., once daily) during days 7–21 of SPS. The ability of JTC-801 to inhibit N/OFQ-stimulated [35S]-GTPγS binding was confirmed in rat brain membranes. Anxiety-like behaviour and pain sensitivity were monitored by changes in elevated plus maze performance and withdrawal responses to thermal and mechanical stimuli. Serum corticosterone and N/OFQ content in CSF, serum and brain tissues were determined by radioimmunoassay; NOP receptor protein and gene expression in amygdala, hippocampus and periaqueductal grey (PAG) were examined by immunoblotting and real-time PCR respectively. KEY RESULTS JTC-801 treatment reversed SPS-induced mechanical allodynia, thermal hyperalgesia, anxiety-like behaviour and hypocortisolism. Elevated N/OFQ levels in serum, CSF, PAG and hippocampus at day 21 of SPS were blocked by JTC-801; daily JTC-801 treatment also reversed NOP receptor protein and mRNA up-regulation in amygdala and PAG. CONCLUSION AND IMPLICATIONS JTC-801 reversed SPS-induced anxiety- and pain-like behaviours, and NOP receptor system up-regulation. These findings suggest that N/OFQ plays an important role in hyperalgesia and allodynia maintenance after SPS. NOP receptor antagonists may provide effective treatment for co-morbid PTSD and pain. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24666365

Localized Sympathectomy Reduces Mechanical Hypersensitivity by Restoring Normal Immune Homeostasis in Rat Models of Inflammatory Pain

PubMed Central

Xie, Wenrui; Chen, Sisi; Strong, Judith A.; Li, Ai-Ling; Lewkowich, Ian P.

2016-01-01

Some forms of chronic pain are maintained or enhanced by activity in the sympathetic nervous system (SNS), but attempts to model this have yielded conflicting findings. The SNS has both pro- and anti-inflammatory effects on immunity, confounding the interpretation of experiments using global sympathectomy methods. We performed a “microsympathectomy” by cutting the ipsilateral gray rami where they entered the spinal nerves near the L4 and L5 DRG. This led to profound sustained reductions in pain behaviors induced by local DRG inflammation (a rat model of low back pain) and by a peripheral paw inflammation model. Effects of microsympathectomy were evident within one day, making it unlikely that blocking sympathetic sprouting in the local DRGs or hindpaw was the sole mechanism. Prior microsympathectomy greatly reduced hyperexcitability of sensory neurons induced by local DRG inflammation observed 4 d later. Microsympathectomy reduced local inflammation and macrophage density in the affected tissues (as indicated by paw swelling and histochemical staining). Cytokine profiling in locally inflamed DRG showed increases in pro-inflammatory Type 1 cytokines and decreases in the Type 2 cytokines present at baseline, changes that were mitigated by microsympathectomy. Microsympathectomy was also effective in reducing established pain behaviors in the local DRG inflammation model. We conclude that the effect of sympathetic fibers in the L4/L5 gray rami in these models is pro-inflammatory. This raises the possibility that therapeutic interventions targeting gray rami might be useful in some chronic inflammatory pain conditions. SIGNIFICANCE STATEMENT Sympathetic blockade is used for many pain conditions, but preclinical studies show both pro- and anti-nociceptive effects. The sympathetic nervous system also has both pro- and anti-inflammatory effects on immune tissues and cells. We examined effects of a very localized sympathectomy. By cutting the gray rami to the spinal nerves near the lumbar sensory ganglia, we avoided widespread sympathetic denervation. This procedure profoundly reduced mechanical pain behaviors induced by a back pain model and a model of peripheral inflammatory pain. One possible mechanism was reduction of inflammation in the sympathetically denervated regions. This raises the possibility that therapeutic interventions targeting gray rami might be useful in some inflammatory conditions. PMID:27535916

Activation of Corticostriatal Circuitry Relieves Chronic Neuropathic Pain

PubMed Central

Lee, Michelle; Manders, Toby R.; Eberle, Sarah E.; Su, Chen; D'amour, James; Yang, Runtao; Lin, Hau Yueh; Deisseroth, Karl; Froemke, Robert C.

2015-01-01

Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation. PMID:25834050

Surgical animal models of neuropathic pain: Pros and Cons.

PubMed

Challa, Siva Reddy

2015-03-01

One of the biggest challenges for discovering more efficacious drugs for the control of neuropathic pain has been the diversity of chronic pain states in humans. It is now acceptable that different mechanisms contribute to normal physiologic pain, pain arising from tissue damage and pain arising from injury to the nervous system. To study pain transmission, spot novel pain targets and characterize the potential analgesic profile of new chemical entities, numerous experimental animal pain models have been developed that attempt to simulate the many human pain conditions. Among the neuropathic pain models, surgical models have paramount importance in the induction of pain states. Many surgical animal models exist, like the chronic constriction injury (CCI) to the sciatic nerve, partial sciatic nerve ligation (pSNL), spinal nerve ligation (SNL), spared nerve injury (SNI), brachial plexus avulsion (BPA), sciatic nerve transaction (SNT) and sciatic nerve trisection. Most of these models induce responses similar to those found in causalgia, a syndrome of sustained burning pain often seen in the distal extremity after partial peripheral nerve injury in humans. Researchers most commonly use these surgical models in both rats and mice during drug discovery to screen new chemical entities for efficacy in the area of neuropathic pain. However, there is scant literature that provides a comparative discussion of all these surgical models. Each surgical model has its own benefits and limitations. It is very difficult for a researcher to choose a suitable surgical animal model to suit their experimental set-up. Therefore, particular attention has been given in this review to comparatively provide the pros and cons of each model of surgically induced neuropathic pain.

High-frequency electroacupuncture versus carprofen in an incisional pain model in rats

PubMed Central

Teixeira, F.M.; Castro, L.L.; Ferreira, R.T.; Pires, P.A.; Vanderlinde, F.A.; Medeiros, M.A.

2012-01-01

The objective of the present study was to compare the effect of electroacupuncture (EA) and carprofen (CP) on postoperative incisional pain using the plantar incision (PI) model in rats. A 1-cm longitudinal incision was made through skin, fascia and muscles of a hind paw of male Wistar rats and the development of mechanical and thermal hypersensitivity was determined over 4 days using the von Frey and Hargreaves methods, respectively. Based on the experimental treatments received on the third postoperative day, the animals were divided into the following groups: PI+CP (CP, 2 mg/kg, po); PI+EAST36 (100-Hz EA applied bilaterally at the Zusanli point (ST36)); PI+EANP (EA applied to a non-acupoint region); PI+IMMO (immobilization only); PI (vehicle). In the von Frey test, the PI+EAST36 group had higher withdrawal force thresholds in response to mechanical stimuli than the PI, PI+IMMO and PI+EANP groups at several times studied. Furthermore, the PI+EAST36 group showed paw withdrawal thresholds in response to mechanical stimuli that were similar to those of the PI+CP group. In the Hargreaves test, all groups had latencies higher than those observed with PI. The PI+EAST36 group was similar to the PI+IMMO, PI+EANP and PI+CP groups. We conclude that 100-Hz EA at the ST36 point, but not at non-acupoints, can reduce mechanical nociception in the rat model of incisional pain, and its effectiveness is comparable to that of carprofen. PMID:22911345

Dual effects of Rho-kinase inhibitors on a rat model of inflammatory pain.

PubMed

Paiva-Lima, Patricia; Bakhle, Y S; Francischi, Janetti Nogueira

2014-01-01

Rho-kinases (ROCKs), a family of small GTP-dependent enzymes, are involved in a range of pain models, and their inhibition typically leads to antinociceptive effects. To study the effects of inhibiting ROCKs using two known inhibitors, Y27632 and HA1077 (fasudil), administered locally, on nociception and paw edema in rats. A range of doses of Y27632 or HA1077 (2.5 μg to 1000 μg) were injected locally into rat paws alone or in combination with carrageenan, a known proinflammatory stimulus. Nociceptive responses to mechanical stimuli and increased paw volume, reflecting edema formation, were measured at 2 h and 3 h, using a Randall-Selitto apparatus and a hydroplethysmometer, respectively. Animals treated with either ROCK inhibitor showed biphasic nociceptive effects, with lower doses being associated with pronociceptive, and higher doses with antinociceptive responses. In contrast, a monophasic dose-dependent increase in edema was observed in the same animals. Local injection of 8-bromo-cyclic (c)GMP, an activator of the nitric oxide⁄cGMP⁄protein kinase G pathway, also produced biphasic effects on nociceptive responses in rat paws; however, low doses were antinociceptive and high doses were pronociceptive. Local administration of cytochalasin B, an inhibitor of actin polymerization and a downstream mediator of ROCK activity, reversed the antinociceptive effect of Y27632. The results of the present study suggest that ROCKs participate in the local mechanisms associated with nociception⁄antinociception and inflammation, with a possible involvement of the nitric oxide⁄cGMP⁄protein kinase G pathway. Also, drug effects following local administration may differ markedly from the effects following systemic administration. Finally, separate treatment of pain and edema may be needed to maximize clinical benefit in inflammatory pain.

INFORMATIONAL STRESS AS A DEPRESSION INDUCING FACTOR (EXPERIMENTAL STUDY).

PubMed

Matitaishvili, T; Domianidze, T; Burdjanadze, G; Nadareishvili, D; Khananashvili, M

2017-01-01

Chronic psychogenic stress represents the major initiating agent of psychoneural diseases including depression. We used informational stress model for the purpose of modelling chronic psychogenic stress and depression. The aim of the research was to study behavior of dominant and submissive rats at different stages of informational stress and during depression state. In order to study anxiety and depressive behavior of rats we used "forced swim", "elevated cross maze" and "open-field" tests. The obtained results showed that chronic stressing procedure performed on rats by using the mentioned "informational" stress model led to the development of depression both in dominant and submissive rats. Stressing procedure caused sharp increase of serotonin concentration in hypothalamus of dominant and submissive rats. Under behavioral depression background, sharp increase of serotonin concentration in hypothalamus has been revealed which is caused by the peculiarities of stress model (by uncontrollable stressor. Specifically, by inevitable electric painful irritation).

Enhanced excitability and down-regulated voltage-gated potassium channels in colonic drg neurons from neonatal maternal separation rats.

PubMed

Luo, Jia-Lie; Qin, Hong-Yan; Wong, Chun-Kit; Tsang, Suk-Ying; Huang, Yu; Bian, Zhao-Xiang

2011-05-01

Irritable bowel syndrome (IBS), characterized mainly by abdominal pain, is a functional bowel disorder. The present study aimed to examine changes in the excitability and the activity of the voltage-gated K(+) channel in dorsal root ganglia (DRG) neurons innervating the colon of rats subjected to neonatal maternal separation (NMS). Colonic DRG neurons from NMS rats as identified by FAST DiI™ labeling showed an increased cell size compared with those from nonhandled (NH) rats. Whole cell current-clamp recordings showed that colonic DRG neurons from NMS rats displayed: 1) depolarized resting membrane potential; 2) increased input resistance; 3) a dramatic reduction in rheobase; and 4) a significant increase in the number of action potentials evoked at twice rheobase. Whole cell voltage-clamp recordings revealed that neurons from both groups exhibited transient A-type (I(A)) and delayed rectifier (I(K)) K(+) currents. Compared with NH rat neurons, the averaged density of I(K) was significantly reduced in NMS rat neurons. Furthermore, the Kv1.2 expression was significantly decreased in NMS rat colonic DRG neurons. These results suggest that NMS increases the excitability of colonic DRG neurons mainly by suppressing the I(K) current, which is likely accounted for by the downregulation of the Kv1.2 expression and somal hypertrophy. This study demonstrates the alteration of delayed rectifier K current and Kv1.2 expression in DRG neurons from IBS model rats, representing a molecular mechanism underlying visceral pain and sensitization in IBS, suggesting the potential of Kv1.2 as a therapeutic target for the treatment of IBS. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

Morphine hyposensitivity in streptozotocin-diabetic rats: Reversal by dietary l-arginine treatment.

PubMed

Lotfipour, Shahrdad; Smith, Maree T

2018-01-01

Painful diabetic neuropathy (PDN) is a long-term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine hyposensitivity. In our previous work using the streptozotocin (STZ)-diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post-STZ and maintained for 6 months post-STZ. As this time course mimicked that for the temporal development of hyposensitivity to the pain-relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3-methylfuroxan-4-carbaldehyde) in STZ-diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ-diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mmol/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3 weeks of STZ-diabetes in rats and this was maintained for the study duration. Morphine hyposensitivity developed in a temporal manner with efficacy abolished by 3 months post-STZ. Administration of dietary l-arginine (NO precursor) at 1 g/d to STZ-diabetic rats according to a 15-week prevention protocol initiated at 9 weeks post-STZ prevented abolition of morphine efficacy. When given as an 8-week intervention protocol in rats where morphine efficacy was abolished, dietary l-arginine at 1 g/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine hyposensitivity in STZ-diabetic rats. © 2017 John Wiley & Sons Australia, Ltd.

[Effect of bee venom injection on TrkA and TRPV1 expression in the dorsal root ganglion of rats with collagen-induced arthritis].

PubMed

Xian, Pei-Feng; Chen, Ying; Yang, Lu; Liu, Guo-Tao; Peng, Peng; Wang, Sheng-Xu

2016-06-01

To investigate the therapeutic effect of acupoint injection of bee venom on collagen-induced arthritis (CIA) in rats and explore the mechanism of bee venom therapy in the treatment of rheumatoid arthritis. Fifteen male Wistar rats were randomly divided into bee venom treatment group (BV group), CIA model group, and control group. In the former two groups, CIA was induced by injections of collagen II+IFA (0.2 mL) via the tail vein, and in the control group, normal saline was injected instead. The rats in BV group received daily injection of 0.1 mL (3 mg/mL) bee venom for 7 consecutive days. All the rats were assessed for paw thickness and arthritis index from days 14 to 21, and the pain threshold was determined on day 21. The expressions of TRPV1 and TrkA in the dorsal root ganglion at the level of L4-6 were detected using immunohistochemistry and Western blotting, respectively. The rats in CIA model group started to show paw swelling on day 10, and by day 14, all the rats in this group showed typical signs of CIA. In BV group, the rats receiving been venom therapy for 7 days showed a significantly smaller paw thickness and a low arthritis index than those in the model group. The pain threshold was the highest in the control group and the lowest in the model group. TRPV1-positive cells and TrkA expression in the dorsal root ganglion was significantly reduced in BV group as compared with that in the model group. s Injection of bee venom can decrease expression of TRPV1 and TrkA in the dorsal root ganglion to produce anti-inflammatory and analgesic effects, suggesting the potential value of bee venom in the treatment of rheumatoid arthritis.

Mu-Opioid Receptors in Ganglia, But Not in Muscle, Mediate Peripheral Analgesia in Rat Muscle Pain.

PubMed

Bagues, Ana; Martín, María Isabel; Higuera-Matas, Alejandro; Esteban-Hernández, Jesús; Ambrosio, Emilio; Sánchez-Robles, Eva María

2018-04-01

Previous studies have demonstrated the participation of peripheral μ-opioid receptors (MOR) in the antinociceptive effect of systemically administered morphine and loperamide in an orofacial muscle pain model, induced by hypertonic saline, but not in a spinally innervated one, in rats. In this study, we determine whether this peripheral antinociceptive effect is due to the activation of MOR localized in the muscle, ganglia, or both. To determine the local antinociceptive effect of morphine and loperamide, 2 models of acute muscle pain (trigeminal and spinal) were used. Also, to study the MOR expression, protein quantification was performed in the trigeminal and spinal ganglia, and in the muscles. The behavioral results show that the intramuscular injection of morphine and loperamide did not exert an antinociceptive effect in either muscle (morphine: P = .63, loperamide: P = .9). On the other hand, MOR expression was found in the ganglia but not in the muscles. This expression was on average 44% higher (95% confidence interval, 33.3-53.9) in the trigeminal ganglia than in the spinal one. The peripheral antinociceptive effect of systemically administered opioids may be due to the activation of MOR in ganglia. The greater expression of MOR in trigeminal ganglia could explain the higher antinociceptive effect of opioids in orofacial muscle pain than in spinal muscle pain. Therefore, peripheral opioids could represent a promising approach for the treatment of orofacial pain.

Effects of exogenous galanin on neuropathic pain state and change of galanin and its receptors in DRG and SDH after sciatic nerve-pinch injury in rat.

PubMed

Xu, Xiaofeng; Yang, Xiangdong; Zhang, Ping; Chen, Xiuying; Liu, Huaxiang; Li, Zhenzhong

2012-01-01

A large number of neuroanatomical, neurophysiologic, and neurochemical mechanisms are thought to contribute to the development and maintenance of neuropathic pain. However, mechanisms responsible for neuropathic pain have not been completely delineated. It has been demonstrated that neuropeptide galanin (Gal) is upregulated after injury in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) where it plays a predominantly antinociceptive role. In the present study, sciatic nerve-pinch injury rat model was used to determine the effects of exogenous Gal on the expression of the Gal and its receptors (GalR1, GalR2) in DRG and SDH, the alterations of pain behavior, nerve conduction velocity (NCV) and morphology of sciatic nerve. The results showed that exogenous Gal had antinociceptive effects in this nerve-pinch injury induced neuropathic pain animal model. It is very interesting that Gal, GalR1 and GalR2 change their expression greatly in DRG and SDH after nerve injury and intrathecal injection of exougenous Gal. Morphological investigation displays a serious damage after nerve-pinch injury and an amendatory regeneration after exogenous Gal treatment. These findings imply that Gal, via activation of GalR1 and/or GalR2, may have neuroprotective effects in reducing neuropathic pain behaviors and improving nerve regeneration after nerve injury.

Alleviating neuropathic pain mechanical allodynia by increasing Cdh1 in the anterior cingulate cortex.

PubMed

Tan, Wei; Yao, Wen-Long; Hu, Rong; Lv, You-You; Wan, Li; Zhang, Chuan-Han; Zhu, Chang

2015-09-12

Plastic changes in the anterior cingulate cortex (ACC) are critical in the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. Cdh1, a co-activator subunit of anaphase-promoting complex/cyclosome (APC/C) regulates synaptic differentiation and transmission. Based on this, we hypothesised that the APC/C-Cdh1 played an important role in long-term plastic changes induced by neuropathic pain in ACC. We employed spared nerve injury (SNI) model in rat and found Cdh1 protein level in the ACC was down-regulated 3, 7 and 14 days after SNI surgery. We detected increase in c-Fos expression, numerical increase of organelles, swollen myelinated fibre and axon collapse of neuronal cells in the ACC of SNI rat. Additionally, AMPA receptor GluR1 subunit protein level was up-regulated on the membrane through a pathway that involves EphA4 mediated by APC/C-Cdh1, 3 and 7 days after SNI surgery. To confirm the effect of Cdh1 in neuropathic pain, Cdh1-expressing lentivirus was injected into the ACC of SNI rat. Intra-ACC treatment with Cdh1-expressing lentivirus vectors elevated Cdh1 levels, erased synaptic strengthening, as well as alleviating established mechanical allodynia in SNI rats. We also found Cdh1-expressing lentivirus normalised SNI-induced redistribution of AMPA receptor GluR1 subunit in ACC by regulating AMPA receptor trafficking. These results provide evidence that Cdh1 in ACC synapses may offer a novel therapeutic strategy for treating chronic neuropathic pain.

Antinociceptive Effect of Racemic Flurbiprofen and Caffeine Co-Administration in an Arthritic Gout-Type Pain in Rats.

PubMed

Liévano-Reyes, Ricardo; Pérez-Méndez, Hermínia Ines; Solís-Oba, Aida; Jaramillo-Morales, Osmar Antonio; Espinosa-Juárez, Josué Vidal; López-Muñoz, Francisco Javier

2016-06-01

Preclinical Research Drug combinations are routinely used in the treatment of pain. In drug associations, adjuvants such as caffeine, are employed with different non-steroidal anti-inflammatories drugs (NSAIDs), however, at present does not exist studies showing the effect of the combination of racemic flurbiprofen (rac-Flur) in association with caffeine. The objective of this work was to evaluate the combination of rac-Flur + caffeine oral in arthritic gout-type pain in rats. The antinociceptive effects of the rac-Flur alone and in combination with caffeine were analyzed on a pain-induced functional impairment model in rat. rac-Flur induced a dose-dependent antinociceptive effect and caffeine did not present any effect. The combination of rac-Flur and caffeine achieve a higher percentage of antinociceptive effect compared with the individual administration of rac-Flur. The dose-response curve (DRCs) shows that the combination of rac-Flur (31.6 mg/kg) + caffeine (17.8 mg/kg) exhibited the maximal antinociceptive efficacy (294.0 ± 21.2 area units), while rac-Flur alone (31.6 mg/kg) showed 207.2 ± 35.2 au, thus indicating an increase in efficacy (potentiation). Furthermore, the DRCs of the combinations presented a displacement to the left, indicating a change in the potency. Caffeine is able to increase the effect of rac-Flur in the arthritic gout-type pain in rats. Drug Dev Res 77 : 192-198, 2016.   © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A back translation of pregabalin and carbamazepine against evoked and non-evoked endpoints in the rat spared nerve injury model of neuropathic pain.

PubMed

Lau, W; Dykstra, C; Thevarkunnel, S; Silenieks, L B; de Lannoy, I A M; Lee, D K H; Higgins, G A

2013-10-01

The purpose of the present study was twofold. First to characterize endpoints distinct to the reflexive responses to sensory stimuli typically used in neuropathic pain models. A second aim was to evaluate two clinically approved drugs carbamazepine (Tegretol) and pregabalin (Lyrica) against these endpoints with the purpose to backtranslate from the clinical to preclinical setting. The selected neuropathic pain model was the spared nerve injury (SNI) model and the endpoints were burrowing and measures of paw posture in Sprague Dawley rats. As previously described, SNI surgery produced a robust heightened sensitivity to tactile and thermal (cold) stimuli. SNI surgery also produced robust decreases in burrowing and affected multiple measures of paw position. There was no correlation between magnitude of change in burrowing and sensory allodynia within SNI operated rats. Pregabalin (10-30 mg/kg IP) produced a reliable reversal of both tactile and cold allodynia and also the burrowing deficit, with minimal effect on neurological function evaluated using rotorod, beam walking and open field activity. Pregabalin did not affect any measure of paw position. Pharmacokinetic studies conducted in satellite animals identified plasma levels of pregabalin at the 10 mg/kg IP dose to be equivalent to clinically efficacious levels recorded in neuropathic patients (3-6 μg/ml). In contrast carbamazepine (10-60 mg/kg IP) had only a very modest effect against a reflexive (tactile) measure, and no effect against the burrowing deficit. Carbamazepine also affected various measures of neurological function, complicating interpretation of the reflexive measure. Measurement of burrowing appears to detect a behavioural deficit associated with the SNI model, that may be attenuated by pregabalin but not carbamazepine. Overall the present findings support an advantage of pregabalin over carbamazepine in terms of both efficacy and tolerability which is consistent with clinical experience. The inclusion of additional endpoints beyond traditional reflexive behaviours further supports the value of rodent neuropathic pain models, such as the SNI, as behavioural assays to detect new chemical entities to treat this pain condition. Copyright © 2013 Elsevier Ltd. All rights reserved.

Spinal translocator protein (TSPO) modulates pain behavior in rats with CFA-induced monoarthritis.

PubMed

Hernstadt, Hayley; Wang, Shuxing; Lim, Grewo; Mao, Jianren

2009-08-25

Translocator protein 18 kDa (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), is predominantly located in the mitochondrial outer membrane and plays an important role in steroidogenesis, immunomodulation, cell survival and proliferation. Previous studies have shown an increased expression of TSPO centrally in neuropathology, as well as in injured nerves. TSPO has also been implicated in modulation of nociception. In the present study, we examined the hypothesis that TSPO is involved in the initiation and maintenance of inflammatory pain using a rat model of Complete Freund's Adjuvant (CFA)-induced monoarthritis of the tibio-tarsal joint. Immunohistochemistry was performed using Iba-1 (microglia), NeuN (neurons), anti-Glial Fibrillary Acidic Protein, GFAP (astrocytes) and anti-PBR (TSPO) on Days 1, 7 and 14 after CFA-induced arthritis. Rats with CFA-induced monoarthritis showed mechanical allodynia and thermal hyperalgesia on the ipsilateral hindpaw, which correlated with the increased TSPO expression in ipsilateral laminae I-II on all experimental days. Iba-1 expression in the ipsilateral dorsal horn was also increased on Days 7 and 14. Moreover, TSPO was colocalized with Iba-1, GFAP and NeuN within the spinal cord dorsal horn. The TSPO agonist Ro5-4864, given intrathecally, dose-dependently retarded or prevented the development of mechanical allodynia and thermal hyperalgesia in rats with CFA-induced monoarthritis. These findings provide evidence that spinal TSPO is involved in the development and maintenance of inflammatory pain behaviors in rats. Thus, spinal TSPO may present a central target as a complementary therapy to reduce inflammatory pain.

SPINAL TRANSLOCATOR PROTEIN (TSPO) MODULATES PAIN BEHAVIOR IN RATS WITH CFA-INDUCED MONOARTHRITIS

PubMed Central

Hernstadt, Hayley; Wang, Shuxing; Lim, Grewo; Mao, Jianren

2009-01-01

Translocator protein 18kDa (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), is predominantly located in the mitochondrial outer membrane and plays an important role in steroidogenesis, immunomodulation, cell survival and proliferation. Previous studies have shown an increased expression of TSPO centrally in neuropathology, as well as in injured nerves. TSPO has also been implicated in modulation of nociception. In the present study, we examined the hypothesis that TSPO is involved in the initiation and maintenance of inflammatory pain using a rat model of Complete Freund’s Adjuvant (CFA)-induced monoarthritis of the tibio-tarsal joint. Immunohistochemistry was performed using Iba-1 (microglia), NeuN (neurons), anti-Glial Fibrillary Acidic Protein, GFAP (astrocytes) and anti-PBR (TSPO) on day 1, 7 and 14 after CFA-induced arthritis. Rats with CFA-induced monoarthritis showed mechanical allodynia and thermal hyperalgesia on the ipsilateral hindpaw, which correlated with the increased TSPO expression in ipsilateral lamina I-II on all experimental days. Iba-1 expression in the ipsilateral dorsal horn was also increased on Day 7 and 14. Moreover, TSPO was co-localized with Iba-1, GFAP and NeuN within the spinal cord dorsal horn. The TSPO agonist Ro5-4864, given intrathecally, dose-dependently retarded or prevented the development of mechanical allodynia and thermal hyperalgesia in rats with CFA-induced monoarthritis. These findings provide evidence that spinal TSPO is involved in the development and maintenance of inflammatory pain behaviors in rats. Thus, spinal TSPO may present a central target as a complementary therapy to reduce inflammatory pain. PMID:19555675

Sound stress-induced long-term enhancement of mechanical hyperalgesia in rats is maintained by sympathoadrenal catecholamines.

PubMed

Khasar, Sachia G; Dina, Olayinka A; Green, Paul G; Levine, Jon D

2009-10-01

Although stress plays an important role in chronic widespread pain syndromes, such as fibromyalgia, the underlying mechanism has remained elusive. We have recently demonstrated, in a model of chronic widespread pain, that prolonged enhancement of immune mediator hyperalgesia, induced by unpredictable sound stress, requires a contribution of both the sympathoadrenal (epinephrine) and the hypothalamic-pituitary adrenal (corticosterone) neuroendocrine stress axes. Because this stress protocol produced sustained elevation of plasma epinephrine, in the current study we tested the hypothesis that the sympathoadrenal axis also plays a role in maintenance of symptoms in this model of chronic widespread pain. After establishment, adrenal medullectomy abolished the enhancement of epinephrine-induced cutaneous and muscle hyperalgesia. Administration of stress levels of epinephrine to adrenal medullectomized rats reconstituted the pain phenotype. These observations suggest that the sympathoadrenal stress axis plays a major role in the induction as well as maintenance of stress-induced enhancement of mechanical hyperalgesia, mediated by prolonged elevation of circulating epinephrine. We present data showing mechanical hyperalgesia persisting for up to 28 days after exposure to sound stress, with evidence that the sympathoadrenal axis mediator epinephrine plays a major role. These findings could have clinical implications with regard to novel potential treatments for chronic widespread pain syndromes, such as fibromyalgia.

Effects of a water extract of Lepidium meyenii root in different models of persistent pain in rats.

PubMed

Tenci, Barbara; Di Cesare Mannelli, Lorenzo; Maresca, Mario; Micheli, Laura; Pieraccini, Giuseppe; Mulinacci, Nadia; Ghelardini, Carla

2017-10-26

Lepidium meyenii (Walp.), commonly called maca, is an Andean crop belonging to the Brassicaceae family. Maca hypocotils are habitually consumed as customary food as well as traditional remedies for pathological conditions such as infertility. Moreover, the characterization of maca extracts revealed the presence of compounds that are able to modulate the nervous system. Aimed to evaluate the efficacy of L. meyenii in persistent pain, the present study analyzed the effects of a commercial root extract from maca in different animal models reproducing the most common causes of chronic painful pathologies. A qualitative characterization of this commercial extract by high performance liquid chromatography-mass spectrometry and tandem mass spectrometry analyses allowed us to confirm the presence of some macamides known as bioactive constituents of this root and the absence of the main aromatic glucosinolates. The acute oral administration of maca extract is able to reduce mechanical hypersensitivity and postural unbalance induced by the intra-articular injection of monoiodoacetate and the chronic-constriction injury of the sciatic nerve. Furthermore, L. meyenii extract reverts pain threshold alterations evoked by oxaliplatin and paclitaxel. A good safety profile in mice and rats was shown. In conclusion, the present maca extract could be considered as a therapeutic opportunity to relieve articular and neuropathic pain.

Analgesic effect of Minocycline in rat model of inflammation-induced visceral pain

PubMed Central

Kannampalli, Pradeep; Pochiraju, Soumya; Bruckert, Mitchell; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N.

2014-01-01

The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5 min of administration, systemic injection of the drug produced a delayed effect (60 min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. PMID:24485889

Mechanisms mediating vibration-induced chronic musculoskeletal pain analyzed in the rat.

PubMed

Dina, Olayinka A; Joseph, Elizabeth K; Levine, Jon D; Green, Paul G

2010-04-01

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and reexposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60-80Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a proinflammatory cytokine or reexposure to vibration. Exposure of a hind limb to vibration-produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for approximately 2 weeks. When nociceptive thresholds had returned to baseline, exposure to a proinflammatory cytokine or reexposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cepsilon, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-alpha (TNFalpha) receptor. Finally, in TNFalpha-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged. These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFalpha and the second messenger protein kinase Cepsilon as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome. Copyright 2010 American Pain Society. All rights reserved.

Adenovector GAD65 gene delivery into the rat trigeminal ganglion produces orofacial analgesia

PubMed Central

Vit, Jean-Philippe; Ohara, Peter T; Sundberg, Christopher; Rubi, Blanca; Maechler, Pierre; Liu, Chunyan; Puntel, Mariana; Lowenstein, Pedro; Castro, Maria; Jasmin, Luc

2009-01-01

Background Our goal is to use gene therapy to alleviate pain by targeting glial cells. In an animal model of facial pain we tested the effect of transfecting the glutamic acid decarboxylase (GAD) gene into satellite glial cells (SGCs) of the trigeminal ganglion by using a serotype 5 adenovector with high tropisms for glial cells. We postulated that GABA produced from the expression of GAD would reduce pain behavior by acting on GABA receptors on neurons within the ganglion. Results Injection of adenoviral vectors (AdGAD65) directly into the trigeminal ganglion leads to sustained expression of the GAD65 isoform over the 4 weeks observation period. Immunohistochemical analysis showed that adenovirus-mediated GAD65 expression and GABA synthesis were mainly in SGCs. GABAA and GABAB receptors were both seen in sensory neurons, yet only GABAA receptors decorated the neuronal surface. GABA receptors were not found on SGCs. Six days after injection of AdGAD65 into the trigeminal ganglion, there was a statistically significant decrease of pain behavior in the orofacial formalin test, a model of inflammatory pain. Rats injected with control virus (AdGFP or AdLacZ) had no reduction in their pain behavior. AdGAD65-dependent analgesia was blocked by bicuculline, a selective GABAA receptor antagonist, but not by CGP46381, a selective GABAB receptor antagonist. Conclusion Transfection of glial cells in the trigeminal ganglion with the GAD gene blocks pain behavior by acting on GABAA receptors on neuronal perikarya. PMID:19656360

Adenovector GAD65 gene delivery into the rat trigeminal ganglion produces orofacial analgesia.

PubMed

Vit, Jean-Philippe; Ohara, Peter T; Sundberg, Christopher; Rubi, Blanca; Maechler, Pierre; Liu, Chunyan; Puntel, Mariana; Lowenstein, Pedro; Castro, Maria; Jasmin, Luc

2009-08-05

Our goal is to use gene therapy to alleviate pain by targeting glial cells. In an animal model of facial pain we tested the effect of transfecting the glutamic acid decarboxylase (GAD) gene into satellite glial cells (SGCs) of the trigeminal ganglion by using a serotype 5 adenovector with high tropisms for glial cells. We postulated that GABA produced from the expression of GAD would reduce pain behavior by acting on GABA receptors on neurons within the ganglion. Injection of adenoviral vectors (AdGAD65) directly into the trigeminal ganglion leads to sustained expression of the GAD65 isoform over the 4 weeks observation period. Immunohistochemical analysis showed that adenovirus-mediated GAD65 expression and GABA synthesis were mainly in SGCs. GABAA and GABAB receptors were both seen in sensory neurons, yet only GABAA receptors decorated the neuronal surface. GABA receptors were not found on SGCs. Six days after injection of AdGAD65 into the trigeminal ganglion, there was a statistically significant decrease of pain behavior in the orofacial formalin test, a model of inflammatory pain. Rats injected with control virus (AdGFP or AdLacZ) had no reduction in their pain behavior. AdGAD65-dependent analgesia was blocked by bicuculline, a selective GABAA receptor antagonist, but not by CGP46381, a selective GABAB receptor antagonist. Transfection of glial cells in the trigeminal ganglion with the GAD gene blocks pain behavior by acting on GABAA receptors on neuronal perikarya.

Impaired diffuse noxious inhibitory controls in specific alternation of rhythm in temperature-stressed rats.

PubMed

Itomi, Yasuo; Tsukimi, Yasuhiro; Kawamura, Toru

2016-08-05

Fibromyalgia is characterized by chronic widespread musculoskeletal pain. A hypofunction in descending pain inhibitory systems is considered to be involved in the chronic pain of fibromyalgia. We examined functional changes in descending pain inhibitory systems in rats with specific alternation of rhythm in temperature (SART) stress, by measuring the strength of diffuse noxious inhibitory controls (DNIC). Hindpaw withdrawal thresholds to mechanical von Frey filament or fiber-specific electrical stimuli by the Neurometer system were used to measure the pain response. To induce DNIC, capsaicin was injected into the intraplantar of the forepaw. SART-stressed rats were established by exposure to repeated cold stress for 4 days. In the control rats, heterotopic intraplantar capsaicin injection increased withdrawal threshold, indicative of analgesia by DNIC. The strength of DNIC was reduced by naloxone (μ-opioid receptor antagonist, intraperitoneally and intracerebroventricularly), yohimbine (α2-adrenoceptor antagonist, intrathecally), and WAY-100635 (5-HT1A receptor antagonist, intrathecally) in the von Frey test. In SART-stressed rats, capsaicin injection did not increase withdrawal threshold in the von Frey test, indicating deficits in DNIC. In the Neurometer test, deficient DNIC in SART-stressed rats were observed only for Aδ- and C-fibers, but not Aβ-fibers stimulation. Analgesic effect of intracerebroventricular morphine was markedly reduced in SART-stressed rats compared with the control rats. Taken together, in SART-stressed rats, capsaicin-induced DNIC were deficient, and a hypofunction of opioid-mediated central pain modulation system may cause the DNIC deficit. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of styrene maleic acid WIN55,212-2 micelles on neuropathic pain in a rat model.

PubMed

Linsell, Oliver; Brownjohn, Philip W; Nehoff, Hayley; Greish, Khaled; Ashton, John C

2015-05-01

Cannabinoid receptor agonists are moderately effective at reducing neuropathic pain but are limited by psychoactivity. We developed a styrene maleic acid (SMA) based on the cannabinoid WIN 55,212-2 (WIN) and tested in a rat model of neuropathic pain and in the rotarod test. We hypothesized that miceller preparation can ensure prolonged plasma half-life being above the renal threshold of excretion. Furthermore, SMA-WIN could potentially reduce the central nervous system effects of encapsulated WIN by limiting its transport across the blood-brain barrier. Using the chronic constriction injury model of sciatic neuropathy, the SMA-WIN micelles were efficacious in the treatment of neuropathic pain for a prolonged period compared to control (base WIN). Attenuation of chronic constriction injury-induced mechanical allodynia occurred for up to 8 h at a dose of 11.5 mg/kg of SMA-WIN micelles. To evaluate central effects on motor function, the rotarod assessment was utilized. Results showed initial impairment caused by SMA-WIN micelles to be identical to WIN control for up to 1.5 h. Despite this, the SMA-WIN micelle formulation was able to produce prolonged analgesia over a time when there was decreased impairment in the rotarod test compared with base WIN.

[Analgesic effect and related mechanism of peripheral acupoints electroacupuncture on superficial partial-thickness burn rats].

PubMed

Sun, X; Wei, Z R; Xiao, Z

2017-03-20

Objective: To observe the analgesic effect and related mechanism of peripheral acupoints electroacupuncture on superficial partial-thickness burn rats. Methods: Eighty SD rats were divided into sham injury group (SI), pure burn group (PB), electroacupuncture group (E), and sham electroacupuncture group (SE) according to the random number table, with 20 rats in each group. Right posterior leg of rats in group SI were sham injured, while superficial partial-thickness scald (hereinafter referred to as burn) model was reproduced on the right posterior leg of rats in the latter three groups. Electroacupuncture of peripheral acupoints of right posterior leg of rats (equivalent to Zusanli point and Sanyinjiao point of human) in group E were performed from post injury hour (PIH) 12 on, while rats in group SE were treated with sham electroacupuncture, with 30 min each time, one time a day for 3 days. Before injury and at PIH 12, 24, 36, 48, 60, and 72, the threshold of mechanical pain of 5 rats in each group was tested, and the threshold of heat pain of another 5 rats in each group was tested. At PIH 48, brain tissue of 5 rats in each group was obtained to observe the morphology and distribution of astrocytes with positive expression of glia fibrillary acidic protein (GFAP) in periaqueductal gray (PAG) area by immunohistochemical staining, and the number of astrocytes was calculated. At the same time, brain tissue of the rest 5 rats in each group was obtained to determine the expression of GFAP of astrocytes in PAG area with Western blotting. Data were possessed with analysis of variance of repeated measurement, one-way analysis of variance, and SNK test. Results: (1) Compared with that in group SI, the threshold of mechanical pain of rats in groups PB and SE had no significant change before injury and at PIH 12 (with P values above 0.05), but was significantly decreased from PIH 24 to 72 (with P values below 0.05); while the threshold of mechanical pain of rats in group E was significantly decreased from PIH 36 to 72 (with P values below 0.05). The threshold of mechanical pain of rats in group E was significantly higher than that in groups PB and SE at PIH 24 (with P values below 0.05). (2) Compared with that in group SI, the threshold of heat pain of rats in groups PB and SE had no significant change before injury (with P values above 0.05), but was significantly decreased from PIH 12 to 72 (with P values below 0.05); while the threshold of heat pain of rats in group E was significantly decreased from PIH 12 to 60 (with P values below 0.05). The threshold of heat pain of rats in group E was significantly higher than that in groups PB and SE from PIH 24 to 48 (with P values below 0.05). (3) The distribution of astrocytes with positive expression of GFAP in PAG area of rats in group SI was diffuse. The cell volume was small with cell body unobvious, and the projections were sparse, fine and short. The distribution of astrocytes with positive expression of GFAP in PAG area of rats in group PB was relatively concentrated. The cell body was hypertrophy and swelling, and the projections were increased and extended. The morphology and distribution of astrocytes with positive expression of GFAP in PAG area of rats in groups SE and E was similar to that in group PB. The numbers of astrocytes with positive expression of GFAP in PAG area of rats in groups SI, PB, E, and SE were 44±4, 39±4, 27±4, and 36±5, respectively. The number of astrocytes with positive expression of GFAP in PAG area of rats in group PB was significantly less than that in group SI ( P <0.05), but similar to that in group SE ( P >0.05). The number of astrocytes with positive expression of GFAP in PAG area of rats in group E was significantly less than that in groups PB and SE (with P values below 0.05). (4) The expressions of GFAP of astrocytes in PAG area of rats in groups SI, PB, E, and SE were 1.11±0.16, 0.66±0.15, 0.34±0.06, and 0.56±0.09, respectively. The expression of GFAP of astrocytes in PAG area of rats in group PB was significantly lower than that in group SI ( P <0.05), but similar to that in group SE ( P >0.05). The expression of GFAP of astrocytes in PAG area of rats in group E was significantly lower than that in groups PB and SE (with P values below 0.05). Conclusions: Electroacupuncture of peripheral acupoints can release the pain followed superficial partial-thickness burn in rats at early stage, and the possible mechanism is that it reduces the activation of astrocytes in PAG area.

Descending serotonergic facilitation mediated by spinal 5-HT3 receptors engages spinal rapamycin-sensitive pathways in the rat

PubMed Central

Asante, Curtis O.; Dickenson, Anthony H.

2010-01-01

We have recently reported the importance of spinal rapamycin-sensitive pathways in maintaining persistent pain-like states. A descending facilitatory drive mediated through spinal 5-HT3 receptors (5-HT3Rs) originating from superficial dorsal horn NK1-expressing neurons and that relays through the parabrachial nucleus and the rostroventral medial medulla to act on deep dorsal horn neurons is known be important in maintaining these pain-like states. To determine if spinal rapamycin-sensitive pathways are activated by a descending serotonergic drive, we investigated the effects of spinally administered rapamycin on responses of deep dorsal horn neurons that had been pre-treated with the selective 5-HT3R antagonist ondansetron. We also investigated the effects of spinally administered cell cycle inhibitor (CCI)-779 (a rapamycin ester analogue) on deep dorsal horn neurons from rats with carrageenan-induced inflammation of the hind paw. Unlike some other models of persistent pain, this model does not involve an altered 5-HT3R-mediated descending serotonergic drive. We found that the inhibitory effects of rapamycin were significantly reduced for neuronal responses to mechanical and thermal stimuli when the spinal cord was pre-treated with ondansetron. Furthermore, CCI-779 was found to be ineffective in attenuating spinal neuronal responses to peripheral stimuli in carrageenan-treated rats. Therefore, we conclude that 5-HT3R-mediated descending facilitation is one requirement for activation of rapamycin-sensitive pathways that contribute to persistent pain-like states. PMID:20709148

Prostanoid-dependent spontaneous pain and PAR2-dependent mechanical allodynia following oral mucosal trauma

PubMed Central

Ito, Misa; Hitomi, Suzuro; Nodai, Tomotaka; Sago, Teppei; Yamaguchi, Kiichiro; Harano, Nozomu; Gunjigake, Kaori; Hosokawa, Ryuji; Kawamoto, Tatsuo; Inenaga, Kiyotoshi

2017-01-01

During dental treatments, intraoral appliances frequently induce traumatic ulcers in the oral mucosa. Such mucosal injury-induced mucositis leads to severe pain, resulting in poor quality of life and decreased cooperation in the therapy. To elucidate mucosal pain mechanisms, we developed a new rat model of intraoral wire-induced mucositis and investigated pain mechanisms using our proprietary assay system for conscious rats. A thick metal wire was installed in the rats between the inferior incisors for one day. In the mucosa of the mandibular labial fornix region, which was touched with a free end of the wire, traumatic ulcer and submucosal abscess were induced on day 1. The ulcer was quickly cured until next day and abscess formation was gradually disappeared until five days. Spontaneous nociceptive behavior was induced on day 1 only, and mechanical allodynia persisted over day 3. Antibiotic pretreatment did not affect pain induction. Spontaneous nociceptive behavior was sensitive to indomethacin (cyclooxygenase inhibitor), ONO-8711 (prostanoid receptor EP1 antagonist), SB-366791, and HC-030031 (TRPV1 and TRPA1 antagonists, respectively). Prostaglandin E2 and 15-deoxyΔ12,14-prostaglandin J2 were upregulated only on day 1. In contrast, mechanical allodynia was sensitive to FSLLRY-NH2 (protease-activated receptor PAR2 antagonist) and RN-1734 (TRPV4 antagonist). Neutrophil elastase, which is known as a biased agonist for PAR2, was upregulated on days 1 to 2. These results suggest that prostanoids and PAR2 activation elicit TRPV1- and TRPA1-mediated spontaneous pain and TRPV4-mediated mechanical allodynia, respectively, independently of bacterial infection, following oral mucosal trauma. The pathophysiological pain mechanism suggests effective analgesic approaches for dental patients suffering from mucosal trauma-induced pain. PMID:28381109

Electrical stimulation of the insular cortex as a novel target for the relief of refractory pain: An experimental approach in rodents.

PubMed

Dimov, Luiz Fabio; Toniolo, Elaine Flamia; Alonso-Matielo, Heloísa; de Andrade, Daniel Ciampi; Garcia-Larrea, Luis; Ballester, Gerson; Teixeira, Manoel Jacobsen; Dale, Camila Squarzoni

2018-07-02

Cortical electrical stimulation (CES) has shown to be an effective therapeutic alternative for neuropathic pain refractory to pharmacological treatment. The primary motor cortex(M1) was the main cortical target used in the vast majority of both invasive and non-invasive studies. Despite positive results M1-based approaches still fail to relieve pain in a significant proportion of individuals. It has been advocated that the direct stimulation of cortical areas directly implicated in the central integration of pain could increase the efficacy of analgesic brain stimulation. Here, we evaluated the behavioral effects of electrical stimulation of the insular cortex (ESI) on pain sensitivity in an experimental rat model of peripheral neuropathy, and have described the pathways involved. Animals underwent chronic constriction of the sciatic nerve in the right hind limb and had concentric electrodes implanted in the posterior dysranular insular cortex. Mechanical nociception responses were evaluated before and at the end of a 15-min session of ESI (60Hz, 210μs, 1V). ESI reversed mechanical hypersensitivity in the paw contralateral to the brain hemisphere stimulated, without inducing motor impairment in the open-field test. Pharmacological blockade of μ-opioid (MOR) or type 1-cannabinoid receptors (CB1R) abolished ESI-induced antinociceptive effects. Evaluation of CB1R and MOR spatial expression demonstrated differential modulation of CB1R and MOR in the periaqueductal gray matter (PAG) of ESI-treated rats in sub-areas involved in pain processing/modulation. These results indicate that ESI induces antinociception by functionally modulating opioid and cannabinoid systems in the PAG pain circuitry in rats with experimentally induced neuropathic pain. Copyright © 2017 Elsevier B.V. All rights reserved.

In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain.

PubMed

Saffarpour, S; Shaabani, M; Naghdi, N; Farahmandfar, M; Janzadeh, A; Nasirinezhad, F

2017-06-01

Patients with chronic pain usually suffer from learning and memory impairment which may significantly decrease their quality of life. Despite laboratory and clinical studies, the mechanism underlying this memory impairment remains elusive. We evaluated the effect of chronic pain on the glutamate and GABA levels and BDNF expression in the CA1 region of hippocampus as a possible explanation for memory impairment related to neuropathic pain. In this respect, 30 male rats were randomly allocated to 3 groups as control, sham and neuropathic. Neuropathic pain was induced by a chronic constriction injury of the sciatic nerve (CCI) and mechanical allodynia and the spatial memory was assessed using the Von Frey filaments and Morris water maze respectively. To determine the potential mechanisms, the in vivo extracellular levels of glutamate and γ-aminobutyric acid (GABA) were measured by microdialysis and the brain-derived neurotrophic factor (BDNF) expression was determined by using western blots technique in the hippocampus on days 14 and 21 post-CCI. We showed that CCI impaired spatial learning and memory in Morris water maze (MWM) task. BDNF expression level and glutamate concentration significantly decreased in rats with chronic constriction injury of the sciatic nerve (P<0.001, F=7.3, F=23.23). In addition, GABA increased in hippocampal CA1 region (P<0.001, F=39.2) when the pain threshold was minimum. Nevertheless, these changes reversed while pain was relieved spontaneously. Chronic pain induced by constriction of the sciatic nerve impairs the spatial learning and memory function in rats. This effect exerts through the increase in GABA concentration and decrease in the glutamate and BDNF levels in the CA1 region of the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Attenuation of Activity in an Endogenous Analgesia Circuit by Ongoing Pain in the Rat

PubMed Central

Ferrari, Luiz F.; Gear, Robert W.; Levine, Jon D.

2010-01-01

Analgesic efficacy varies depending on the pain syndrome being treated. One reason for this may be a differential effect of individual pain syndromes on the function of endogenous pain control circuits at which these drugs act to produce analgesia. To test this hypothesis we examined the effects of diverse (i.e., ongoing inflammatory, neuropathic, or chronic widespread) pain syndromes on analgesia induced by activation of an opioid-mediated noxious stimulus-induced endogenous pain control circuit. This circuit was activated by subdermal capsaicin injection at a site remote from the site of nociceptive testing. Analgesia was not affected by carrageenan-induced inflammatory pain nor the early-phase of oxaliplatin neuropathy (a complication of cancer chemotherapy). However, the duration of analgesia was markedly shorter in the late-phase of oxaliplatin neuropathy and in alcoholic neuropathy. A model of fibromyalgia syndrome produced by chronic unpredictable stress and proinflammatory cytokines also shortened analgesia duration, but so did the same stress alone. Therefore, since chronic pain can activate neuroendocrine stress axes, we tested whether they are involved in the attenuation of analgesic duration induced by these pain syndromes. Rats in which the sympathoadrenal axis was ablated by adrenal medullectomy showed normal duration pain-induced analgesia in groups with either late-phase oxaliplatin neuropathy, alcoholic neuropathy, or exposure to sound stress. These results support the suggestion that pain syndromes can modulate activity in endogenous pain control circuits, and this effect is sympathoadrenal dependent. PMID:20943910

Increased miR-132-3p expression is associated with chronic neuropathic pain

PubMed Central

Leinders, M.; Üçeyler, N.; Pritchard, R.A.; Sommer, C.; Sorkin, L.S.

2016-01-01

Alterations in the neuro-immune balance play a major role in the pathophysiology of chronic neuropathic pain. MicroRNAs (miRNA) can regulate both immune and neuronal processes and may function as master switches in chronic pain development and maintenance. We set out to analyze the role of miR-132-3p, first in patients with peripheral neuropathies and second in an animal model of neuropathic pain. We initially determined miR-132-3p expression by measuring its levels in white blood cells (WBC) of 30 patients and 30 healthy controls and next in sural nerve biopsies of 81 patients with painful or painless inflammatory or non-inflammatory neuropathies based on clinical diagnosis. We found a 2.6 fold increase in miR-132-3p expression in WBC of neuropathy patients compared to healthy controls (p<0.001). MiR-132-3p expression was also slightly up-regulated in sural nerve biopsies from neuropathy patients suffering from neuropathic pain compared to those without pain (1.2 fold; p<0.001). These promising findings were investigated further in an animal model of neuropathic pain, the spared nerve injury model (SNI). For this purpose miR-132-3p expression levels were measured in dorsal root ganglia and spinal cord of rats. Subsequently, miR-132-3p expression was pharmacologically modulated with miRNA antagonists or mimetics, and evoked pain and pain aversion were assessed. Spinal miR-132-3p levels were highest 10 days after SNI, a time when persistent allodynia was established (p<0.05). Spinal administration of miR-132-3p antagonists via intrathecal (i.t.) catheters dose dependently reversed mechanical allodyina (p<0.001) and eliminated pain behavior in the place escape avoidance paradigm (p<0.001). Intrathecal administration of miR-132-3p mimetic dose-dependently induced pain behavior in naïve rats (p<0.001). Taken together these results indicate a pro-nociceptive effect of miR-132-3p in chronic neuropathic pain. PMID:27349406

Lidocaine/ketorolac-loaded biodegradable nanofibrous anti-adhesive membranes that offer sustained pain relief for surgical wounds.

PubMed

Kao, Ching-Wei; Lee, Demei; Wu, Min-Hsuan; Chen, Jan-Kan; He, Hong-Lin; Liu, Shih-Jung

2017-01-01

The aim of this study was to develop and evaluate the effectiveness of biodegradable nanofibrous lidocaine/ketorolac-loaded anti-adhesion membranes to sustainably release analgesics on abdominal surgical wounds. The analgesic-eluting membranes with two polymer-to-drug ratios (6:1 and 4:1) were produced via an electrospinning technique. A high-performance liquid chromatography (HPLC) assay was employed to characterize the in vivo and in vitro release behaviors of the pharmaceuticals from the membranes. It was found that all biodegradable anti-adhesion nanofibers released effective concentrations of lidocaine and ketorolac for over 20 days post surgery. In addition, a transverse laparotomy was setup in a rat model for an in vivo assessment of activity of postoperative recovery. No tissue adhesion was observed at 2 weeks post surgery, demonstrating the potential anti-adhesion capability of the drug-eluting nanofibrous membrane. The postoperative activities were recorded for two groups of rats as follows: rats that did not have any membrane implanted (group A) and rats that had the analgesic-eluting membrane implanted (group B). Rats in group B exhibited faster recovery times than those in group A with regard to postoperative activities, confirming the pain relief effectiveness of the lidocaine- and ketorolac-loaded nanofibrous membranes. The experimental results suggested that the anti-adhesion nanofibrous membranes with sustainable elution of lidocaine and ketorolac are adequately effective and durable for the purposes of postoperative pain relief in rats.

Lidocaine/ketorolac-loaded biodegradable nanofibrous anti-adhesive membranes that offer sustained pain relief for surgical wounds

PubMed Central

Kao, Ching-Wei; Lee, Demei; Wu, Min-Hsuan; Chen, Jan-Kan; He, Hong-Lin; Liu, Shih-Jung

2017-01-01

The aim of this study was to develop and evaluate the effectiveness of biodegradable nanofibrous lidocaine/ketorolac-loaded anti-adhesion membranes to sustainably release analgesics on abdominal surgical wounds. The analgesic-eluting membranes with two polymer-to-drug ratios (6:1 and 4:1) were produced via an electrospinning technique. A high-performance liquid chromatography (HPLC) assay was employed to characterize the in vivo and in vitro release behaviors of the pharmaceuticals from the membranes. It was found that all biodegradable anti-adhesion nanofibers released effective concentrations of lidocaine and ketorolac for over 20 days post surgery. In addition, a transverse laparotomy was setup in a rat model for an in vivo assessment of activity of postoperative recovery. No tissue adhesion was observed at 2 weeks post surgery, demonstrating the potential anti-adhesion capability of the drug-eluting nanofibrous membrane. The postoperative activities were recorded for two groups of rats as follows: rats that did not have any membrane implanted (group A) and rats that had the analgesic-eluting membrane implanted (group B). Rats in group B exhibited faster recovery times than those in group A with regard to postoperative activities, confirming the pain relief effectiveness of the lidocaine- and ketorolac-loaded nanofibrous membranes. The experimental results suggested that the anti-adhesion nanofibrous membranes with sustainable elution of lidocaine and ketorolac are adequately effective and durable for the purposes of postoperative pain relief in rats. PMID:28860755

Augmented chondroprotective effect of coadministration of celecoxib and rebamipide in the monosodium iodoacetate rat model of osteoarthritis.

PubMed

Moon, Su-Jin; Park, Jin-Sil; Jeong, Jeong-Hee; Yang, Eun-Ji; Park, Mi-Kyung; Kim, Eun-Kyung; Park, Sung-Hwan; Kim, Ho-Youn; Cho, Mi-La; Min, Jun-Ki

2013-01-01

Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive loss of articular cartilage and chronic pain. Although cyclooxygenase-2 (COX-2) inhibitors such as celecoxib are recommended to patients at high risk of gastrointestinal (GI) adverse events, COX-2 inhibitors do not completely prevent GI adverse events. Rebamipide, a gastroprotective agent, has anti-inflammatory properties and acts as an oxygen radical scavenger. The aim of this study was to investigate the in vivo effects of coadministration of rebamipide and celecoxib in an OA rat model. OA was induced by intra-articular injection of monosodium iodoacetate. Oral administration of rebamipide was initiated on the day of OA induction. In this study, rebamipide showed antinociceptive properties and attenuated cartilage degeneration. Rebamipide reduced the expression of matrix metalloproteinase 13, interleukin-1β, inducible nitric oxide synthase, and nitrotyrosine in OA cartilage. OA rats treated with celecoxib in combination with rebamipide demonstrated a higher pain threshold than those treated with monotherapy. Histological examination also showed that the joints from OA animals treated with combination therapy demonstrated less cartilage damage than those of animals treated with monotherapy. We showed that the potential benefit of combination therapy with celecoxib and rebamipide on pain and cartilage degeneration in OA.

Analgesia or addiction?: implications for morphine use after spinal cord injury.

PubMed

Woller, Sarah A; Moreno, Georgina L; Hart, Nigel; Wellman, Paul J; Grau, James W; Hook, Michelle A

2012-05-20

Opioid analgesics are among the most effective agents for treatment of moderate to severe pain. However, the use of morphine after a spinal cord injury (SCI) can potentiate the development of paradoxical pain symptoms, and continuous administration can lead to dependence, tolerance, and addiction. Although some studies suggest that the addictive potential of morphine decreases when it is used to treat neuropathic pain, this has not been studied in a SCI model. Accordingly, the present studies investigated the addictive potential of morphine in a rodent model of SCI using conditioned place preference (CPP) and intravenous self-administration paradigms. A contusion injury significantly increased the expression of a CPP relative to sham and intact controls in the acute phase of injury. However, contused animals self-administered significantly less morphine than sham and intact controls, but this was dose-dependent; at a high concentration, injured rats exhibited an increase in drug-reinforced responses over time. Exposure to a high concentration of morphine impeded weight gain and locomotor recovery. We suggest that the increased preference observed in injured rats reflects a motivational effect linked in part to the drug's anti-nociceptive effect. Further, although injured rats exhibited a suppression of opiate self-administration, when given access to a high concentration, addictive-like behavior emerged and was associated with poor recovery.

Peripheral Nerve Injury Leads to Working Memory Deficits and Dysfunction of the Hippocampus by Upregulation of TNF-α in Rodents

PubMed Central

Ren, Wen-Jie; Liu, Yong; Zhou, Li-Jun; Li, Wei; Zhong, Yi; Pang, Rui-Ping; Xin, Wen-Jun; Wei, Xu-Hong; Wang, Jun; Zhu, He-Quan; Wu, Chang-You; Qin, Zhi-Hai; Liu, Guosong; Liu, Xian-Guo

2011-01-01

Patients with chronic pain usually suffer from working memory deficits, which may decrease their intellectual ability significantly. Despite intensive clinical studies, the mechanism underlying this form of memory impairment remains elusive. In this study, we investigated this issue in the spared nerve injury (SNI) model of neuropathic pain, a most common form of chronic pain. We found that SNI impaired working memory and short-term memory in rats and mice. To explore the potential mechanisms, we studied synaptic transmission/plasticity in hippocampus, a brain region critically involved in memory function. We found that frequency facilitation, a presynaptic form of short-term plasticity, and long-term potentiation at CA3–CA1 synapses were impaired after SNI. Structurally, density of presynaptic boutons in hippocampal CA1 synapses was reduced significantly. At the molecular level, we found that tumor necrosis factor-α (TNF-α) increased in cerebrospinal fluid, in hippocampal tissue and in plasma after SNI. Intracerebroventricular or intrahippocampal injection of recombinant rat TNF mimicked the effects of SNI in naive rats, whereas inhibition of TNF-α or genetic deletion of TNF receptor 1 prevented both memory deficits and synaptic dysfunction induced by SNI. As TNF-α is critical for development of neuropathic pain, we suggested that the over-production of TNF-α following peripheral nerve injury might lead to neuropathic pain and memory deficits, simultaneously. PMID:21289602

The Glt1 glutamate receptor mediates the establishment and perpetuation of chronic visceral pain in an animal model of stress-induced bladder hyperalgesia.

PubMed

Ackerman, A Lenore; Jellison, Forrest C; Lee, Una J; Bradesi, Sylvie; Rodríguez, Larissa V

2016-04-01

Psychological stress exacerbates interstitial cystitis/bladder pain syndrome (IC/BPS), a lower urinary tract pain disorder characterized by increased urinary frequency and bladder pain. Glutamate (Glu) is the primary excitatory neurotransmitter modulating nociceptive networks. Glt1, an astrocytic transporter responsible for Glu clearance, is critical in pain signaling termination. We sought to examine the role of Glt1 in stress-induced bladder hyperalgesia and urinary frequency. In a model of stress-induced bladder hyperalgesia with high construct validity to human IC/BPS, female Wistar-Kyoto (WKY) rats were subjected to 10-day water avoidance stress (WAS). Referred hyperalgesia and tactile allodynia were assessed after WAS with von Frey filaments. After behavioral testing, we assessed Glt1 expression in the spinal cord by immunoblotting. We also examined the influence of dihydrokainate (DHK) and ceftriaxone (CTX), which downregulate and upregulate Glt1, respectively, on pain development. Rats exposed to WAS demonstrated increased voiding frequency, increased colonic motility, anxiety-like behaviors, and enhanced visceral hyperalgesia and tactile allodynia. This behavioral phenotype correlated with decreases in spinal Glt1 expression. Exogenous Glt1 downregulation by DHK resulted in hyperalgesia similar to that following WAS. Exogenous Glt1 upregulation via intraperitoneal CTX injection inhibited the development of and reversed preexisting pain and voiding dysfunction induced by WAS. Repeated psychological stress results in voiding dysfunction and hyperalgesia that correlate with altered central nervous system glutamate processing. Manipulation of Glu handling altered the allodynia developing after psychological stress, implicating Glu neurotransmission in the pathophysiology of bladder hyperalgesia in the WAS model of IC/BPS. Copyright © 2016 the American Physiological Society.

The effects of dexmedetomidine alone and in combination with tramadol or amitriptyline in a neuropathic pain model.

PubMed

Farghaly, Hanan Sm; Abd-Ellatief, Rasha B; Moftah, Marie Z; Mostafa, Mostafa G; Khedr, Eman M; Kotb, Hassan I

2014-01-01

Interactions between the sympathetic and somatic nervous system play an essential role in the pathophysiologic mechanisms of neuropathic pain. The α2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Multidrug therapy is potentially valuable to decrease side effects. The aim of the present study was to investigate the possible antinociceptive effect of dexmedetomidine, an α2-adrenoceptor agonist, and its combination with front-line treatment of neuropathic pain, i.e., amitriptyline or tramadol, in a chronic constriction injury (CCI) model of the sciatic nerve in rats. Controlled animal study. Following unilateral ligation of the left sciatic nerve, the effect of intraperitoneal (i.p.) dexmedetomidine (5 ug/kg), tramadol (5 mg/kg), and amitriptyline (30 mg/kg) on mechanical allodynia (measured by electrical von Frey apparatus) and hyperalgesia (measured by Randall and Selitto test) was studied. The sham-operated rats and un-operated hind paw (right paw) press normally on the floor reproduced by a weighted pain score of 0. Behavioral and mechanical tests confirmed the development of neuropathic pain after CCI. All individual drugs and dexmedetomidine combination with either tramadol or amitriptyline were effective in reducing mechanical allodynia and hyperalgesia. Dexmedetomidine, amitriptyline, tramadol, amitriptyline+dexmedetomidine, and tramadol+dexmedetomidine combination did not produce any sedation/motor impairment (P > 0.05). Although the combination of these drugs improved the CCI model of neuropathic pain in this study, an additional interpretation of the underlying mechanism(s) will be needed to confirm these findings. The combination of these drugs appears to be more effective in increasing the pain threshold after peripheral nerve injury, when compared with the administration of either of amitriptyline or tramadol alone and should be considered as a possible alternative to decrease side effects of individual drug therapy.

Acetaminophen and non-steroidal anti-inflammatory drugs interact with morphine and tramadol analgesia for the treatment of neuropathic pain in rats.

PubMed

Shinozaki, Tomonari; Yamada, Toshihiko; Nonaka, Takahiro; Yamamoto, Tatsuo

2015-06-01

Although non-steroidal anti-inflammatory drugs and acetaminophen have no proven efficacy against neuropathic pain, they are frequently prescribed for neuropathic pain patients. We examined whether the combination of opioids (tramadol and morphine) with indomethacin or acetaminophen produce favorable effects on neuropathic pain and compared the efficacy for neuropathic pain with that for inflammatory pain. The carrageenan model was used as the inflammatory pain model while the tibial neuroma transposition (TNT) model was used as the neuropathic pain model. The tibial nerve is transected in the TNT model, with the tibial nerve stump then transpositioned to the lateral aspect of the hindlimb. Neuropathic pain (mechanical allodynia and neuroma pain) is observed after TNT injury. Drugs were administered orally. In the carrageenan model, all drugs produced anti-allodynic effects and all drug combinations, but not tramadol + indomethacin combination, produced synergistic anti-allodynic effects. In the TNT model, tramadol and morphine, but not acetaminophen and indomethacin, produced anti-neuropathic pain effects. In the combination, with the exception of morphine + acetaminophen combination, both acetaminophen and indomethacin reduced the 50% effective dose (ED50) of tramadol and morphine as compared with the ED50s for the single drug study in the TNT model. The ED50s of tramadol and morphine in the carrageenan combination test were not statistically significantly different from the ED50s in the TNT model combination study. The combination of opioids with indomethacin or acetaminophen produced a synergistic analgesic effect both in inflammatory and neuropathic pain with some exceptions. The efficacy of these combinations for neuropathic pain was not different from that for inflammatory pain.

CHARACTER OF THE CHANGES IN FEAR MOTIVATED DECLARATIVE MEMORY IN THE HIGH IMMOBILIZATION "DEPRESSIVE" RATS.

PubMed

Nachkebia, N; Shavgulidze, M; Babilodze, M; Chkhartishvili, E; Rogava, N

2016-10-01

Present study investigated possible differences in the learning and memory of declarative memory task in rats selected according to the differences in immobilization response that is in high immobilization "depressive" and low immobilization "non-depressive" rats. Understanding the character of learning and memory disturbances in basal conditions of animal models of depression is still very topical for more intimate definition of the pathophysiology of major depressive disorder and appropriate searching the ways of its correction. Experiments were carried out on the adult white wild rats (with the weight 200-250 g, n=20). Selection of rats according to the level of immobilization was made by means of forced swim test. Learning and memory disturbances were studied using passive avoidance test that is fear motivated one trial declarative memory task. It was shown by us that 100% of low immobilization "non-depressive" rats remember painful stimulation and therefore they are not enter in the dark compartment during whole period of observation during testing session. Behavior of high immobilization "depressive" rats is not similar in passive avoidance camera; 50% of "depressive" rats, with long escape latency during training session (92±10 sec), remember painful stimulation during testing session and therefore they are not enter in the dark compartment during whole observation period. The remaining 50%, that are not differ significantly from the low immobility "non-depressive" rats by the latency of escape (5±1 sec) during training session, are not able to remember painful stimulation during testing session and therefore they enter in the dark compartment with shortest escape latency (6±1 sec). In conclusion, high immobility "depressive" rats perform passive avoidance declarative memory task at the chance level that is a direct indicator for the serious disturbances of declarative memory mechanisms in "depressive" rats selected in forced swim test according to the level of immobility.

Transient Receptor Potential Channel and Interleukin-17A Involvement in LTTL Gel Inhibition of Bone Cancer Pain in a Rat Model.

PubMed

Wang, Juyong; Zhang, Ruixin; Dong, Changsheng; Jiao, Lijing; Xu, Ling; Liu, Jiyong; Wang, Zhengtao; Lao, Lixing

2015-07-01

Cancer pain management is a challenge for which Chinese herbal medicine might be useful. To study the spinal mechanisms of the Chinese medicated gel Long-Teng-Tong-Luo (LTTL), a 7-herb compound, on bone cancer pain, a bone cancer pain model was made by inoculating the tibias of female rats with Walker 256 cells. LTTL gel or inert gel, 0.5 g/cm(2)/d, was applied to the skin of tumor-bearing tibias for 21 days beginning a day after the inoculation. Mechanical threshold and paw withdrawal latency to thermal stimulation was measured. Transient receptor potential (TRP) cation channels in lumbar dorsal root ganglia (DRG) were immunostained and counted, and lumbar spinal cord interleukin-17A (IL-17A) was measured with real-time polymerase chain reaction and enzyme-linked immunosorbent assay. TRP antagonists and interleukin (IL)-17A antibodies were intrathecally administered to determine their effects on bone cancer pain. The gel significantly (P < .05) alleviated cancer-induced mechanical allodynia and thermal hyperalgesia and inhibited cancer-enhanced expression of IL-17A in spinal astrocytes and the TRP subfamily members V1, A1, and V4 in lumbar DRG. Intrathecal TRP antagonists at 10 µg significantly (P < .05) attenuated mechanical allodynia, thermal hyperalgesia, and IL-17A expression, indicating that TRP channels facilitate spinal IL-17 expression and cancer pain. IL-17A antibodies inhibited cancer pain, suggesting that IL-17A promotes such pain. The data show that LTTL gel inhibits cancer pain, and this might be accounted for by the decrease in expression of DRG TRP channels and spinal astrocyte IL-17A. © The Author(s) 2015.

CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties.

PubMed

Nakao, Kazunari; Murase, Akio; Ohshiro, Hiroyuki; Okumura, Takako; Taniguchi, Kana; Murata, Yoko; Masuda, Masatoshi; Kato, Tomoki; Okumura, Yoshiyuki; Takada, Junji

2007-08-01

The prostaglandin (PG) EP(4) receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP(4) receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP(4) or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP(4) receptor antagonist, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl]ethyl}amino) carbonyl]-4-methylbenzenesulfonamide (CJ-023,423). In vitro, CJ-023,423 inhibits [(3)H]PGE(2) binding to both human and rat EP(4) receptors with K(i) of 13 +/- 4 and 20 +/- 1 nM, respectively. CJ-023,423 is highly selective for the human EP(4) receptor over other human prostanoid receptor subtypes. It also inhibits PGE(2)-evoked elevation in intracellular cAMP at the human and rat EP(4) receptors with pA(2) of 8.3 +/- 0.03 and 8.2 +/- 0.2 nM, respectively. In vivo, oral administration of CJ-023,423 significantly reduces thermal hyperalgesia induced by intraplantar injection of PGE(2) (ED(50) = 12.8 mg/kg). CJ-023,423 is also effective in models of acute and chronic inflammatory pain. CJ-023,423 significantly reduces mechanical hyperalgesia in the carrageenan model. Furthermore, CJ-023,423 significantly reverses complete Freund's adjuvant-induced chronic inflammatory pain response. Taken together, the present data indicate that CJ-023,423, a highly potent and selective antagonist of both human and rat EP(4) receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP(4) receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.

Stable Rat Model of Mechanical Allodynia in Diabetic Peripheral Neuropathy: The Role of Nerve Compression.

PubMed

Liao, Chenlong; Yang, Min; Liu, Pengfei; Zhong, Wenxiang; Zhang, Wenchuan

2018-05-01

 Preclinical studies involving animal models are essential for understanding the underlying mechanisms of diabetic neuropathic pain.  Rats were divided into four groups: two controls and two experimental. Diabetes mellitus was induced by streptozotocin (STZ) injection in two experimental groups. The first group involved one sham operation. The second group involved one latex tube encircling the sciatic nerve. The vehicle-injection rats were used as two corresponding control groups: sham operation and encircled nerves. By the third week, STZ-injected rats with encircled nerves were further divided into three subgroups: one involving continuing observation and the other two involving decompression (removal of the latex tube) at different time points (third week and fifth week). Weight and blood glucose were monitored, and behavioral analysis, including paw withdrawal threshold (PWT) and latency, was performed every week during the experimental period (7 weeks).  Hyperglycemia was induced in all STZ-injected rats. A significant increase in weight was observed in the control groups when compared with the experimental groups. By the third week, more STZ-injected rats with encircled nerves developed mechanical allodynia than those without ( P  < 0.05), while no significant difference was noted ( P  > 0.05) on the incidence of thermal hyperalgesia. Mechanical allodynia, but not thermal hyperalgesia, could be ameliorated by the removal of the latex tube at an early stage (third week).  With the combined use of a latex tube and STZ injection, a stable rat model of painful diabetic peripheral neuropathy (DPN) manifesting both thermal hyperalgesia and mechanical allodynia has been established. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Sex differences in sleep pattern of rats in an experimental model of osteoarthritis.

PubMed

Silva, Andressa; Araujo, Paula; Zager, Adriano; Tufik, Sergio; Andersen, Monica Levy

2011-07-01

Osteoarthritis (OA) is a major healthcare burden with increasing incidence, and is characterised by the degeneration of articular cartilage. OA is associated with chronic pain and sleep disturbance. The current study examined and compared the long-term effects of chronic articular pain on sleep patterns between female and male rats in an experimental model of OA. Rats were implanted with electrodes for electrocorticography and electromyography and assigned to control, sham or OA groups. OA was induced by the intra-articular administration of (2 mg) monosodium iodoacetate into the left knee joint in male and female rats (at estrus and diestrus phases). Sleep was monitored at days 1, 10, 15, 20 and 28 after iodoacetate injection during light and dark periods. The results showed that the overall sleep architecture changed in both sexes. These alterations occurred during the light and dark periods, began on D1 and persisted until the end of the study. OA rats, regardless of sex, showed a fragmented sleep pattern with reduced sleep efficiency, slow-wave sleep and paradoxical sleep, and fewer paradoxical sleep bouts. However, the males showed lower sleep efficiency and reduced slow-wave sleep compared to females during the dark period. Additionally, OA affected the hormonal levels in male rats, as testosterone levels were reduced in comparison to the control and sham groups. In females, progesterone and estradiol remained unchanged throughout the study. Our results suggest that the chronic model of OA influenced the sleep patterns in both sexes. However, males appeared to be more affected. Copyright © 2010. Published by Elsevier Ltd.

AMPK activation by peri-sciatic nerve administration of ozone attenuates CCI-induced neuropathic pain in rats.

PubMed

Lu, Lijuan; Pan, Cailong; Chen, Lu; Hu, Liang; Wang, Chaoyu; Han, Yuan; Yang, Yanjing; Cheng, Zhixiang; Liu, Wen-Tao

2017-04-01

Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. Ozone is widely used as an alternative therapy for many different pain conditions, with exact mechanisms still elusive. In this study, we found that a single peri-sciatic nerve injection of ozone decreased mechanical allodynia and thermal hyperalgesia, and normalized the phosphorylation of protein kinase C γ, N-methyl-D-aspartate receptor, and extracellular signal-regulated kinase in a chronic constriction injury (CCI) model in rat sciatic nerve. Meanwhile, ozone significantly suppressed CCI-induced activation of spinal microglia. More importantly, the anti-nociceptive effect of ozone depended on the activation of 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), which was proved by the fact that the phosphorylated AMPK level increased during the ozone therapy and AMPK antagonist abolished the effect of ozone in vivo and in vitro. In addition, direct injection of AMPK agonist could replicate the anti-nociceptive effect of ozone in CCI rats. In conclusion, our observations indicate that peri-sciatic nerve injection of ozone activates AMPK to attenuate CCI-induced neuropathic pain. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Intrathecal Infusion of Hydrogen-Rich Normal Saline Attenuates Neuropathic Pain via Inhibition of Activation of Spinal Astrocytes and Microglia in Rats

PubMed Central

Sun, Xuejun; Xiang, Zhenghua; Yang, Liqun; Huang, Shengdong; Lu, Zhijie; Sun, Yuming; Yu, Wei-Feng

2014-01-01

Background Reactive oxygen and nitrogen species are key molecules that mediate neuropathic pain. Although hydrogen is an established antioxidant, its effect on chronic pain has not been characterized. This study was to investigate the efficacy and mechanisms of hydrogen-rich normal saline induced analgesia. Methodology/Principal findings In a rat model of neuropathic pain induced by L5 spinal nerve ligation (L5 SNL), intrathecal injection of hydrogen-rich normal saline relieved L5 SNL-induced mechanical allodynia and thermal hyperalgesia. Importantly, repeated administration of hydrogen-rich normal saline did not lead to tolerance. Preemptive treatment with hydrogen-rich normal saline prevented development of neuropathic pain behavior. Immunofluorochrome analysis revealed that hydrogen-rich normal saline treatment significantly attenuated L5 SNL-induced increase of 8-hydroxyguanosine immunoreactive cells in the ipsilateral spinal dorsal horn. Western blot analysis of SDS/PAGE-fractionated tyrosine-nitrated proteins showed that L5 SNL led to increased expression of tyrosine-nitrated Mn-containing superoxide dismutase (MnSOD) in the spinal cord, and hydrogen-rich normal saline administration reversed the tyrosine-nitrated MnSOD overexpression. We also showed that the analgesic effect of hydrogen-rich normal saline was associated with decreased activation of astrocytes and microglia, attenuated expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the spinal cord. Conclusion/Significance Intrathecal injection of hydrogen-rich normal saline produced analgesic effect in neuropathic rat. Hydrogen-rich normal saline-induced analgesia in neuropathic rats is mediated by reducing the activation of spinal astrocytes and microglia, which is induced by overproduction of hydroxyl and peroxynitrite. PMID:24857932

Botulinum toxin decreases hyperalgesia and inhibits P2X3 receptor over-expression in sensory neurons induced by ventral root transection in rats.

PubMed

Xiao, Lizu; Cheng, Jianguo; Dai, Juanli; Zhang, Deren

2011-09-01

We aim to determine the effects of Botulinum toxin type A (BTX-A) on neuropathic pain behavior and the expression of P2X(3) receptor in dorsal root ganglion (DRG) in rats with neuropathic pain induced by L5 ventral root transection (L5 VRT). Neuropathic pain was induced by L5 VRT in male Sprague-Dawley rats. Either saline or BTX-A was administered to the plantar surface. Behavioral tests were conducted preoperatively and at predefined postoperative days. The expression of P2X(3) receptors in DRG neurons was detected by immunoreactivity at postoperative days 3, 7, 14, and 21. The number of positive P2X(3) neurons in the ipsilateral L5 DRG increased significantly after L5 VRT (P<0.001). This increase persisted for at least 3 weeks after the operation. No significant changes in P2X(3) expression were detected in the contralateral L5, or in the L4 DRGs bilaterally. Subcutaneous administration of BTX-A, performed on the left hindpaw at days 4, 8, or 16 post VRT surgery, significantly reduced mechanical allodynia bilaterally and inhibited P2X(3) over-expression induced by L5 VRT. L5 VRT led to over-expression of P2X(3) receptors in the L5 DRG and bilateral mechanical allodynia in rats. Subcutaneous injection of BTX-A significantly reversed the neuropathic pain behavior and the over-expression of P2X(3) receptor in nociceptive neurons. These data not only show over-expression of purinergic receptors in the VRT model of neuropathic pain but also reveal a novel mechanism of botulinum toxin action on nociceptive neurons. Wiley Periodicals, Inc.

A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models.

PubMed

Chen, Q; Muramoto, K; Masaaki, N; Ding, Y; Yang, H; Mackey, M; Li, W; Inoue, Y; Ackermann, K; Shirota, H; Matsumoto, I; Spyvee, M; Schiller, S; Sumida, T; Gusovsky, F; Lamphier, M

2010-05-01

Rheumatoid arthritis (RA) is an autoimmune disorder involving subsets of activated T cells, in particular T helper (Th) 1 and Th17 cells, which infiltrate and damage tissues and induce inflammation. Prostaglandin E(2) (PGE(2)) enhances the Th17 response, exacerbates collagen-induced arthritis (CIA) and promotes inflammatory pain. The current study investigated whether selective antagonism of the PGE(2) EP(4) receptor would suppress Th1/Th17 cell development and inflammatory arthritis in animal models of RA. Effects of PGE(2) and a novel EP(4) receptor antagonist ER-819762 on Th1 differentiation, interleukin-23 (IL-23) production by dendritic cells (DCs), and Th17 development were assessed in vitro. The effect of ER-819762 was evaluated in CIA and glucose-6-phosphate isomerase (GPI)-induced arthritis models. In addition, the effects of ER-819762 on pain were evaluated in a model of chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in the rat. Stimulation of the EP(4) receptor enhanced Th1 differentiation via phosphatidylinositol 3 kinase signalling, selectively promoted Th17 cell expansion, and induced IL-23 secretion by activated DCs, effects suppressed by ER-819762 or anti-PGE(2) antibody. Oral administration of ER-19762 suppressed Th1 and Th17 cytokine production, suppressed disease in collagen- and GPI-induced arthritis in mice, and suppressed CFA-induced inflammatory pain in rats. PGE(2) stimulates EP(4) receptors to promote Th1 differentiation and Th17 expansion and is critically involved in development of arthritis in two animal models. Selective suppression of EP(4) receptor signalling may have therapeutic value in RA both by modifying inflammatory arthritis and by relieving pain.

Lateralized kappa opioid receptor signaling from the amygdala central nucleus promotes stress-induced functional pain.

PubMed

Nation, Kelsey M; De Felice, Milena; Hernandez, Pablo I; Dodick, David W; Neugebauer, Volker; Navratilova, Edita; Porreca, Frank

2018-05-01

The response of diffuse noxious inhibitory controls (DNIC) is often decreased, or lost, in stress-related functional pain syndromes. Because the dynorphin/kappa opioid receptor (KOR) pathway is activated by stress, we determined its role in DNIC using a model of stress-induced functional pain. Male, Sprague-Dawley rats were primed for 7 days with systemic morphine resulting in opioid-induced hyperalgesia. Fourteen days after priming, when hyperalgesia was resolved, rats were exposed to environmental stress and DNIC was evaluated by measuring hind paw response threshold to noxious pressure (test stimulus) after capsaicin injection in the forepaw (conditioning stimulus). Morphine priming without stress did not alter DNIC. However, stress produced a loss of DNIC in morphine-primed rats in both hind paws that was abolished by systemic administration of the KOR antagonist, nor-binaltorphimine (nor-BNI). Microinjection of nor-BNI into the right, but not left, central nucleus of the amygdala (CeA) prevented the loss of DNIC in morphine-primed rats. Diffuse noxious inhibitory controls were not modulated by bilateral nor-BNI in the rostral ventromedial medulla. Stress increased dynorphin content in both the left and right CeA of primed rats, reaching significance only in the right CeA; no change was observed in the rostral ventromedial medulla or hypothalamus. Although morphine priming alone is not sufficient to influence DNIC, it establishes a state of latent sensitization that amplifies the consequences of stress. After priming, stress-induced dynorphin/KOR signaling from the right CeA inhibits DNIC in both hind paws, likely reflecting enhanced descending facilitation that masks descending inhibition. Kappa opioid receptor antagonists may provide a new therapeutic strategy for stress-related functional pain disorders.

Mangiferin attenuates contusive spinal cord injury in rats through the regulation of oxidative stress, inflammation and the Bcl‑2 and Bax pathway.

PubMed

Luo, Yang; Fu, Changfeng; Wang, Zhenyu; Zhang, Zhuo; Wang, Hongxia; Liu, Yi

2015-11-01

Mangiferin has antioxidant, antiviral, apoptosis regulating, anti‑inflammatory, antitumor and antidiabetic effects, which can also inhibit osteoclast formation and bone resorption. However, whether mangiferin ameliorates the neurological pain of spinal cord injury (SCI) in ratS remains to be elucidated. The present study investigated the therapeutic effects of mangiferin on neurological function, the water content of spinal cord, oxidative stress, the expression of inflammatory cytokines and the protein expression of Bcl‑2/Bax in a SCI rat model. In the present study, the Basso, Beattie and Bresnahan scores, and the water content of the spinal cord were used to analyze the therapeutic effects of mangiferin on neurological pain in the SCI rat. The concentrations of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and the serum levels of glutathione peroxidase (GSH‑PX), nuclear factor‑κB p65 unit, tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and caspase‑3/9 were detected using commercial kits. The expression levels of Bcl‑2 and Bax were measured using western blot analysis. The results demonstrated that administrating mangiferin began to ameliorate neurological function and the water content of the spinal cord in the SCI rat. The mangiferin‑treated group were found to have lower oxidative stress activity and lower expression levels of inflammatory cytokines, compared with the SCI rat. In addition, mangiferin significantly reduced the protein expression of Bax and promoted the protein expression of Bcl-2 in the SCI rat model. Finally, mangiferin markedly suppressed the expression of caspase‑3/9, indicating that the protective action of mangiferin may be associated with anti‑apoptosis activation. In conclusion, mangiferin attenuated contusive SCI in the rats through regulating oxidative stress, inflammation and the Bcl‑2 and Bax pathway.

Effect of electroacupuncture on the cervicospinal P2X7 receptor/fractalkine/CX3CR1 signaling pathway in a rat neck-incision pain model.

PubMed

Gao, Y H; Li, C W; Wang, J Y; Tan, L H; Duanmu, C L; Jing, X H; Chang, X R; Liu, J L

2017-06-01

Increasing evidence supports that acupuncture intervention is an effective approach for intraoperative and postoperative pain. Neuron-microglia crosstalk, mediated by the purinergic P2X7 receptor (R)/fractalkine/CX3CR1 cascade in the spinal cord dorsal horn, plays a pivotal role in pain processing. However, its involvement in the analgesic effect of electroacupuncture (EA) remains unclear. In this study, a rat neck-incision pain model was established by making a longitudinal incision along the midline of the neck and subsequent repeated mechanical stimulation. EA stimulation was applied to bilateral LI18, LI4-PC6, or ST36-GB34. The thermal pain threshold, cervicospinal ATP concentration, expression levels of purinergic P2XR and P2YR subunits mRNAs, and fractalkine, CX3CR1 and p38 MAPK proteins, were detected separately. The neck incision induced strong thermal hyperalgesia and upregulation of spinal ATP within 48 h. No significant change was found in thermal hyperalgesia after a single session of EA intervention. However, a single session of EA dramatically enhanced the neck incision-induced upregulation of ATP and upregulated the expression of P2X7R, which was reversed by two sessions of EA. Two sessions of EA at bilateral LI18 or LI4-PC6 attenuated hyperalgesia significantly, accompanied with downregulation of P2X7R/fractalkine/ CX3CR1 signaling after three sessions of EA. EA stimulation of LI18 or LI4-PC6 alleviates thermal hyperalgesia in neck-incision pain rats, which may be associated with its effects in regulating the neck incision-induced increase of ATP and P2X7R and subsequently suppressing fractalkine/CX3CR1 signaling in the cervical spinal cord.

Mechanisms Mediating Vibration-induced Chronic Musculoskeletal Pain Analyzed in the Rat

PubMed Central

Dina, Olayinka A.; Joseph, Elizabeth K.; Levine, Jon D.; Green, Paul G.

2009-01-01

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and re-exposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60–80 Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a pro-inflammatory cytokine or re-exposure to vibration. Exposure of a hind limb to vibration produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for ~2 weeks. When nociceptive thresholds had returned to baseline, exposure to a pro-inflammatory cytokine or re-exposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia induced by vibration was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cε, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-α (TNFα) receptor. Finally, in TNFα-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged. Perspective These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFα and the second messenger PKCε as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome. PMID:19962353

Chemical stimulation of the lateral hypothalamus by carbachol attenuated the formalin-induced pain behaviors in rats.

PubMed

Ezzatpanah, Somayeh; Babapour, Vahab; Sadeghi, Bahman; Haghparast, Abbas

2015-02-01

Electrical and chemical stimulation of the lateral hypothalamus (LH) produces analgesia. Previous studies emphasized the importance of LH in the modulation of nociceptive behaviors in the acute pain models. In the current study, for the first time, we examined the effect of direct chemical stimulation of the LH with cholinergic receptor agonist, carbachol, on pain-related behaviors in the formalin test as a model of persistent inflammatory pain. Forty-eight adult male Wistar rats were implanted unilaterally with cannula into the LH. Four doses of carbachol (62.5, 125, 250 and 500 nM/0.5 μl saline) were microinjected into the LH just 5 min before the formalin test. Vehicle group received 0.5 μl saline into the LH. Pain-related behaviors were quantified and monitored in 5-min blocks for 60 min test period. Average nociceptive scores and area under the curve (AUC) as raw pain scores × time by the linear trapezoidal method were used for the statistical analyses. One important finding of our study was that carbachol blocks the nociceptive responses in both phases of formalin-induced nociception in a dose-dependent manner. Altogether, the percentage decrease of AUC values calculated for treatment groups, compared to the control group, was more significant in the late phase than the early phase. These findings suggest that LH modulates formalin-induced nociception through spinal and/or supraspinal sites. Copyright © 2014 Elsevier Inc. All rights reserved.

[Effects of intrathecal injection PI3K antagonist on inflammatory cytokines in spinal cord of bone cancer pain model in rats].

PubMed

Xu, Shijie; Yao, Ming; Xu, Longsheng; Wang, Hanqi; Li, Hongbo; Huang, Bing; Zhou, Xuyan

2016-01-26

To investigate the roles of PI3K in bone cancer pain, the present study was performed to demonstrate the changes of pain-related behavior and the production of IL-1β, IL-6 and TNF-α after intrathecal injection of wortmannin (antagonist of PI3K receptors) in rat model. A total of 44 SD rats were randomly divided into 4 groups, sham group (group S), sham + wormannin group (group SW), cancer group (group A), cancer + wortmannin group (group AW). Group S and group W were injected with 10 μl Hank's solution into left tibial medullary cavity; group A and group AW received injections of Walker 256 mammary cancer cells(10 μl, 2×10 cells/ml) into the same place to establish the model of bone cancer pain. In the meantime intratheacal catheterization was performed between L3 and L4 vertrbra on the rats of every group. Nine days after the operation, group S and group A received a single intratheacal injection of saline (0.9%, 10 μl), group SW and group AW received intratheacal wortmannin 0.5 μg/10 μl. Mechanical withdrawal thresholds were measured on the left hind paw before and every 10 min after intrathecal injection. Then the L4-L6 sections of spinal cord 30 min after injection were collected to determine the expression of IL-1β, IL-6 and TNF-α. At 30 min post-injection, mechanical withdrawal thresholds of groups S, SW, A and AW were (30.1±4.3), (31.7±1.3), (17.2±2.0), (24.8±2.3) g respectively at Day 9 postinoculation (F=22.403, P<0.01), the mechanical withdrawal thresholds in group AW increased obviously versus group A. The expressions of TNF-α in groups S, SW, A and AW were (84.5±6.3), (78.7±12.5), (110.5±7.3), (57.8±4.6) pg/ml. Compared with groups S and W, the expression of TNF-α in group A showed a significant upregulation (F=28.119, P<0.01). An intrathecal injection of wortmannin may alleviate hyperalgesia, and inhibit the up-regulated expression of spinal cord inflammatory cytokines TNF-α in rats with bone cancer. PI3K may be involved in the development of bone cancer pain by regulating the expressions of TNF-α.

Intraarticularly-Injected Mesenchymal Stem Cells Stimulate Anti-Inflammatory Molecules and Inhibit Pain Related Protein and Chondrolytic Enzymes in a Monoiodoacetate-Induced Rat Arthritis Model

PubMed Central

Ichiseki, Toru; Shimasaki, Miyako; Ueda, Yoshimichi; Tsuchiya, Masanobu; Souma, Daisuke; Kaneuji, Ayumi; Kawahara, Norio

2018-01-01

Persistent inflammation is well known to promote the progression of arthropathy. mesenchymal stem cells (MSCs) have been shown to possess anti-inflammatory properties and tissue differentiation potency. Although the experience so far with the intraarticular administration of mesenchymal stem cell (MSC) to induce cartilage regeneration has been disappointing, MSC implantation is now being attempted using various surgical techniques. Meanwhile, prevention of osteoarthritis (OA) progression and pain control remain important components of the treatment of early-stage OA. We prepared a shoulder arthritis model by injecting monoiodoacetate (MIA) into a rat shoulder, and then investigated the intraarticular administration of MSC from the aspects of the cartilage protective effect associated with their anti-inflammatory property and inhibitory effect on central sensitization of pain. When MIA was administered in this rat shoulder arthritis model, anti-Calcitonin Gene Related Peptide (CGRP) was expressed in the joint and C5 spinal dorsal horn. Moreover, expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), a marker of joint cartilage injury, was similarly elevated following MIA administration. When MSC were injected intraarticularly after MIA, the expression of CGRP in the spinal dorsal horn was significantly deceased, indicating suppression of the central sensitization of pain. The expression of ADAMTS 5 in joint cartilage was also significantly inhibited by MSC administration. In contrast, a significant increase in the expression of TNF-α stimulated gene/protein 6 (TSG-6), an anti-inflammatory and cartilage protective factor shown to be produced and secreted by MSC intraarticularly, was found to extend to the cartilage tissue following MSC administration. In this way, the intraarticular injection of MSC inhibited the central sensitization of pain and increased the expression of the anti-inflammatory and cartilage protective factor TSG-6. As the least invasive conservative strategies possible are desirable in the actual clinical setting, the intraarticular administration of MSC, which appears to be effective for the treatment of pain and cartilage protection in early-stage arthritis, may achieve these aims. PMID:29315262

NMDA or non-NMDA receptor antagonism within the amygdaloid central nucleus suppresses the affective dimension of pain in rats: evidence for hemispheric synergy.

PubMed

Spuz, Catherine A; Borszcz, George S

2012-04-01

The amygdala contributes to generation of affective behaviors to threats. The prototypical threat to an individual is exposure to a noxious stimulus and the amygdaloid central nucleus (CeA) receives nociceptive input that is mediated by glutamatergic neurotransmission. The present study evaluated the contribution of glutamate receptors in CeA to generation of the affective response to acute pain in rats. Vocalizations that occur following a brief noxious tail shock (vocalization afterdischarges) are a validated rodent model of pain affect, and were preferentially suppressed by bilateral injection into CeA of the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (AP5, 1 μg, 2 μg, or 4 μg) or the non-NMDA receptor antagonist 6-Cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX, .25 μg, .5 μg, 1 μg, or 2 μg). Vocalizations that occur during tail shock were suppressed to a lesser degree, whereas spinal motor reflexes (tail flick and hind limb movements) were unaffected by injection of AP5 or CNQX into CeA. Unilateral administration of AP5 or CNQX into CeA of either hemisphere also selectively elevated vocalization thresholds. Bilateral administration of AP5 or CNQX produced greater increases in vocalization thresholds than the same doses of antagonists administered unilaterality into either hemisphere indicating synergistic hemispheric interactions. The amygdala contributes to production of emotional responses to environmental threats. Blocking glutamate neurotransmission within the central nucleus of the amygdala suppressed rats' emotional response to acute painful stimulation. Understanding the neurobiology underlying emotional responses to pain will provide insights into new treatments for pain and its associated affective disorders. Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.

Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain.

PubMed

Moloney, Rachel D; Golubeva, Anna V; O'Connor, Richard M; Kalinichev, Mikhail; Dinan, Timothy G; Cryan, John F

2015-01-01

Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect through ionotropic and metabotropic receptors. Of these, group III mGlu receptors (mGlu 4, 6, 7, 8) are among the least studied due to a lack of pharmacological tools. mGlu7 receptors, the most highly conserved isoform, are abundantly distributed in the brain, especially in regions, such as the amygdala, known to be crucial for the emotional processing of painful stimuli. Visceral hypersensitivity is a poorly understood phenomenon manifesting as an increased sensitivity to visceral stimuli. Glutamate has long been associated with somatic pain processing leading us to postulate that crossover may exist between these two modalities. Moreover, stress has been shown to exacerbate visceral pain. ADX71743 is a novel, centrally penetrant, negative allosteric modulator of mGlu7 receptors. Thus, we used this tool to explore the possible involvement of this receptor in the mediation of visceral pain in a stress-sensitive model of visceral hypersensitivity, namely the Wistar Kyoto (WKY) rat. ADX71743 reduced visceral hypersensitivity in the WKY rat as exhibited by increased visceral sensitivity threshold with concomitant reductions in total number of pain behaviours. Moreover, AD71743 increased total distance and distance travelled in the inner zone of the open field. These findings show, for what is to our knowledge, the first time, that mGlu7 receptor signalling plays a role in visceral pain processing. Thus, negative modulation of the mGlu7 receptor may be a plausible target for the amelioration of stress-induced visceral pain where there is a large unmet medical need.

Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain

PubMed Central

Moloney, Rachel D.; Golubeva, Anna V.; O'Connor, Richard M.; Kalinichev, Mikhail; Dinan, Timothy G.; Cryan, John F.

2015-01-01

Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect through ionotropic and metabotropic receptors. Of these, group III mGlu receptors (mGlu 4, 6, 7, 8) are among the least studied due to a lack of pharmacological tools. mGlu7 receptors, the most highly conserved isoform, are abundantly distributed in the brain, especially in regions, such as the amygdala, known to be crucial for the emotional processing of painful stimuli. Visceral hypersensitivity is a poorly understood phenomenon manifesting as an increased sensitivity to visceral stimuli. Glutamate has long been associated with somatic pain processing leading us to postulate that crossover may exist between these two modalities. Moreover, stress has been shown to exacerbate visceral pain. ADX71743 is a novel, centrally penetrant, negative allosteric modulator of mGlu7 receptors. Thus, we used this tool to explore the possible involvement of this receptor in the mediation of visceral pain in a stress-sensitive model of visceral hypersensitivity, namely the Wistar Kyoto (WKY) rat. ADX71743 reduced visceral hypersensitivity in the WKY rat as exhibited by increased visceral sensitivity threshold with concomitant reductions in total number of pain behaviours. Moreover, AD71743 increased total distance and distance travelled in the inner zone of the open field. These findings show, for what is to our knowledge, the first time, that mGlu7 receptor signalling plays a role in visceral pain processing. Thus, negative modulation of the mGlu7 receptor may be a plausible target for the amelioration of stress-induced visceral pain where there is a large unmet medical need. PMID:26844237

[6]-gingerol and [6]-shogaol, active ingredients of the traditional Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced pain via action on Na+ channels.

PubMed

Hitomi, Suzuro; Ono, Kentaro; Terawaki, Kiyoshi; Matsumoto, Chinami; Mizuno, Keita; Yamaguchi, Kiichiro; Imai, Ryota; Omiya, Yuji; Hattori, Tomohisa; Kase, Yoshio; Inenaga, Kiyotoshi

2017-03-01

The traditional Japanese herbal medicine hangeshashinto (HST) has beneficial effects for the treatment of oral ulcerative mucositis (OUM) in cancer patients. However, the ingredient-based mechanism that underlies its pain-relieving activity remains unknown. In the present study, to clarify the analgesic mechanism of HST on OUM-induced pain, we investigated putative HST ingredients showing antagonistic effects on Na + channels in vitro and in vivo. A screen of 21 major ingredients using automated patch-clamp recordings in channel-expressing cells showed that [6]-gingerol and [6]-shogaol, two components of a Processed Ginger extract, considerably inhibited voltage-activated Na + currents. These two ingredients inhibited the stimulant-induced release of substance P and action potential generation in cultured rat sensory neurons. A submucosal injection of a mixture of [6]-gingerol and [6]-shogaol increased the mechanical withdrawal threshold in healthy rats. In a rat OUM model, OUM-induced mechanical pain was alleviated 30min after the swab application of HST despite the absence of anti-bacterial and anti-inflammatory actions in the OUM area. A swab application of a mixture of [6]-gingerol and [6]-shogaol induced sufficient analgesia of OUM-induced mechanical or spontaneous pain when co-applied with a Ginseng extract containing abundant saponin. The Ginseng extract demonstrated an acceleration of substance permeability into the oral ulcer tissue without an analgesic effect. These findings suggest that Na + channel blockage by gingerol/shogaol plays an essential role in HST-associated analgesia of OUM-induced pain. This pharmacological mechanism provides scientific evidence supporting the use of this herbal medicine in patients suffering from OUM-induced pain. Copyright © 2017 Elsevier Ltd. All rights reserved.

Spinal intracellular metabotropic glutamate receptor 5 (mGluR5) contributes to pain and c-fos expression in a rat model of inflammatory pain.

PubMed

Vincent, Kathleen; Wang, Shu Fan; Laferrière, André; Kumar, Naresh; Coderre, Terence J

2017-04-01

Metabotropic glutamate receptor 5 (mGluR5) is an excitatory G-protein-coupled receptor (GPCR) present in the spinal cord dorsal horn (SCDH) where it has a well-established role in pain. In addition to its traditional location on the cytoplasmic membrane, recent evidence shows that these receptors are present intracellularly on the nuclear membrane in the spinal cord dorsal horn and are implicated in neuropathic pain. Nuclear mGluR5 is a functional receptor that binds glutamate entering the cell through the neuronal glutamate transporter (GT) EAAT3 and activates transcription factor c-fos, whereas plasma membrane mGluR5 is responsible for c-jun activation. Here, we extend these findings to a model of inflammatory pain using complete Freund's adjuvant (CFA) and show that nuclear mGluR5 is also upregulated in the spinal cord dorsal horn following inflammation. We also show that pretreatment with an excitatory amino acid transporter (EAAT) inhibitor attenuates pain and decreases Fos, but not Jun, expression in complete Freund's adjuvant rats. In contrast, selective glial glutamate transporter inhibitors are pronociceptive and increase spinal glutamate concentrations. Additionally, we found that permeable mGluR5 antagonists are more effective at attenuating pain and Fos expression than nonpermeable group I mGluR antagonists. Taken together, these results suggest that under inflammatory conditions, intracellular mGluR5 is actively involved in the relay of nociceptive information in the spinal cord.

Pharmacokinetics and Pharmacodynamics of (S)-Ketoprofen Co-Administered with Caffeine: A Preclinical Study in Arthritic Rats.

PubMed

Medina-López, Raúl; Vara-Gama, Nancy; Soria-Arteche, Olivia; Moreno-Rocha, Luis A; López-Muñoz, Francisco J

2018-01-26

The purpose of the present study was to determine whether caffeine modifies the pharmacokinetics and pharmacodynamics of ( S )-ketoprofen following oral administration in a gout-type pain model. 3.2 mg/kg of ( S )-ketoprofen alone and combined with 17.8 mg/kg of caffeine were administered to Wistar rats and plasma levels were determined between 0.5 and 24.0 h. Additionally, antinociception was evaluated based on the protocol of the PIFIR (pain-induced functional impairment in the rat) model before blood sampling between 0.5 and 4.0 h. Significant differences in C max , AUC 0-24 , and AUC 0-∞ values were observed with caffeine administration ( p < 0.05). Also, significant differences in E max , T max , and AUC 0-4 values were determined when comparing the treatments with and without caffeine ( p < 0.05). By relating the pharmacokinetic and pharmacodynamic data, a counter-clockwise hysteresis loop was observed regardless of the administration of caffeine. When the relationship between AUCe and AUCp was fitted to the sigmoidal E max model, a satisfactory correlation was found (R² > 0.99) as well as significant differences in E max and EC 50 values ( p < 0.05). With caffeine, E max and EC 50 values changed by 489.5% and 695.4%, respectively. The combination studied represents a convenient alternative for the treatment of pain when considering the advantages offered by using drugs with different mechanisms of action.

Pharmacokinetics and Pharmacodynamics of (S)-Ketoprofen Co-Administered with Caffeine: A Preclinical Study in Arthritic Rats

PubMed Central

Vara-Gama, Nancy; Soria-Arteche, Olivia; Moreno-Rocha, Luis A.; López-Muñoz, Francisco J.

2018-01-01

The purpose of the present study was to determine whether caffeine modifies the pharmacokinetics and pharmacodynamics of (S)-ketoprofen following oral administration in a gout-type pain model. 3.2 mg/kg of (S)-ketoprofen alone and combined with 17.8 mg/kg of caffeine were administered to Wistar rats and plasma levels were determined between 0.5 and 24.0 h. Additionally, antinociception was evaluated based on the protocol of the PIFIR (pain-induced functional impairment in the rat) model before blood sampling between 0.5 and 4.0 h. Significant differences in Cmax, AUC0-24, and AUC0-∞ values were observed with caffeine administration (p < 0.05). Also, significant differences in Emax, Tmax, and AUC0-4 values were determined when comparing the treatments with and without caffeine (p < 0.05). By relating the pharmacokinetic and pharmacodynamic data, a counter-clockwise hysteresis loop was observed regardless of the administration of caffeine. When the relationship between AUCe and AUCp was fitted to the sigmoidal Emax model, a satisfactory correlation was found (R2 > 0.99) as well as significant differences in Emax and EC50 values (p < 0.05). With caffeine, Emax and EC50 values changed by 489.5% and 695.4%, respectively. The combination studied represents a convenient alternative for the treatment of pain when considering the advantages offered by using drugs with different mechanisms of action. PMID:29373537

Pressure hyperalgesia in hind limb suspended rats.

PubMed

Chowdhury, Parimal; Soulsby, Michael E; Jayroe, John; Akel, Nisreen S; Gaddy, Dana; Dobretsov, Maxim

2011-10-01

Spaceflight and simulated microgravity often associate with pain and prediabetes. Streptozotocin (STZ)-induced moderate insulinopenia rat models of prediabetes result in pressure hyperalgesia. The current study was designed to determine whether or not simulated microgravity induced by hind limb suspension (HLS) in rats lead to insulinopenia and pressure hyperalgesia. Adult male rats were divided into HLS (N = 20) and control, non-suspended (N = 16) groups, respectively. Bodyweight and hind limb pressure-pain withdrawal threshold (PPT) were measured at regular 2-5 d intervals for 7 d before and 12-13 d after HLS. Bodyweights and PPT of control and HLS animals measured on the day of suspension were not different. During the experiment, control rats gained 61 +/- 5 g, but maintained their PPT at the baseline level. Suspended rats gained 26 +/- 3 g of weight during the same time period and their PPT declined from 105 +/- 6 g to 84 +/- 6 g. Neither blood glucose nor pancreatic islet density and area were affected by HLS. However, the random plasma insulin of HLS rats was significantly lower than that of control animals (1.6 +/- 0.2 vs. 2.7 +/- 0.2 ng ml(-1)). The observed relationship between insulin and PPT levels in the HLS rats was similar to that observed in rats with STZ-induced insulinopenia. These data suggest that moderate insulinopenia may affect the rat's sensitivity to deep pressure directly, without affecting glucose homeostasis. In addition, our data suggest that HLS rats may develop peripheral neuropathy.

Activation of Extracellular Signal-Regulated Kinases (ERK 1/2) in the Locus Coeruleus Contributes to Pain-Related Anxiety in Arthritic Male Rats

PubMed Central

Borges, Gisela; Miguelez, Cristina; Neto, Fani; Mico, Juan Antonio; Ugedo, Luisa

2017-01-01

Abstract Background: There is increasing evidence suggesting that the Locus Coeruleus plays a role in pain-related anxiety. Indeed, we previously found that prolonged arthritis produces anxiety-like behavior in rats, along with enhanced expression of phosphorylated extracellular signal-regulated kinase 1/2 (a marker of plasticity) in the Locus Coeruleus. However, it is unknown how this effect correlates with the electrophysiological activity of Locus Coeruleus neurons or pain-related anxiety. Methods: Using the complete Freund’s adjuvant model of monoarthritis in male Sprague-Dawley rats, we studied the behavioral attributes of pain and anxiety as well as Locus Coeruleus electrophysiology in vivo 1 (MA1W) and 4 weeks (MA4W) after disease induction. Results: The manifestation of anxiety in MA4W was accompanied by dampened tonic Locus Coeruleus activity, which was coupled to an exacerbated evoked Locus Coeruleus response to noxious stimulation of the inflamed and healthy paw. When a mitogen-activating extracellular kinase inhibitor was administered to the contralateral Locus Coeruleus of MA4W, the phosphorylated extracellular signal-regulated kinase 1/2 levels in the Locus Coeruleus were restored and the exaggerated evoked response was blocked, reversing the anxiogenic-like behavior while pain hypersensitivity remained unaltered. Conclusion: As phosphorylated extracellular signal-regulated kinase 1/2 blockade in the Locus Coeruleus relieved anxiety and counteracted altered LC function, we propose that phosphorylated extracellular signal-regulated kinase 1/2 activation in the Locus Coeruleus plays a crucial role in pain-related anxiety. PMID:28158734

Activation of Extracellular Signal-Regulated Kinases (ERK 1/2) in the Locus Coeruleus Contributes to Pain-Related Anxiety in Arthritic Male Rats.

PubMed

Borges, Gisela; Miguelez, Cristina; Neto, Fani; Mico, Juan Antonio; Ugedo, Luisa; Berrocoso, Esther

2017-06-01

There is increasing evidence suggesting that the Locus Coeruleus plays a role in pain-related anxiety. Indeed, we previously found that prolonged arthritis produces anxiety-like behavior in rats, along with enhanced expression of phosphorylated extracellular signal-regulated kinase 1/2 (a marker of plasticity) in the Locus Coeruleus. However, it is unknown how this effect correlates with the electrophysiological activity of Locus Coeruleus neurons or pain-related anxiety. Using the complete Freund's adjuvant model of monoarthritis in male Sprague-Dawley rats, we studied the behavioral attributes of pain and anxiety as well as Locus Coeruleus electrophysiology in vivo 1 (MA1W) and 4 weeks (MA4W) after disease induction. The manifestation of anxiety in MA4W was accompanied by dampened tonic Locus Coeruleus activity, which was coupled to an exacerbated evoked Locus Coeruleus response to noxious stimulation of the inflamed and healthy paw. When a mitogen-activating extracellular kinase inhibitor was administered to the contralateral Locus Coeruleus of MA4W, the phosphorylated extracellular signal-regulated kinase 1/2 levels in the Locus Coeruleus were restored and the exaggerated evoked response was blocked, reversing the anxiogenic-like behavior while pain hypersensitivity remained unaltered. As phosphorylated extracellular signal-regulated kinase 1/2 blockade in the Locus Coeruleus relieved anxiety and counteracted altered LC function, we propose that phosphorylated extracellular signal-regulated kinase 1/2 activation in the Locus Coeruleus plays a crucial role in pain-related anxiety. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Sequential variation in brain functional magnetic resonance imaging after peripheral nerve injury: A rat study.

PubMed

Onishi, Okihiro; Ikoma, Kazuya; Oda, Ryo; Yamazaki, Tetsuro; Fujiwara, Hiroyoshi; Yamada, Shunji; Tanaka, Masaki; Kubo, Toshikazu

2018-04-23

Although treatment protocols are available, patients experience both acute neuropathic pain and chronic neuropathic pain, hyperalgesia, and allodynia after peripheral nerve injury. The purpose of this study was to identify the brain regions activated after peripheral nerve injury using functional magnetic resonance imaging (fMRI) sequentially and assess the relevance of the imaging results using histological findings. To model peripheral nerve injury in male Sprague-Dawley rats, the right sciatic nerve was crushed using an aneurysm clip, under general anesthesia. We used a 7.04T MRI system. T 2 * weighted image, coronal slice, repetition time, 7 ms; echo time, 3.3 ms; field of view, 30 mm × 30 mm; pixel matrix, 64 × 64 by zero-filling; slice thickness, 2 mm; numbers of slices, 9; numbers of average, 2; and flip angle, 8°. fMR images were acquired during electrical stimulation to the rat's foot sole; after 90 min, c-Fos immunohistochemical staining of the brain was performed in rats with induced peripheral nerve injury for 3, 6, and 9 weeks. Data were pre-processed by realignment in the Statistical Parametric Mapping 8 software. A General Linear Model first level analysis was used to obtain T-values. One week after the injury, significant changes were detected in the cingulate cortex, insular cortex, amygdala, and basal ganglia; at 6 weeks, the brain regions with significant changes in signal density were contracted; at 9 weeks, the amygdala and hippocampus showed activation. Histological findings of the rat brain supported the fMRI findings. We detected sequential activation in the rat brain using fMRI after sciatic nerve injury. Many brain regions were activated during the acute stage of peripheral nerve injury. Conversely, during the chronic stage, activation of the amygdala and hippocampus may be related to chronic-stage hyperalgesia, allodynia, and chronic neuropathic pain. Copyright © 2018 Elsevier B.V. All rights reserved.

Trypsin-protease activated receptor-2 signaling contributes to pancreatic cancer pain

PubMed Central

Zhu, Jiao; Miao, Xue-Rong; Tao, Kun-Ming; Zhu, Hai; Liu, Zhi-Yun; Yu, Da-Wei; Chen, Qian-Bo; Qiu, Hai-Bo; Lu, Zhi-Jie

2017-01-01

Pain treatment is a critical aspect of pancreatic cancer patient clinical care. This study investigated the role of trypsin-protease activated receptor-2 (PAR-2) in pancreatic cancer pain. Pancreatic tissue samples were collected from pancreatic cancer (n=22) and control patients (n=22). Immunofluorescence analyses confirmed colocalization of PAR-2 and neuronal markers in pancreatic cancer tissues. Trypsin levels and protease activities were higher in pancreatic cancer tissue specimens than in the controls. Supernatants from cultured human pancreatic cancer tissues (PC supernatants) induced substance P and calcitonin gene-related peptide release in dorsal root ganglia (DRG) neurons, and FS-NH2, a selective PAR-2 antagonist, inhibited this effect. A BALB/c nude mouse orthotopic tumor model was used to confirm the role of PAR-2 signaling in pancreatic cancer visceral pain, and male Sprague-Dawley rats were used to assess ambulatory pain. FS-NH2 treatment decreased hunch scores, mechanical hyperalgesia, and visceromotor reflex responses in tumor-bearing mice. In rats, subcutaneous injection of PC supernatant induced pain behavior, which was alleviated by treatment with FS-NH2 or FUT-175, a broad-spectrum serine protease inhibitor. Our findings suggest that trypsin-PAR-2 signaling contributes to pancreatic cancer pain in vivo. Treatment strategies targeting PAR-2 or its downstream signaling molecules might effectively relieve pancreatic cancer pain. PMID:28977906

Effect of spinal monoaminergic neuronal system dysfunction on pain threshold in rats, and the analgesic effect of serotonin and norepinephrine reuptake inhibitors.

PubMed

Tamano, Ryuta; Ishida, Mitsuhiro; Asaki, Toshiyuki; Hasegawa, Minoru; Shinohara, Shunji

2016-02-26

Dysfunction in the central serotonin (5-HT) and norepinephrine (NE) systems cause depression and pain. Descending spinal pain modulatory pathways are important in the analgesic mechanisms of antidepressants, particularly serotonin and norepinephrine reuptake inhibitors (SNRIs). While many non-clinical studies have demonstrated the roles of central monoaminergic systems in pain, there is little evidence to illuminate the direct contribution of spinal descending pain modulatory systems independently of depressive-like behavior. To examine the effects of dysfunction of spinal monoaminergic systems on pain sensitivity, we established a rat chronic pain model by administering lumbar-intrathecal reserpine to minimize its influence on brain. Lumbar-intrathecal reserpine evoked persistent mechanical hypersensitivity and corresponding reductions in spinal 5-HT and NE concentrations (from 767.2 to 241.6ng/g and from 455.9 to 41.7ng/g, respectively after reserpine 30nmol). Lumbar-intrathecal reserpine did not deplete brain monoamines or bring about depressive-like behavior in the forced swim test. Spinal monoamines depletion-induced pain sensitivity was ameliorated by lumbar-intrathecal administration of the SNRIs (duloxetine and milnacipran) in dose-dependent manners. These suggest that increased pain sensitivity could be induced by dysfunction solely of the descending pain modulatory system, regardless of depressive-like behavior, and lumbar-intrathecal administration of SNRIs could ameliorate the pain sensitivity which might be mediated by affecting the descending pain modulatory system in the spinal cord, not via their antidepressant effects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Prefrontal cortex and mediodorsal thalamus reduced connectivity is associated with spatial working memory impairment in rats with inflammatory pain.

PubMed

Cardoso-Cruz, Helder; Sousa, Mafalda; Vieira, Joana B; Lima, Deolinda; Galhardo, Vasco

2013-11-01

The medial prefrontal cortex (mPFC) and the mediodorsal thalamus (MD) form interconnected neural circuits that are important for spatial cognition and memory, but it is not known whether the functional connectivity between these areas is affected by the onset of an animal model of inflammatory pain. To address this issue, we implanted 2 multichannel arrays of electrodes in the mPFC and MD of adult rats and recorded local field potential activity during a food-reinforced spatial working memory task. Recordings were performed for 3weeks, before and after the establishment of the pain model. Our results show that inflammatory pain caused an impairment of spatial working memory performance that is associated with changes in the activity of the mPFC-MD circuit; an analysis of partial directed coherence between the areas revealed a global decrease in the connectivity of the circuit. This decrease was observed over a wide frequency range in both the frontothalamic and thalamofrontal directions of the circuit, but was more evident from MD to mPFC. In addition, spectral analysis revealed significant oscillations of power across frequency bands, namely with a strong theta component that oscillated after the onset of the painful condition. Finally, our data revealed that chronic pain induces an increase in theta/gamma phase coherence and a higher level of mPFC-MD coherence, which is partially conserved across frequency bands. The present results demonstrate that functional disturbances in mPFC-MD connectivity are a relevant cause of deficits in pain-related working memory. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Ultrasound of alternating frequencies and variable emotional impact evokes depressive syndrome in mice and rats.

PubMed

Morozova, Anna; Zubkov, Eugene; Strekalova, Tatyana; Kekelidze, Zurab; Storozeva, Zinaida; Schroeter, Careen A; Bazhenova, Nataliia; Lesch, Klaus-Peter; Cline, Brandon H; Chekhonin, Vladimir

2016-07-04

Emotional stress is primarily triggered by the cognitive processing of negative input; it is regarded as a serious pathogenetic factor of depression that is challenging to model in animals. While available stress paradigms achieve considerable face and construct validity in modelling depressive disorders, broader use of naturalistic stressors instead of the more prevalent models with artificial challenges inducing physical discomfort or pain may substantially contribute to the development of novel antidepressants. Here, we investigated whether a 3-week exposure of Wistar rats and Balb/c mice to unpredictably alternating frequencies of ultrasound between the ranges of 20-25 and 25-45kHz, which are known to correspond with an emotionally negative and with a neutral emotional state, respectively, for small rodents in nature, can induce behavioural and molecular depressive-like changes. Both rats and mice displayed decreased sucrose preference, elevated "despair" behaviour in a swim test, reduced locomotion and social exploration. Rats showed an increased expression of SERT and 5-HT2A receptor, a decreased expression of 5-HT1A receptor in the prefrontal cortex and hippocampus, diminished BDNF on gene and protein levels in the hippocampus. Fluoxetine, administered to rats at the dose of 10mg/kg, largely precluded behavioural depressive-like changes. Thus, the here applied paradigm of emotional stress is generating an experimental depressive state in rodents, which is not related to any physical stressors or pain. In essence, this ultrasound stress model, besides enhancing animal welfare, is likely to provide improved validity in the modelling of clinical depression and may help advance translational research and drug discovery for this disorder. Copyright © 2016. Published by Elsevier Inc.

Bioactive Turmerosaccharides from Curcuma longa Extract (NR-INF-02): Potential Ameliorating Effect on Osteoarthritis Pain.

PubMed

Bethapudi, Bharathi; Murugan, Sasikumar; Illuri, Ramanaiah; Mundkinajeddu, Deepak; Velusami, Chandrasekaran Chinampudur

2017-10-01

Curcuma longa has long history of medicinal use in Ayurveda. A unique product NR-INF-02 was prepared from C. longa that was standardized to contain turmerosaccharides. The present study investigated the effect of turmerosaccharides rich fraction of NR-INF-02 on monosodium iodoacetate (MIA)-induced OA pain animal model that mimics human OA. Further, the analgesic effect of turmerosaccharides rich fraction was compared to turmerosaccharides less fraction of NR-INF-02. OA pain was chemically induced by intra-articular administration of single dose of 25 μl of 0.9% saline containing 0.3 mg MIA into the right knee of male albino Wistar rat. Turmerosaccharides rich fraction and turmerosaccharides less fraction (at 22.5, 45 and 90 mg/kg rat body weight dose levels) were administered as a single dose orally on day 5 of post-MIA injection. OA pain was measured using hind limb weight-bearing ability at 1, 3, 6, and 24 h post-test substance administration on day 5. Oral administration of turmerosaccharides rich fraction and turmerosaccharides less fraction (at 45 and 90 mg/kg) although significantly decreased the OA pain at all the intervals, the effect of turmerosaccharides rich fraction (57%) on OA pain was superior to turmerosaccharides less fraction (35%). Bioactive turmerosaccharides from C. longa extract contribute to the observed anti-arthritic effect in rats. Osteoarthritic pain was induced by intra-articular injection of MIA into the right kneeSingle administration of TRF/TLF on day 5 resulted in dose-dependent significant reduction of OA painTRF showed better analgesic activity than TLFTRF at 45 and 90 mg/kg has similar effects on OA pain as that of tramadolTurmerosaccharides identified as bioactive constituents of C. longa extract. Abbreviations used: MIA: Monosodium iodoacetate; i.ar: Intra-articular; OA: Osteoarthritis; TRF: Turmerosaccharides rich fraction; TLF: Turmerosaccharides less fraction; PGE2: Prostaglandin E2; ROS: Reactive oxygen species.

Role of Kv4.3 in Vibration-Induced Muscle Pain in the Rat.

PubMed

Conner, Lindsay B; Alvarez, Pedro; Bogen, Oliver; Levine, Jon D

2016-04-01

We hypothesized that changes in the expression of voltage-gated potassium channel (Kv) 4.3 contribute to the mechanical hyperalgesia induced by vibration injury, in a rodent model for hand-arm vibration syndrome in humans. Here we show that the exposure of the gastrocnemius muscle to vibration injury induces muscle hyperalgesia that is accompanied by a significant downregulation of Kv4.3 in affected sensory nerve fibers in dorsal root ganglia. We additionally show that the intrathecal administration of antisense oligonucleotides for Kv4.3 messenger RNA itself induces muscle hyperalgesia in the rat. Our results suggest that attenuation in the expression of Kv4.3 may contribute to neuropathic pain in people affected by hand-arm vibration syndrome. Our findings establish Kv4.3 as a potential molecular target for the treatment of hand-arm vibration syndrome. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Antinociceptive effects, acute toxicity and chemical composition of Vitex agnus-castus essential oil.

PubMed

Khalilzadeh, Emad; Vafaei Saiah, Gholamreza; Hasannejad, Hamideh; Ghaderi, Adel; Ghaderi, Shahla; Hamidian, Gholamreza; Mahmoudi, Razzagh; Eshgi, Davoud; Zangisheh, Mahsa

2015-01-01

Vitex agnus-castus (VAC) and its essential oil have been traditionally used to treat many conditions and symptoms such as premenstrual problems, mastalgia, inflammation, sexual dysfunction, and pain. In this study, the effects of essential oil extracted from Vitex agnus-castus (EOVAC) leaves were investigated in three behavioral models of nociception in adult male Wistar rats. Chemical composition of EOVAC was analyzed using gas chromatography - mass spectrometry (GC-MS) and also its possible toxicity was determined in mice. Analgesic effect of EOVAC was determined using tail immersion test, formalin test, and acetic acid-induced visceral pain in rats. EOVAC (s.c.) and morphine (i.p.) significantly (p<0.05) reduced pain responses in both formalin and tail immersion tests. In the study of evolved mechanisms, pretreatment with naloxone or atropine significantly (p <0.05) reversed the essential oil-induced analgesia in both formalin and tail immersion tests. Moreover, EOVAC and Piroxicam produced significant (p<0.05) inhibition in the acetic acid-induced writhing response. EOVAC did not show any mortality even at high dose (5 g/kg, p.o.) of administration in toxicity test. Moreover, according to GC-MS results, major components of the EOVAC were α-pinene (14.83%), limonene (10.29%), β-caryophyllene (6.9%), sabinene (5.27%), and β-farnesene (5.9%). These results suggest that endogenous opioidergic system as well as muscarinergic receptors of cholinergic system may be involve in the antinociceptive activity of Vitex agnus-castus essential oil in these models of pain in rats.

Antinociceptive effects, acute toxicity and chemical composition of Vitex agnus-castus essential oil

PubMed Central

Khalilzadeh, Emad; Vafaei Saiah, Gholamreza; Hasannejad, Hamideh; Ghaderi, Adel; Ghaderi, Shahla; Hamidian, Gholamreza; Mahmoudi, Razzagh; Eshgi, Davoud; Zangisheh, Mahsa

2015-01-01

Objective: Vitex agnus-castus (VAC) and its essential oil have been traditionally used to treat many conditions and symptoms such as premenstrual problems, mastalgia, inflammation, sexual dysfunction, and pain. In this study, the effects of essential oil extracted from Vitex agnus-castus (EOVAC) leaves were investigated in three behavioral models of nociception in adult male Wistar rats. Materials and methods: Chemical composition of EOVAC was analyzed using gas chromatography – mass spectrometry (GC-MS) and also its possible toxicity was determined in mice. Analgesic effect of EOVAC was determined using tail immersion test, formalin test, and acetic acid-induced visceral pain in rats. Results: EOVAC (s.c.) and morphine (i.p.) significantly (p<0.05) reduced pain responses in both formalin and tail immersion tests. In the study of evolved mechanisms, pretreatment with naloxone or atropine significantly (p <0.05) reversed the essential oil-induced analgesia in both formalin and tail immersion tests. Moreover, EOVAC and Piroxicam produced significant (p<0.05) inhibition in the acetic acid-induced writhing response. EOVAC did not show any mortality even at high dose (5 g/kg, p.o.) of administration in toxicity test. Moreover, according to GC-MS results, major components of the EOVAC were α-pinene (14.83%), limonene (10.29%), β-caryophyllene (6.9%), sabinene (5.27%), and β-farnesene (5.9%). Conclusions: These results suggest that endogenous opioidergic system as well as muscarinergic receptors of cholinergic system may be involve in the antinociceptive activity of Vitex agnus-castus essential oil in these models of pain in rats. PMID:26101755

Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study.

PubMed

Wodarski, Rachel; Delaney, Ada; Ultenius, Camilla; Morland, Rosie; Andrews, Nick; Baastrup, Catherine; Bryden, Luke A; Caspani, Ombretta; Christoph, Thomas; Gardiner, Natalie J; Huang, Wenlong; Kennedy, Jeffrey D; Koyama, Suguru; Li, Dominic; Ligocki, Marcin; Lindsten, Annika; Machin, Ian; Pekcec, Anton; Robens, Angela; Rotariu, Sanziana M; VoB, Sabrina; Segerdahl, Marta; Stenfors, Carina; Svensson, Camilla I; Treede, Rolf-Detlef; Uto, Katsuhiro; Yamamoto, Kazumi; Rutten, Kris; Rice, Andrew S C

2016-10-01

Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats (Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP-all animals allocated to treatment; n = 249) and a selected population (SP-TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding "poor" burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of -374 g (-479 to -269 g) for TP and -498 g (-609 to -386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future.

Rubus occidentalis alleviates hyperalgesia induced by repeated intramuscular injection of acidic saline in rats.

PubMed

Choi, Geun Joo; Kang, Hyun; Kim, Won Joong; Baek, Chong Wha; Jung, Yong Hun; Woo, Young Cheol; Kwon, Ji Wung

2016-07-11

The purpose of this study was to evaluate the antinociceptive effect of black raspberry (Rubus occidentalis) fruit extract (ROE) in a rat model of chronic muscle pain and examine the mechanisms involved. Adult male Sprague-Dawley rats were used, and chronic muscle pain was induced by two injections of acidic saline into one gastrocnemius muscle. For the first experiment, 50 rats were randomly assigned to five groups. After the development of hyperalgesia, rats were injected intraperitoneally with 0.9 % saline or ROE (10, 30, 100, or 300 mg/kg). For the second experiment, 70 rats were randomly assigned to seven groups. Rats were injected intraperitoneally with saline, yohimbine, dexmedetomidine, prazosin, atropine, mecamylamine, or naloxone after the development of hyperalgesia. Ten minutes later, ROE (300 mg/kg) was administered intraperitoneally. For both experiments, the mechanical withdrawal threshold (MWT) was evaluated with von Frey filaments before the first acidic saline injection, 24 h after the second injection, and at 15, 30, 45, 60, 80, 100, and 120 min, 24 and 48 h after the drug administration. Compared with the control group, the MWT significantly increased up to 45 min after injection of ROE 100 mg/kg and up to 60 min after injection of ROE 300 mg/kg, respectively. Injection of ROE together with yohimbine or mecamylamine significantly decreased the MWT compared with the effect of ROE alone, while ROE together with dexmedetomidine significantly increased the MWT. ROE showed antinociceptive activity against induced chronic muscle pain, which may be mediated by α2-adrenergic and nicotinic cholinergic receptors.

Moxibustion relieves visceral hyperalgesia via inhibition of transient receptor potential vanilloid 1 (TRPV1) and heat shock protein (HSP) 70 expression in rat bone marrow cells.

PubMed

Zou, Weiying; Lin, Hua; Liu, Wenwen; Yang, Bei; Wu, Lei; Duan, Limin; Ling, Ping; Zhu, Lingyan; Dai, Qun; Zhao, Lintong; Zou, Ting; Zhang, Dalei

2016-04-01

To investigate the effects of moxibustion on visceral hyperalgesia (VH) and bone marrow cell transient receptor potential vanilloid type 1 (TRPV1) and heat shock protein (HSP) 70 expression in a rat model of VH. Mechanical colorectal distension was performed to induce VH in neonatal Sprague-Dawley rats. Eight-week-old VH rats were treated with moxibustion at acupuncture point BL25 or an ipsilateral non-acupuncture point. Abdominal withdrawal reflex (AWR) scoring and pain threshold pressure assessment were performed before and after moxibustion treatment for 7 consecutive days. The expression of TRPV1 and HSP70 in bone marrow cells was quantified by real-time quantitative PCR. The expression of TRPV1 and HSP70 in bone marrow cells was increased in rats with VH. Moxibustion at BL25 significantly decreased AWR scores and increased pain threshold pressure in rats with VH. Furthermore, moxibustion at BL25 significantly inhibited the VH-induced increase in the expression of TRPV1 and HSP70 in bone marrow cells. The up-regulation of TRPV1 and HSP70 expression in bone marrow cells may be involved in visceral pain development and the analgesic effect of moxibustion on VH may be mediated through down-regulation of TRPV1 and HSP70 expression in bone marrow cells. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats.

PubMed

Alvarez, Pedro; Green, Paul G; Levine, Jon D

2018-06-01

Neonatal handling (NH) of male rat pups strongly attenuates stress response and stress-induced persistent muscle hyperalgesia in adults. Because female sex is a well established risk factor for stress-induced chronic muscle pain, we explored whether NH provides resilience to stress-induced hyperalgesia in adult female rats. Rat pups underwent NH, or standard (control) care. Muscle mechanical nociceptive threshold was assessed before and after water avoidance (WA) stress, when they were adults. In contrast to male rats, NH produced only a modest protection against WA stress-induced muscle hyperalgesia in female rats. Gonadectomy completely abolished NH-induced resilience in male rats but produced only a small increase in this protective effect in female rats. The administration of the antiestrogen drug fulvestrant, in addition to gonadectomy, did not enhance the protective effect of NH in female rats. Finally, knockdown of the androgen receptor by intrathecal antisense treatment attenuated the protective effect of NH in intact male rats. Together, these data indicate that androgens play a key role in NH-induced resilience to WA stress-induced muscle hyperalgesia. NH induces androgen-dependent resilience to stress-induced muscle pain. Therefore, androgens may contribute to sex differences observed in chronic musculoskeletal pain and its enhancement by stress. Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.

17-β-Estradiol induces spreading depression and pain behavior in alert female rats

PubMed Central

Sandweiss, Alexander J.; Cottier, Karissa E.; McIntosh, Mary I.; Dussor, Gregory; Davis, Thomas P.; Vanderah, Todd W.; Largent-Milnes, Tally M.

2017-01-01

Aims Test the putative contribution of 17-β-estradiol in the development of spreading depression (SD) events and head pain in awake, non-restrained rats. Main Methods Female, Sprague-Dawley rats were intact or underwent ovariectomy followed one week later by surgery to place electrodes onto the dura to detect epidural electroencephalographic activity (dEEG). dEEG activity was recorded two days later for 12 hours after systemic administration of 17-β-estradiol (180 μg/kg, i.p.). A separate set of rats were observed for changes in exploratory, ambulatory, fine, and rearing behaviors; periorbital allodynia was also assessed. Key Findings A bolus of 17-β-estradiol significantly elevated serum estrogen levels, increased SD episodes over a 12-hour recording period and decreased rearing behaviors in ovariectomized rats. Pre-administration of ICI 182,780, an estrogen receptor antagonist, blocked 17-β-estradiol-evoked SD events and pain behaviors; similar results were observed when the antimigraine therapeutic sumatriptan was used. Significance These data indicate that an estrogen receptor-mediated mechanism contributes to SD events in ovariectomized rats and pain behaviors in both ovariectomized -and intact- rats. This suggests that estrogen plays a different role in each phenomenon of migraine where intense fluctuations in concentration may influence SD susceptibility. This is the first study to relate estrogen peaks to SD development and pain behaviors in awake, freely moving female rats, establishing a framework for future preclinical migraine studies. PMID:29371973

Electroacupuncture attenuates mechanical allodynia by suppressing the spinal JNK1/2 pathway in a rat model of inflammatory pain.

PubMed

Du, Jun-Ying; Fang, Jian-Qiao; Liang, Yi; Fang, Jun-Fan

2014-09-01

Electroacupuncture (EA) has a substantial analgesic effect on inflammatory pain induced by complete Freund's adjuvant (CFA). The activation of the c-Jun N-terminal kinase 1/2 (JNK1/2) signal transduction pathway in the spinal cord is associated with inflammatory pain. However, the relationship between EA's analgesic effect and the JNK1/2 signal transduction pathway in the inflammatory pain remain unclear. In the present study, we used the established rat model of CFA-induced inflammatory pain to investigate the role of the spinal JNK1/2 pathway in EA-mediated analgesia. We observed a decrease in paw withdrawal thresholds and an increase in paw edema at 1 and 3 days after injecting CFA into the right hindpaw. CFA, 3 days after injection, upregulated expression of phospho-c-Jun N-terminal kinase1/2 (p-JNK1/2) protein and its downstream targets, the transcriptional regulators p-c-Jun and activator protein-1 (AP-1), as well as cyclooxygenase-2 (COX-2) and the transient receptor potential vanilloid 1 (TRPV1). EA significantly alleviated CFA-induced inflammatory pain. In addition, EA reduced p-JNK1/2 protein levels and COX-2 mRNA expressions, a degree of down-regulated p-c-Jun protein level and AP-1 DNA binding activity in the spinal dorsal horn of CFA-administered animals, but it had no effect on TRPV1 mRNA expression. Furthermore, EA and the JNK inhibitor SP600125 synergistically inhibited CFA-induced hyperalgesia and suppressed the COX-2 mRNA expression in the spinal dorsal horn. Our findings indicate that EA alleviates inflammatory pain behavior, at least in part, by reducing COX-2 expression in the spinal cord via the JNK1/2 signaling pathway. Inactivation of the spinal JNK1/2 signal transduction pathway maybe the potential mechanism of EA's antinociception in the inflammatory pain model. Copyright © 2014 Elsevier Inc. All rights reserved.

Development of Intra-knee Joint Sustained-Release Gel Formulation and Evaluation of Its Pharmacological Efficiency in Rats.

PubMed

Noda, Takehiro; Okuda, Tomoyuki; Ban, Kousuke; Mizuno, Ryota; Tagami, Tatsuaki; Ozeki, Tetsuya; Okamoto, Hirokazu

2017-06-01

In the development of a drug for intra-articular administration, a sustained-release formulation is desirable since it is difficult to sustain the effects of conventional injections due to fast drug leakage from the joint cavity. In this study, we prepared sustained release gel formulations for intra-articular administration containing indocyanine green (ICG) as a model drug to follow its fate after intra-articular administration in rats with in-vivo imaging system (IVIS). ICG administered as an aqueous solution leaked from the joint cavity in a short time and was excreted out of the body within a day. On the other hand, ICG in the sustained-release formulations was retained and released in the joint cavity for a week. Next, we prepared a sustained-release formulation with hyaluronic acid (HA) as the gel base containing a pain-relief drug (Drug A). We had administered it and other formulations into the rat knee where we injected bradykinin to evaluate their walking distance after 1 and 3 d. The effect of an aqueous solution of Drug A disappeared on day 3. The HA gel formulation without Drug A was more effective than the aqueous solution. The HA gel formulation with Drug A was the most effective; the walking distance was about 85% of the baseline on day 3. This study showed that the gel formulations were effective to sustain the release of a drug in the knee joint, and that the combination of a pain-relief drug with HA gel was effective to improve the mobility of the acute pain model rats.

Intrathecal clonidine and bupivacaine have synergistic analgesia for acute thermally or inflammatory-induced pain in rats.

PubMed

Nishiyama, Tomoki; Hanaoka, Kazuo

2004-04-01

We investigated the interaction between spinally administered bupivacaine and clonidine using an animal model of acute and inflammatory pain. Rats implanted with lumbar intrathecal catheters were injected intrathecally with saline (control), bupivacaine (1 to 100 microg), or clonidine (0.1 to 3 microg) and tested for their responses to thermal stimulation to the tail (tail flick test) and subcutaneous formalin injection into the hindpaw (formalin test). The effects of the combination of bupivacaine and clonidine on both stimuli were tested by isobolographic analysis. General behavior and motor function were examined as side effects. The 50% effective doses of bupivacaine and clonidine were significantly smaller when combined compared with each single drug in both the tail flick test (2.82 and 0.11 microg versus 7.1 and 0.29 microg, respectively) and phase 1 (0.24 and 0.009 microg versus 5.7 and 0.15 microg) and phase 2 (0.31 and 0.012 microg versus 3.2 and 0.16 microg) of the formalin test. Side effects were decreased by the combination. These results suggest a favorable combination of intrathecal bupivacaine and clonidine in the management of acute and inflammatory pain. The analgesic interaction between intrathecally administered bupivacaine and clonidine was examined during acute thermal and inflammatory-induced pain in rats. The analgesia produced by the combination of these two drugs was synergistic in both acute thermal and inflammatory induced pain, with a decrease in behavioral side effects.

Nonlinear Inverted-U Shaped Relationship between Aging and Epidermal Innervation in the Rat Plantar Hind Paw: a Laser Scanning Confocal Microscopy Study.

PubMed

Kaliappan, Sankaranarayanan; Simone, Donald A; Banik, Ratan K

2018-04-13

The under-reporting of pain and atypical manifestations of painful syndromes within the elderly population have been well-documented, however, the specific relationship between pain and aging remains ambiguous. Previous studies have reported degenerative changes in primary afferents with aging. In this study, we questioned whether there is any change in the density of primary afferent endings within the epidermis of aged animals. Rats were categorically assessed in four age groups, each representing a key developmental stage across their life span: juvenile (2 months); adult (7 months); aged (18 months); and senescent (24-26 months). The plantar hind paw skin was removed, post-fixed, cut, and immunostained for protein gene product 9.5 and type IV collagen. Rats in the adult aged groups had significantly increased epidermal nerve densities and total lengths of immunoreactive nerve fibers, compared to both juvenile and senescent rats. However, the paw withdrawal thresholds to punctate mechanical stimulation progressively increased with age, and did not exhibit a clear relationship with epidermal innervation. We conclude a non-linear, inverted-U shaped relationship between rat plantar epidermal nerve density with aging, which does not correlate with mechanically-induced paw withdrawal behaviors. This article presents age-related decreased epidermal innervation in rat hind paw skin, which partly explains mechanisms underlying decreased pain sensitivity in aged subjects. The article may help clinicians to understand that any compromise of pain-sensing pathway can lead to under-reporting of pain, inadequate analgesia, and slower recovery from a painful condition. Copyright © 2018. Published by Elsevier Inc.

Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.

PubMed

Rojewska, Ewelina; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

2016-03-01

Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Spinal cord processing of cardiac nociception: are there sex differences between male and proestrous female rats?

PubMed

Little, Janine M; Qin, Chao; Farber, Jay P; Foreman, Robert D

2011-09-21

Sex differences in the characteristics of cardiac pain have been reported from clinical studies. For example, women experience chest pain less frequently than men. Women describe their chest pain as sharp and stabbing, while men have chest pain that is felt as a pressure or heaviness. Pain is also referred to the back more often in women than men. The mechanisms underlying sex differences in cardiac pain are unknown. One possible mechanism for the observed differences could be related to plasma estradiol. This study investigated the actions of estradiol on the activity of T(3) spinal neurons that process cardiosomatic information in male and female rats. Extracellular potentials of T(3) spinal neurons were recorded in response to mechanical somatic stimulation and noxious chemical cardiac stimulation in pentobarbital-anesthetized male and proestrous female rats. Fifty one percent and fifty percent of neurons responded to intrapericardial algogenic chemicals (0.2 ml) in male and female rats, respectively. Somatic fields were located by applying brush, pressure, and pinch to the upper body. Of those neurons receiving cardiac input, 54% in female and 55% in male rats also received somatic input. In both male and female rats, 81% of neurons responding to somatic stimuli had somatic fields located on the side of the upper body, while 19% of neurons had somatic fields located on the chest. These results indicate there are no significant differences in the responses of T(3) spinal neurons to cardiosomatic stimulation between male and proestrous female rats, despite differences in estradiol levels. Published by Elsevier B.V.

Epigenetic suppression of potassium-chloride co-transporter 2 expression in inflammatory pain induced by complete Freund's adjuvant (CFA).

PubMed

Lin, C-R; Cheng, J-K; Wu, C-H; Chen, K-H; Liu, C-K

2017-02-01

Multiple mechanisms contribute to the stimulus-evoked pain hypersensitivity that may be experienced after peripheral inflammation. Persistent pathological stimuli in many pain conditions affect the expression of certain genes through epigenetic alternations. The main purpose of our study was to investigate the role of epigenetic modification on potassium-chloride co-transporter 2 (KCC2) gene expression in the persistence of inflammatory pain. Persistent inflammatory pain was induced through the injection of complete Freund's adjuvant (CFA) in the left hind paw of rats. Acetyl-histone H3 and H4 level was determined by chromatin immunoprecipitation in the spinal dorsal horn. Pain behaviour and inhibitory synaptic function of spinal cord were determined before and after CFA injection. KCC2 expression was determined by real time RT-PCR and Western blot. Intrathecal KCC2 siRNA (2 μg per 10 μL per rat) or HDAC inhibitor (10 μg per 10 μL per rat) was injected once daily for 3 days before CFA injection. Persistent inflammatory pain epigenetically suppressed KCC2 expression through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in decreased inhibitory signalling efficacy. KCC2 knock-down caused by intrathecal administration of KCC2 siRNA in naïve rats reduced KCC2 expression in the spinal cord, leading to sensitized pain behaviours and impaired inhibitory synaptic transmission in their spinal cords. Moreover, intrathecal HDAC inhibitor injection in CFA rats increased KCC2 expression, partially restoring the spinal inhibitory synaptic transmission and relieving the sensitized pain behaviour. These findings suggest that the transcription of spinal KCC2 is regulated by histone acetylation epigenetically following CFA. Persistent pain suppresses KCC2 expression through HDAC-mediated histone hypoacetylation and consequently impairs the inhibitory function of inhibitory interneurons. Drugs such as HDAC inhibitors that suppress the influences of persistent pain on the expression of KCC2 may serve as a novel analgesic. © 2016 European Pain Federation - EFIC®.

Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature.

PubMed

Reilly, Regina M; McDonald, Heath A; Puttfarcken, Pamela S; Joshi, Shailen K; Lewis, LaGeisha; Pai, Madhavi; Franklin, Pamela H; Segreti, Jason A; Neelands, Torben R; Han, Ping; Chen, Jun; Mantyh, Patrick W; Ghilardi, Joseph R; Turner, Teresa M; Voight, Eric A; Daanen, Jerome F; Schmidt, Robert G; Gomtsyan, Arthur; Kort, Michael E; Faltynek, Connie R; Kym, Philip R

2012-08-01

The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.

Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents.

PubMed

Gui, Wen-Shan; Wei, Xiao; Mai, Chun-Lin; Murugan, Madhuvika; Wu, Long-Jun; Xin, Wen-Jun; Zhou, Li-Jun; Liu, Xian-Guo

2016-01-01

Chronic pain is often accompanied by short-term memory deficit and depression. Currently, it is believed that short-term memory deficit and depression are consequences of chronic pain. Here, we test the hypothesis that the symptoms might be caused by overproduction of interleukin-1beta (IL-1β) in the injured nerve independent of neuropathic pain following spared nerve injury in rats and mice. Mechanical allodynia, a behavioral sign of neuropathic pain, was not correlated with short-term memory deficit and depressive behavior in spared nerve injury rats. Spared nerve injury upregulated IL-1β in the injured sciatic nerve, plasma, and the regions in central nervous system closely associated with pain, memory and emotion, including spinal dorsal horn, hippocampus, prefrontal cortex, nucleus accumbens, and amygdala. Importantly, the spared nerve injury-induced memory deficits, depressive, and pain behaviors were substantially prevented by peri-sciatic administration of IL-1β neutralizing antibody in rats or deletion of IL-1 receptor type 1 in mice. Furthermore, the behavioral abnormalities induced by spared nerve injury were mimicked in naïve rats by repetitive intravenous injection of re combinant rat IL-1β (rrIL-1β) at a pathological concentration as determined from spared nerve injury rats. In addition, microglia were activated by both spared nerve injury and intravenous injection of rrIL-1β and the effect of spared nerve injury was substantially reversed by peri-sciatic administration of anti-IL-1β. Neuropathic pain was not necessary for the development of cognitive and emotional disorders, while the overproduction of IL-1β in the injured sciatic nerve following peripheral nerve injury may be a common mechanism underlying the generation of neuropathic pain, memory deficit, and depression. © The Author(s) 2016.

Pharmacological interaction between oxcarbazepine and two COX inhibitors in a rat model of inflammatory hyperalgesia.

PubMed

Stepanović-Petrović, Radica M; Tomić, Maja A; Vučković, Sonja M; Poznanović, Goran; Ugrešić, Nenad D; Prostran, Milica Š; Bošković, Bogdan

2011-01-01

Oxcarbazepine, ibuprofen and etodolac have efficacy in inflammatory pain. The combination of different drugs activates both central and peripheral pain inhibitory pathways to induce additive or synergistic antinociception, and this interaction may allow lower doses of each drug combined and improve the safety profile, with lower side-effects. This study aimed to examine the effects of oxcarbazepine-ibuprofen and oxcarbazepine-etodolac combinations, in a rat model of inflammatory hyperalgesia, and determine the type of interaction between drugs. Rats were intraplantarly injected with carrageenan (0.1 ml, 1%) and the hyperalgesia was assessed by modified paw pressure test. The anti-hyperalgesic effects of oxcarbazepine, ibuprofen and etodolac and oxcarbazepine-ibuprofen and oxcarbazepine-etodolac combinations were examined. Drugs were co-administered in a fixed-dose fractions of the ED₅₀ and the type of interaction was determined by isobolographic analysis. Oxcarbazepine (40-160 mg/kg; p.o.), ibuprofen (10-120 mg/kg; p.o.) and etodolac (5-20 mg/kg; p.o.) produced a significant, dose-dependent anti-hyperalgesia in carrageenan-injected rats. ED₅₀ values (mean±SEM) for oxcarbazepine, ibuprofen and etodolac were 88.17±3.65, 47.07±10.27 and 13.05±1.42 mg/kg, respectively. Oxcarbazepine-ibuprofen and oxcarbazepine-etodolac combinations induced significant and dose-dependent anti-hyperalgesia. Isobolographic analysis revealed that oxcarbazepine exerts a synergistic interaction with ibuprofen, with almost 4-fold reduction of doses of both drugs in combination. In contrast, there was an additive interaction with etodolac. Synergistic interaction of oxcarbazepine with ibuprofen and its additive interaction with etodolac provide new information about the combination pain treatment and could be explored further in patients with inflammatory pain. Adverse effect analysis of the combinations is necessary to verify possible clinical use of the mixtures. Copyright © 2010 Elsevier Inc. All rights reserved.

Mast cell deficiency attenuates acupuncture analgesia for mechanical pain using c-kit gene mutant rats.

PubMed

Cui, Xiang; Liu, Kun; Xu, Dandan; Zhang, Youyou; He, Xun; Liu, Hao; Gao, Xinyan; Zhu, Bing

2018-01-01

Acupuncture therapy plays a pivotal role in pain relief, and increasing evidence demonstrates that mast cells (MCs) may mediate acupuncture analgesia. The present study aims to investigate the role of MCs in acupuncture analgesia using c-kit gene mutant-induced MC-deficient rats. WsRC-Ws/Ws rats and their wild-type (WT) littermates (WsRC-+/+) were used. The number of MCs in skin of ST36 area was compared in two rats after immunofluorescence labeling. Mechanical withdrawal latency (MWL), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) were measured on bilateral plantar for pain threshold evaluation before and after each stimulus. Acupuncture- and moxibustion-like stimuli (43°C, 46°C heat, 1 mA electroacupuncture [EA], 3 mA EA, and manual acupuncture [MA]) were applied randomly on different days. Fewer MCs were observed in the skin of ST36 in mutant rats compared to WT rats ( P <0.001). For pain thresholds, MWL and MWT were higher in WsRC-Ws/Ws compared to WsRC-+/+ on bilateral paws ( P <0.05), but TWL was not different between the two rats ( P >0.05). Bilateral MWL and MWT in WsRC-+/+ rats increased significantly after each stimulus compared to baseline ( P <0.01, P <0.001). In WsRC-Ws/Ws rats, only noxious stimuli could produce anti-nociceptive effects for mechanical pain (46°C, 3 mA EA, MA) ( P <0.01, P <0.001). Additionally, the net increases in MWL and MWT induced by most stimuli were greater in WT than in mutant rats ( P <0.05). For thermal nociception, either high- or low-intensity stimuli could significantly augment TWL in two rats ( P <0.001), and the net increases of TWL evoked by most stimuli were to the same extent in two genetic variants. MCs influence the basic mechanical but not thermal pain threshold. MCs participate in acupuncture analgesia in mechanical but not in thermal nociception, in that MC deficiency may attenuate the mechanical analgesia evoked by high-intensity stimuli and eliminate analgesia provoked by low-intensity stimuli.

Effects of intrathecal lidocaine on hyperalgesia and allodynia following chronic constriction injury in rats.

PubMed

Tian, Jie; Gu, Yiwen; Su, Diansan; Wu, Yichao; Wang, Xiangrui

2009-02-01

The present study investigated the effects of different doses of intrathecal lidocaine on established thermal hyperalgesia and tactile allodynia in the chronic constriction injury model of neuropathic pain, defined the effective drug dose range, the duration of pain-relief effects, and the influence of this treatment on the body and tissues. Male Sprague-Dawley rats were divided into five groups and received intrathecal saline or lidocaine (2, 6.5, 15, and 35 mg/kg) 7 days after loose sciatic ligation. Respiratory depression and hemodynamic instability were found to become more severe as doses of lidocaine increased during intrathecal therapy. Two animals in the group receiving 35 mg/kg lidocaine developed pulmonary oedema and died. Behavioral tests indicated that 6.5, 15, and 35 mg/kg intrathecal lidocaine showed different degrees of reversal of thermal hyperalgesia, and lasted for 2-8 days, while 2 mg/kg lidocaine did not. The inhibition of tactile allodynia was only observed in rats receiving 15 and 35 mg/kg lidocaine, and the anti-allodynic effects were identical in these two groups. Histopathologic examinations on the spinal cords revealed mild changes in rats receiving 2-15 mg/kg lidocaine. However, lesions were severe after administration of 35 mg/kg lidocaine. These findings indicate that intrathecal lidocaine has prolonged therapeutic effects on established neuropathic pain. The balance between sympathetic and parasympathetic nervous activities could be well preserved in most cases, except for 35 mg/kg. Considering the ratio between useful effects and side effects, doses of 15 mg/kg are suitable for intrathecal injection for relief of neuropathic pain.

Intrathecal curcumin attenuates pain hypersensitivity and decreases spinal neuroinflammation in rat model of monoarthritis.

PubMed

Chen, Jun-Jie; Dai, Lin; Zhao, Lin-Xia; Zhu, Xiang; Cao, Su; Gao, Yong-Jing

2015-05-19

Curcumin is a major component of turmeric and reportedly has anti-inflammatory and anti-oxidant effects. Neuroinflammation has been recognized to play an important role in the pathogenesis of various diseases in the central nervous system. Here we investigated the anti-nociceptive and anti-neuroinflammatory effect of curcumin on arthritic pain in rats. We found that repeated oral treatment with curcumin, either before or after complete Freund's adjuvant (CFA) injection, dose-dependently attenuated CFA-induced mechanical allodynia and thermal hyperalgesia, but had no effect on joint edema. Repeated intrathecal injection of curcumin reversed CFA-induced pain hypersensitivity. Furthermore, such a curcumin treatment reduced CFA-induced activation of glial cells and production of inflammatory mediators [interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and monocyte inflammatory protein-1 (MIP-1α)] in the spinal cord. Curcumin also decreased lipopolysaccharide-induced production of IL-1β, tumor necrosis factor-α, MCP-1, and MIP-1α in cultured astrocytes and microglia. Our results suggest that intrathecal curcumin attenuates arthritic pain by inhibiting glial activation and the production of inflammatory mediators in the spinal cord, suggesting a new application of curcumin for the treatment of arthritic pain.

Intrathecal curcumin attenuates pain hypersensitivity and decreases spinal neuroinflammation in rat model of monoarthritis

PubMed Central

Chen, Jun-Jie; Dai, Lin; Zhao, Lin-Xia; Zhu, Xiang; Cao, Su; Gao, Yong-Jing

2015-01-01

Curcumin is a major component of turmeric and reportedly has anti-inflammatory and anti-oxidant effects. Neuroinflammation has been recognized to play an important role in the pathogenesis of various diseases in the central nervous system. Here we investigated the anti-nociceptive and anti-neuroinflammatory effect of curcumin on arthritic pain in rats. We found that repeated oral treatment with curcumin, either before or after complete Freund’s adjuvant (CFA) injection, dose-dependently attenuated CFA-induced mechanical allodynia and thermal hyperalgesia, but had no effect on joint edema. Repeated intrathecal injection of curcumin reversed CFA-induced pain hypersensitivity. Furthermore, such a curcumin treatment reduced CFA-induced activation of glial cells and production of inflammatory mediators [interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and monocyte inflammatory protein-1 (MIP-1α)] in the spinal cord. Curcumin also decreased lipopolysaccharide-induced production of IL-1β, tumor necrosis factor-α, MCP-1, and MIP-1α in cultured astrocytes and microglia. Our results suggest that intrathecal curcumin attenuates arthritic pain by inhibiting glial activation and the production of inflammatory mediators in the spinal cord, suggesting a new application of curcumin for the treatment of arthritic pain. PMID:25988362

Analgesic activity of a polysaccharide in experimental osteoarthritis in rats.

PubMed

Castro, Rondinelle Ribeiro; Feitosa, Judith Pessoa Andrade; da Cunha, Pablyana Leila Rodrigues; da Rocha, Francisco Airton Castro

2007-08-01

Viscosupplementation efficacy has been related to the high molecular weight of hyaluronic acid-like compounds, as well as to gel formulation. We evaluated the effect of a galactomannan polysaccharide derived from Guar gum (GG) in joint pain in an osteoarthritis (OA) model. Wistar rats (six animals/group) were subjected to anterior cruciate ligament transection (ACLT-OA group). The OA group was compared to a false-operated group (sham). Joint pain was recorded daily, using the articular incapacitation test, until 7 days after ACLT. Solutions or gel preparations of GG (100 microg) or Hylan G-F 20 (100 microg), used as a comparator, were given intraarticularly (i.a.) at day 4 after ACLT. Controls received saline i.a. The OA group had significantly increased joint pain as compared to sham (P<0.001). GG, either as a gel or solution, significantly inhibited joint pain similar to the inhibition achieved with Hylan G-F20. This is the first demonstration that a galactomannan derived from GG reduces joint pain in experimental OA. This analgesia is independent of the colloidal state. We propose that the analgesic benefit of viscosupplementation may be due to an intrinsic carbohydrate-mediated mechanism rather than to the rheologic properties of the material.

Protective Effect of Ethanol Extracts of Hericium erinaceus on Alloxan-Induced Diabetic Neuropathic Pain in Rats

PubMed Central

Yi, Zhang; Shao-long, Yang; Ai-hong, Wang; Zhi-chun, Sun; Ya-fen, Zhuo; Ye-ting, Xu; Yu-ling, He

2015-01-01

We investigated the effects of Hericium erinaceus (HEE) on alloxan induced diabetic neuropathic pain in laboratory rats. Alloxan induced diabetic rats were administered orally HEE. After 6 weeks of treatments, treatment with HEE 40 mg/kg in diabetic animals showed significant increase in pain threshold and paw withdrawal threshold and significant decrease in serum glucose and urine glucose. We also observed a significant increase in lactate dehydrogenase (LDH), Lipid peroxidation (LPO), glutathione peroxidase (GPx) activity, glutathione reductase (GR) activity, catalase (CAT) activity, Na+K+ATPase activity, and glutathione S transferase (GST) activity along with significant decreased levels of glutathione (GSH) content in diabetic rats. The total antioxidant status (TAOS) in the HEE-treated groups was significantly lower than that in the alloxan-treated group. HEE can offer pain relief in diabetic neuropathic pain. The improvement in diabetic state after HEE treatment along with the antioxidant activity could be the probable way by which it had alleviated diabetic neuropathy. PMID:25960754

Anti-inflammatory and Analgesic Activities of Topical Formulations of Pterocarpus Santalinus Powder in Rat Model of Chronic Inflammation

PubMed Central

Gupta, Amit O; Jain, Sourav; Dawane, Jayshree Shriram

2017-01-01

Introduction The incidence of arthritis is quite high and there is a need for the search of natural products to halt the progression of disease or provide symptomatic relief without significant adverse effects. Aim This study aimed at evaluating the anti-inflammatory and analgesic activities of topical Pterocarpus santalinus in an animal model of chronic inflammation. Materials and Methods Albino rats of either sex were divided into five groups of six rats each (Group I – Control, Group II –Gel base, Group III –P. santalinus paste, Group IV –P. santalinus gel, Group V– Diclofenac gel). Chronic inflammation was induced on day 0 by injecting 0.1 ml Complete Freund’s Adjuvant (CFA) in sub-plantar tissue of left hind paw of the rats. Topical treatment was started from day 12 till day 28. Body weight and paw volume (Plethysmometer) were assessed on day 0, 12 and 28. Pain assessment was done using Randall and Selitto paw withdrawal method. Data was analysed using GraphPad Prism version 5. Unpaired students t-test and ANOVA followed by Tukey’s test was used for comparison among groups. Results Only topical P.santalinus gel significantly reduced the body weight (p=0.02) due to reduction in inflammatory oedema of the left limb. P. santalinus gel also showed significant reduction (p=0.03) in paw volume of rats compared to the other groups. There was significant reduction in pain threshold (gm/sec) due to chronic inflammation, with all the study drugs (p<0.05) but with P. santalinus gel, this reduction was less (p<0.001). Conclusion Gel showed significant anti-inflammatory and mild analgesic activity on topical application in rat model of chronic inflammation. PMID:28892928

Anti-inflammatory and Analgesic Activities of Topical Formulations of Pterocarpus Santalinus Powder in Rat Model of Chronic Inflammation.

PubMed

Dhande, Priti Pravin; Gupta, Amit O; Jain, Sourav; Dawane, Jayshree Shriram

2017-07-01

The incidence of arthritis is quite high and there is a need for the search of natural products to halt the progression of disease or provide symptomatic relief without significant adverse effects. This study aimed at evaluating the anti-inflammatory and analgesic activities of topical Pterocarpus santalinus in an animal model of chronic inflammation. Albino rats of either sex were divided into five groups of six rats each (Group I - Control, Group II -Gel base, Group III - P. santalinus paste, Group IV - P. santalinus gel, Group V- Diclofenac gel). Chronic inflammation was induced on day 0 by injecting 0.1 ml Complete Freund's Adjuvant (CFA) in sub-plantar tissue of left hind paw of the rats. Topical treatment was started from day 12 till day 28. Body weight and paw volume (Plethysmometer) were assessed on day 0, 12 and 28. Pain assessment was done using Randall and Selitto paw withdrawal method. Data was analysed using GraphPad Prism version 5. Unpaired students t-test and ANOVA followed by Tukey's test was used for comparison among groups. Only topical P.santalinus gel significantly reduced the body weight (p=0.02) due to reduction in inflammatory oedema of the left limb. P. santalinus gel also showed significant reduction (p=0.03) in paw volume of rats compared to the other groups. There was significant reduction in pain threshold (gm/sec) due to chronic inflammation, with all the study drugs (p<0.05) but with P. santalinus gel, this reduction was less (p<0.001). Gel showed significant anti-inflammatory and mild analgesic activity on topical application in rat model of chronic inflammation.

Influence of manual therapy on functional mobility after joint injury in a rat model.

PubMed

Ruhlen, Rachel L; Snider, Eric J; Sargentini, Neil J; Worthington, Bart D; Singh, Vineet K; Pazdernik, Vanessa K; Johnson, Jane C; Degenhardt, Brian F

2013-10-01

Animal models can be used to investigate manual therapy mechanisms, but testing manipulation in animal models is problematic because animals cannot directly report their pain. To develop a rat model of inflammatory joint injury to test the efficacy of manual therapy in reducing nociception and restoring function. The authors induced acute inflammatory joint injury in rats by injecting carrageenan into the ankle and then measured voluntary running wheel activity in treated and untreated rats. Treatments included manual therapy applied to the ankle and knee of the injured limb and several analgesic medications (eg, morphine, ketorolac, prednisone). Intra-articular injection of carrageenan to the ankle produced significant swelling (diameter of the ankle increased by 64% after injection; P=.004) and a robust reduction in voluntary running wheel activity (running distance reduced by 91% compared with controls; P<.001). Injured rats gradually returned to running levels equal to controls over 10 days. Neither manual therapy nor analgesic medications increased running wheel activity relative to untreated rats. Voluntary running wheel activity appears to be an appropriate functional measure to evaluate the impact of an acute inflammatory joint injury. However, efforts to treat the injury did not restore running relative to untreated rats.

Models of visceral pain: colorectal distension (CRD).

PubMed

Jones, R Carter W; Gebhart, G F

2004-09-01

The visceromotor response to balloon distension of the colon is a robust behavioral model of visceral nociception in rodents and is ideally suited for studying the visceral antinociceptive activity of drugs. This unit describes, in detail, quantification of this response with the use of electromyography in both rats and mice.

Transcutaneous electrical nerve stimulation attenuates CFA-induced hyperalgesia and inhibits spinal ERK1/2-COX-2 pathway activation in rats

PubMed Central

2013-01-01

Background Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacologic treatment for pain relief. In previous animal studies, TENS effectively alleviated Complete Freund’s Adjuvant (CFA)- or carrageenan-induced inflammatory pain. Although TENS is known to produce analgesia via opioid activation in the brain and at the spinal level, few reports have investigated the signal transduction pathways mediated by TENS. Prior studies have verified the importance of the activation of extracellular signal-regulated kinase (ERK) signal transduction pathway in the spinal cord dorsal horn (SCDH) in acute and persistent inflammatory pains. Here, by using CFA rat model, we tested the efficacy of TENS on inhibiting the expressions of p-ERK1/2 and of its downstream cyclooxygenase-2 (COX-2) and the level of prostaglandin E2 (PGE2) at spinal level. Methods Rats were randomly divided into control, model and TENS groups, and injected subcutaneously with 100 μl CFA or saline in the plantar surface of right hind paw. Rats in the TENS group were treated with TENS (constant aquare wave, 2 Hz and 100 Hz alternating frequencies, intensities ranging from 1 to 2 mA, lasting for 30 min each time) at 5 h and 24 h after injection. Paw withdrawal thresholds (PWTs) were measured with dynamic plantar aesthesiometer at 3d before modeling and 5 h, 6 h, and 25 h after CFA injection. The ipsilateral sides of the lumbar spinal cord dosral horns were harvested for detecting the expressions of p-ERK1/2 and COX-2 by western blot analysis and qPCR, and PGE2 by ELISA. Results CFA-induced periphery inflammation decreased PWTs and increased paw volume of rats. TENS treatment significantly alleviated mechanical hyperalgesia caused by CFA. However, no anti-inflammatory effect of TENS was observed. Expression of p-ERK1/2 protein and COX-2 mRNA was significantly up-regualted at 5 h and 6 h after CFA injection, while COX-2 and PGE2 protein level only increased at 6 h after modeling. Furthermore, the high expression of p-ERK1/2 and COX-2, and over-production of PGE2 induced by CFA, were suppressed by TENS administration. Conclusions TENS may be an effective therapy in controlling inflammatory pain induced by CFA. Its analgesic effect may be associated with the inhibition of activation of the spinal ERK1/2-COX-2 pathway. PMID:23768044

Transcutaneous electrical nerve stimulation attenuates CFA-induced hyperalgesia and inhibits spinal ERK1/2-COX-2 pathway activation in rats.

PubMed

Fang, Jun-Fan; Liang, Yi; Du, Jun-Ying; Fang, Jian-Qiao

2013-06-15

Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacologic treatment for pain relief. In previous animal studies, TENS effectively alleviated Complete Freund's Adjuvant (CFA)- or carrageenan-induced inflammatory pain. Although TENS is known to produce analgesia via opioid activation in the brain and at the spinal level, few reports have investigated the signal transduction pathways mediated by TENS. Prior studies have verified the importance of the activation of extracellular signal-regulated kinase (ERK) signal transduction pathway in the spinal cord dorsal horn (SCDH) in acute and persistent inflammatory pains. Here, by using CFA rat model, we tested the efficacy of TENS on inhibiting the expressions of p-ERK1/2 and of its downstream cyclooxygenase-2 (COX-2) and the level of prostaglandin E2 (PGE2) at spinal level. Rats were randomly divided into control, model and TENS groups, and injected subcutaneously with 100 μl CFA or saline in the plantar surface of right hind paw. Rats in the TENS group were treated with TENS (constant aquare wave, 2 Hz and 100 Hz alternating frequencies, intensities ranging from 1 to 2 mA, lasting for 30 min each time) at 5 h and 24 h after injection. Paw withdrawal thresholds (PWTs) were measured with dynamic plantar aesthesiometer at 3d before modeling and 5 h, 6 h, and 25 h after CFA injection. The ipsilateral sides of the lumbar spinal cord dosral horns were harvested for detecting the expressions of p-ERK1/2 and COX-2 by western blot analysis and qPCR, and PGE2 by ELISA. CFA-induced periphery inflammation decreased PWTs and increased paw volume of rats. TENS treatment significantly alleviated mechanical hyperalgesia caused by CFA. However, no anti-inflammatory effect of TENS was observed. Expression of p-ERK1/2 protein and COX-2 mRNA was significantly up-regualted at 5 h and 6 h after CFA injection, while COX-2 and PGE2 protein level only increased at 6 h after modeling. Furthermore, the high expression of p-ERK1/2 and COX-2, and over-production of PGE2 induced by CFA, were suppressed by TENS administration. TENS may be an effective therapy in controlling inflammatory pain induced by CFA. Its analgesic effect may be associated with the inhibition of activation of the spinal ERK1/2-COX-2 pathway.

The relation between the effect of a subhypnotic dose of thiopental on claw pain threshold in rats and adrenalin, noradrenalin and dopamine levels.

PubMed

Aksoy, Mehmet; Ahiskalioglu, Ali; Ince, Ilker; Celik, Mine; Dostbil, Aysenur; Kuyrukluyildiz, Ufuk; Altuner, Durdu; Kurt, Nezahat; Suleyman, Halis

2015-01-01

Thiopental sodium (TPS) needs to be applied together with adrenalin in order to establish its analgesic effect in general anesthesia. We aimed to investigate the effect of TPS on the claw pain threshold in rats and evaluated its relationship with endogenous adrenalin (ADR), noradrenalin (NDR), and dopamine (DOP) levels. Intact and adrenalectomized rats were used in the experiment. Intact animals were divided into the following groups: 15 mg/kg TPS (TS), 0.3 mg/kg ADR+15 mg/kg TPS (ATS) and 0.3 mg/kg ADR alone (ADR). Adrenalectomized animals were divided into the following groups: 15 mg/kg TPS (A-TS), 0.3 mg/kg ADR+15 mg/kg TPS (A-ATS) and 0.3 mg/kg ADR alone (A-ADR). Claw pain threshold and blood ADR, NDR, and DOP levels were measured. The TS group's claw pain threshold was found low. However, the claw pain thresholds of the ATS and ADR groups increased significantly. In the A-TS group, the pain threshold decreased compared with normal, and in the A-ATS and A-ADR groups, the pain threshold increased. TPS reduced the blood ADR levels in intact rats; however, no significant changes were observed in the NDR and DOP levels. #TPS provides hyperalgesia by reducing the production of ADR in rats. The present study shows that to achieve analgesic activity, TPS needs to be applied together with ADR.

The relation between the effect of a subhypnotic dose of thiopental on claw pain threshold in rats and adrenalin, noradrenalin and dopamine levels

PubMed Central

Aksoy, Mehmet; Ahiskalioglu, Ali; Ince, Ilker; Celik, Mine; Dostbil, Aysenur; Kuyrukluyildiz, Ufuk; Altuner, Durdu; Kurt, Nezahat; Suleyman, Halis

2015-01-01

Thiopental sodium (TPS) needs to be applied together with adrenalin in order to establish its analgesic effect in general anesthesia. We aimed to investigate the effect of TPS on the claw pain threshold in rats and evaluated its relationship with endogenous adrenalin (ADR), noradrenalin (NDR), and dopamine (DOP) levels. Intact and adrenalectomized rats were used in the experiment. Intact animals were divided into the following groups: 15 mg/kg TPS (TS), 0.3 mg/kg ADR+15 mg/kg TPS (ATS) and 0.3 mg/kg ADR alone (ADR). Adrenalectomized animals were divided into the following groups: 15 mg/kg TPS (A-TS), 0.3 mg/kg ADR+15 mg/kg TPS (A-ATS) and 0.3 mg/kg ADR alone (A-ADR). Claw pain threshold and blood ADR, NDR, and DOP levels were measured. The TS group’s claw pain threshold was found low. However, the claw pain thresholds of the ATS and ADR groups increased significantly. In the A-TS group, the pain threshold decreased compared with normal, and in the A-ATS and A-ADR groups, the pain threshold increased. TPS reduced the blood ADR levels in intact rats; however, no significant changes were observed in the NDR and DOP levels. #TPS provides hyperalgesia by reducing the production of ADR in rats. The present study shows that to achieve analgesic activity, TPS needs to be applied together with ADR. PMID:26211784

Swimming Training Reduces Neuroma Pain by Regulating Neurotrophins

PubMed Central

TIAN, JINGE; YU, TINGTING; XU, YONGMING; PU, SHAOFENG; LV, YINGYING; ZHANG, XIN; DU, DONGPING

2018-01-01

ABSTRACT Introduction Neuroma formation after peripheral nerve transection leads to severe neuropathic pain in amputees. Previous studies suggested that physical exercise could bring beneficial effect on alleviating neuropathic pain. However, the effect of exercise on neuroma pain still remained unclear. In addition, long-term exercise can affect the expression of neurotrophins (NT), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which play key roles in nociceptor sensitization and nerve sprouting after nerve injury. Here, we investigated whether long-term swimming exercise could relieve neuroma pain by modulating NT expression. Methods We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. After TNT surgery, rats performed swimming exercise for 5 wk. Neuroma pain and tactile sensitivities were detected using von Frey filaments. Immunofluorescence was applied to analyze neuroma formation. NGF and BDNF expressions in peripheral neuroma, dorsal root ganglion, and the spinal cord were measured using enzyme-linked immunosorbent assay and Western blotting. Results TNT led to neuroma formation, induced neuroma pain, and mechanical allodynia in hind paw. Five-week swimming exercise inhibited neuroma formation and relieved mechanical allodynia in the hind paw and neuroma pain in the lateral ankle. The analgesic effect lasted for at least 1 wk, even when the exercise ceased. TNT elevated the expressions of BDNF and NGF in peripheral neuroma, dorsal root ganglion, and the spinal cord to different extents. Swimming also decreased the elevation of NT expression. Conclusions Swimming exercise not only inhibits neuroma formation induced by nerve transection but also relieves pain behavior. These effects might be associated with the modulation of NT. PMID:28846565

Swimming Training Reduces Neuroma Pain by Regulating Neurotrophins.

PubMed

Tian, Jinge; Yu, Tingting; Xu, Yongming; Pu, Shaofeng; Lv, Yingying; Zhang, Xin; DU, Dongping

2018-01-01

Neuroma formation after peripheral nerve transection leads to severe neuropathic pain in amputees. Previous studies suggested that physical exercise could bring beneficial effect on alleviating neuropathic pain. However, the effect of exercise on neuroma pain still remained unclear. In addition, long-term exercise can affect the expression of neurotrophins (NT), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which play key roles in nociceptor sensitization and nerve sprouting after nerve injury. Here, we investigated whether long-term swimming exercise could relieve neuroma pain by modulating NT expression. We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. After TNT surgery, rats performed swimming exercise for 5 wk. Neuroma pain and tactile sensitivities were detected using von Frey filaments. Immunofluorescence was applied to analyze neuroma formation. NGF and BDNF expressions in peripheral neuroma, dorsal root ganglion, and the spinal cord were measured using enzyme-linked immunosorbent assay and Western blotting. TNT led to neuroma formation, induced neuroma pain, and mechanical allodynia in hind paw. Five-week swimming exercise inhibited neuroma formation and relieved mechanical allodynia in the hind paw and neuroma pain in the lateral ankle. The analgesic effect lasted for at least 1 wk, even when the exercise ceased. TNT elevated the expressions of BDNF and NGF in peripheral neuroma, dorsal root ganglion, and the spinal cord to different extents. Swimming also decreased the elevation of NT expression. Swimming exercise not only inhibits neuroma formation induced by nerve transection but also relieves pain behavior. These effects might be associated with the modulation of NT.

Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain.

PubMed

Podolsky, Alexander T; Sandweiss, Alexander; Hu, Jackie; Bilsky, Edward J; Cain, Jim P; Kumirov, Vlad K; Lee, Yeon Sun; Hruby, Victor J; Vardanyan, Ruben S; Vanderah, Todd W

2013-12-18

Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids have highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists. © 2013. Published by Elsevier Inc. All rights reserved.

Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain

PubMed Central

Podolsky, Alexander T.; Sandweiss, Alexander; Hu, Jackie; Bilsky, Edward J; Cain, Jim P; Kumirov, Vlad K.; Lee, Yeon Sun; Hruby, Victor J; Vardanyan, Ruben S.; Vanderah, Todd W.

2014-01-01

Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids has highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. Aims Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. Main Methods Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. Key findings RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. Significance This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists. PMID:24084045

Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: Evidence from human psychophysics, animal models, and neuroimaging

PubMed Central

Price, Donald D.; Craggs, Jason G.; Zhou, QiQi; Verne, G. Nicholas; Perlstein, William M.; Robinson, Michael E.

2010-01-01

Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder that is often accompanied by both visceral and somatic hyperalgesia (enhanced pain from colorectal and somatic stimuli). Neural mechanisms of both types of hyperalgesia have been analyzed by neuroimaging studies of IBS patients and animal analog studies of “IBS-like” rats with delayed rectal and somatic hypersensitivity. Results from these studies suggest that pains associated with both visceral and widespread secondary cutaneous hyperalgesia are dynamically maintained by tonic impulse input from the non-inflamed colon and/or rectum and by brain-to-spinal cord facilitation. Enhanced visceral and somatic pains are accompanied by enhanced pain-related brain activity in IBS patients as compared to normal control subjects; placebos can normalize both their hyperalgesia and enhanced brain activity. That pain in IBS which is likely to be at least partly maintained by peripheral impulse input from the colon/rectum is supported by results showing that local rectal–colonic anesthesia normalizes visceral and somatic hyperalgesia in IBS patients and visceral and somatic hypersensitivity in “IBS-like” rats. Yet these forms of hyperalgesia are also highly modifiable by placebo and nocebo factors (e.g., expectations of relief or distress, respectively). Our working hypothesis is that synergistic interactions occur between placebo/nocebo factors and enhanced afferent processing so as to enhance, maintain, or reduce hyperalgesia in IBS. This explanatory model may be relevant to other persistent pain conditions. PMID:19375508

Chronic ibuprofen administration reduces neuropathic pain but does not exert neuroprotection after spinal cord injury in adult rats.

PubMed

Redondo-Castro, Elena; Navarro, Xavier

2014-02-01

Ibuprofen is commonly used as an anti-inflammatory analgesic drug, although it is not amongst the first-line treatments for neuropathic pain. Its main effects are mediated by non-specific inhibition of COX enzymes, but it also exerts some COX-independent effects, such as the inhibition of RhoA signaling and the modulation of glial activity. These effects have boosted the use of ibuprofen as a tool to promote axonal regeneration and to increase functional recovery after neural injuries, although with controversial results showing positive and negative outcomes of ibuprofen treatment in several experimental models. We have evaluated the effects of ibuprofen administered at 60 mg/kg twice a day to rats subjected to a mild spinal cord contusion. Our results indicate that ibuprofen ameliorates mechanical hyperalgesia in rats by reducing central hyperexcitability, but failed to produce improvements in the recovery of locomotion. Despite an early effect on reducing microglial reactivity, the ibuprofen treatment did not provide histological evidence of neuroprotection; indeed the volume of cord tissue spared rostral to the lesion was decreased in ibuprofen treated rats. In summary, the early modulation of neuroinflammation produced by the administration of ibuprofen seems to eventually lead to a worse resolution of detrimental events occurring in the secondary injury phase, but also to reduce the development of neuropathic pain. Copyright © 2013 Elsevier Inc. All rights reserved.

Origins, actions and dynamic expression patterns of the neuropeptide VGF in rat peripheral and central sensory neurones following peripheral nerve injury

PubMed Central

Moss, Andrew; Ingram, Rachel; Koch, Stephanie; Theodorou, Andria; Low, Lucie; Baccei, Mark; Hathway, Gareth J; Costigan, Michael; Salton, Stephen R; Fitzgerald, Maria

2008-01-01

Background The role of the neurotrophin regulated polypeptide, VGF, has been investigated in a rat spared injury model of neuropathic pain. This peptide has been shown to be associated with synaptic strengthening and learning in the hippocampus and while it is known that VGFmRNA is upregulated in dorsal root ganglia following peripheral nerve injury, the role of this VGF peptide in neuropathic pain has yet to be investigated. Results Prolonged upregulation of VGF mRNA and protein was observed in injured dorsal root ganglion neurons, central terminals and their target dorsal horn neurons. Intrathecal application of TLQP-62, the C-terminal active portion of VGF (5–50 nmol) to naïve rats caused a long-lasting mechanical and cold behavioral allodynia. Direct actions of 50 nM TLQP-62 upon dorsal horn neuron excitability was demonstrated in whole cell patch recordings in spinal cord slices and in receptive field analysis in intact, anesthetized rats where significant actions of VGF were upon spontaneous activity and cold evoked responses. Conclusion VGF expression is therefore highly modulated in nociceptive pathways following peripheral nerve injury and can cause dorsal horn cell excitation and behavioral hypersensitivity in naïve animals. Together the results point to a novel and powerful role for VGF in neuropathic pain. PMID:19077191

CJ-13610, an orally active inhibitor of 5-lipoxygenase is efficacious in preclinical models of pain.

PubMed

Cortes-Burgos, Luz A; Zweifel, Ben S; Settle, Steven L; Pufahl, Robert A; Anderson, Gary D; Hardy, Medora M; Weir, Dana E; Hu, George; Happa, Fernando A; Stewart, Zachary; Muthian, Shanmugam; Graneto, Matthew J; Masferrer, Jaime L

2009-09-01

Zileuton, a redox and iron chelator 5-lipoxygenase (5-LOX) inhibitor and, leukotriene receptor antagonists are presently used clinically in the long term treatment of asthma. Recent data implicate 5-LOX pathway in pain signaling. We report 5-LOX expression in the central nervous system (CNS) and analyze the pain efficacy of a new class of non redox, non iron chelating 5-LOX inhibitor. CJ-13610, 4-(3-(4-(2-methyl-1H-imidazol-1-yl) phenylthio) phenyl)-tetrahydro-2H-pyran-4-carboxamide, demonstrated antihyperalgesic activity in inflammatory pain models including the acute carrageenan model and the chronic inflammatory model using complete Freund's adjuvant. Following complete Freund's adjuvant stimulus leukotrieneB(4) concentration in the brain was elevated (9+/-1 ng/g, mean+/-S.E.M.) by about 3 times that of the control group (3+/-0.11, mean+/-S.E.M.). Hyperalgesia and leukotrieneB(4) concentration were both reversed following CJ-13610 treatment. Furthermore, we demonstrate CJ-13610 efficacy against osteoarthritis like pain using the rat medial meniscal transection model. CJ-13610 at oral doses of 0.6, 2 and 6 mg/kg/day reversed two modalities of pain in this model; tactile allodynia and weight bearing differential. Taken together, these data suggest that 5-LOX pathway and the leukotriene products are important mediators of pain.

Role of Kv 4.3 in vibration-induced muscle pain in the rat

PubMed Central

Conner, Lindsay; Alvarez, Pedro; Bogen, Oliver; Levine, Jon D.

2015-01-01

We hypothesized that changes in the expression of Kv4.3 contribute to the mechanical hyperalgesia induced by vibration injury, a rodent model for hand-arm vibration syndrome in humans. Here we show that the exposure of the gastrocnemius muscle to vibration injury induces muscle hyperalgesia that is accompanied by a significant down-regulation of Kv4.3 in affected sensory nerve fibers in dorsal root ganglia (DRG). We additionally demonstrate that the intrathecal administration of antisense oligonucleotides for Kv4.3 mRNA itself induces muscle hyperalgesia in the rat. Our results suggest that attenuation in the expression of Kv4.3 may contribute to neuropathic pain in people affected by hand-arm vibration syndrome. PMID:26721612

Albizia zygia (DC.) J.F. Macbr. (Leguminosae-Mimosoideae) root extract exhibits anti-nociceptive and antipyretic activities in murine models.

PubMed

Abotsi, Wonder Kofi Mensah; Lamptey, Stanley Benjamin; Boakye-Gyasi, Eric; Woode, Eric

2017-03-06

The root extract of Albizia zygia (DC.) J.F. Macbr. (Leguminosae-Mimosoideae) is traditionally used in the management of pain and fever. However, little scientific data exists in literature to support its use. The present study evaluated the anti-nociceptive and antipyretic properties of the hydroethanolic extract of the roots of Albizia zygia in animal models. The analgesic effects were investigated in chemical (acetic acid-induced abdominal writhing and formalin tests), thermal (tail-immersion test) and mechanical (carrageenan-induced hyperalgesia) pain models. Possible mechanisms of anti-nociception were also assessed with antagonists in the formalin test. The anti-pyretic effect was evaluated using the baker yeast-induced pyrexia model in young rats. The extract (30-300mg/kg, p.o.) and positive controls, diclofenac (3-30mg/kg, i.p.) and morphine (1-10mg/kg, i.p.), significantly (at least P<0.01) attenuated acetic acid-induced visceral pain, formalin- induced paw pain (both neurogenic and inflammatory), thermal pain as well as carrageenan-induced mechanical hyperalgesia in animals. The anti-nociceptive effect of the extract was reversed (at least P<0.05) by the pre-emptive administration of naloxone and atropine; the administration of theophylline, however, exhibited no significant (P>0.05) inhibition of anti-nociception. The extract (30-300mg/kg, p.o) and paracetamol (15-150mg/kg, p.o.) both reversed yeast-induced pyrexia in rats with ED 50 values of 48.59±2.59 and 26.19±1.33mg/kg respectively. The findings indicate that the extract possesses significant anti-nociceptive and antipyretic effects which justify its traditional use in the management of pain and fever. Also, anti-nociceptive effect of the extract involves opioidergic and muscarinic cholinergic mechanisms. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Role of NFkappaB in an animal model of complex regional pain syndrome-type I (CRPS-I).

PubMed

de Mos, Marissa; Laferrière, André; Millecamps, Magali; Pilkington, Mercedes; Sturkenboom, Miriam C J M; Huygen, Frank J P M; Coderre, Terence J

2009-11-01

NFkappaB is involved in several pathogenic mechanisms that are believed to underlie the complex regional pain syndrome (CRPS), including ischemia, inflammation and sensitization. Chronic postischemia pain (CPIP) has been developed as an animal model that mimics the symptoms of CRPS-I. The possible involvement of NFkappaB in CRPS-I was studied using CPIP rats. Under sodium pentobarbital anesthesia, a tourniquet was placed around the rat left ankle joint, producing 3 hours of ischemia, followed by rapid reperfusion (IR injury). NFkappaB was measured in nuclear extracts of muscle and spinal cord tissue using ELISA. Moreover, the anti-allodynic (mechanical and cold) effect was tested for systemic, intrathecal, or intraplantar treatment with the NFkappaB inhibitor pyrrolidine dithiocarbamate (PDTC). At 2 and 48 hours after IR injury, NFkappaB was elevated in muscle and spinal cord of CPIP rats compared to shams. At 7 days, NFkappaB levels were normalized in muscle, but still elevated in spinal cord tissue. Systemic PDTC treatment relieved mechanical and cold allodynia in a dose-dependent manner, lasting for at least 3 hours. Intrathecal-but not intraplantar-administration also relieved mechanical allodynia. The results suggest that muscle and spinal NFkappaB plays a role in the pathogenesis of CPIP and potentially of human CRPS. Using the CPIP model, we demonstrate that NFkappaB is involved in the development of allodynia after a physical injury (ischemia and reperfusion) without direct nerve trauma. Since CPIP animals exhibit many features of human CRPS-I, this observation indicates a potential role for NFkappaB in human CRPS.

Post-conditioning experience with acute or chronic inflammatory pain reduces contextual fear conditioning in the rat

PubMed Central

Johnston, Ian N.; Maier, Steven F.; Rudy, Jerry W.; Watkins, Linda R.

2017-01-01

There is evidence that pain can impact cognitive function in people. The present study evaluated whether Pavlovian fear conditioning in rats would be reduced if conditioning were followed by persistent inflammatory pain induced by a subcutaneous injection of dilute formalin or complete Freund's adjuvant (CFA) on the dorsal lumbar surface of the back. Formalin-induced pain specifically impaired contextual fear conditioning but not auditory cue conditioning (Experiment 1A). Moreover, formalin pain only impaired contextual fear conditioning if it was initiated within 1 h of conditioning and did not have a significant effect if initiated 2, 8 or 32 h after (Experiments 1A and 1B). Experiment 2 showed that formalin pain initiated after a session of context pre-exposure reduced the ability of that pre-exposure to facilitate contextual fear when the rat was limited to a brief exposure to the context during conditioning. Similar impairments in context- but not CS-fear conditioning were also observed if the rats received an immediate post-conditioning injection with CFA (Experiment 3). Finally, we confirmed that formalin and CFA injected s.c. on the back induced pain-indicative behaviours, hyperalgesia and allodynia with a similar timecourse to intraplantar injections (Experiment 4). These results suggest that persistent pain impairs learning in a hippocampus-dependent task, and may disrupt processes that encode experiences into long-term memory. PMID:21920390

NOV/CCN3 attenuates inflammatory pain through regulation of matrix metalloproteinases-2 and -9

PubMed Central

2012-01-01

Background Sustained neuroinflammation strongly contributes to the pathogenesis of pain. The clinical challenge of chronic pain relief led to the identification of molecules such as cytokines, chemokines and more recently matrix metalloproteinases (MMPs) as putative therapeutic targets. Evidence points to a founder member of the matricial CCN family, NOV/CCN3, as a modulator of these inflammatory mediators. We thus investigated the possible involvement of NOV in a preclinical model of persistent inflammatory pain. Methods We used the complete Freund's adjuvant (CFA)-induced model of persistent inflammatory pain and cultured primary sensory neurons for in vitro experiments. The mRNA expression of NOV and pro-inflammatory factors were measured with real-time quantitative PCR, CCL2 protein expression was assessed using ELISA, MMP-2 and -9 activities using zymography. The effect of drugs on tactile allodynia was evaluated by the von Frey test. Results NOV was expressed in neurons of both dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC). After intraplantar CFA injection, NOV levels were transiently and persistently down-regulated in the DRG and DHSC, respectively, occurring at the maintenance phase of pain (15 days). NOV-reduced expression was restored after treatment of CFA rats with dexamethasone. In vitro, results based on cultured DRG neurons showed that siRNA-mediated inhibition of NOV enhanced IL-1β- and TNF-α-induced MMP-2, MMP-9 and CCL2 expression whereas NOV addition inhibited TNF-α-induced MMP-9 expression through β1 integrin engagement. In vivo, the intrathecal delivery of MMP-9 inhibitor attenuated mechanical allodynia of CFA rats. Importantly, intrathecal administration of NOV siRNA specifically led to an up-regulation of MMP-9 in the DRG and MMP-2 in the DHSC concomitant with increased mechanical allodynia. Finally, NOV intrathecal treatment specifically abolished the induction of MMP-9 in the DRG and, MMP-9 and MMP-2 in the DHSC of CFA rats. This inhibitory effect on MMP is associated with reduced mechanical allodynia. Conclusions This study identifies NOV as a new actor against inflammatory pain through regulation of MMPs thus uncovering NOV as an attractive candidate for therapeutic improvement in pain relief. PMID:22353423

Cortex glial cells activation, associated with lowered mechanical thresholds and motor dysfunction, persists into adulthood after neonatal pain.

PubMed

Sanada, Luciana Sayuri; Sato, Karina Laurenti; Machado, Nathalia Leilane Berto; Carmo, Elisabete de Cássia do; Sluka, Kathleen A; Fazan, Valeria Paula Sassoli

2014-06-01

We investigated if changes in glial activity in cortical areas that process nociceptive stimuli persisted in adult rats after neonatal injury. Neonatal pain was induced by repetitive needle prickling on the right paw, twice per day for 15 days starting at birth. Wistar rats received either neonatal pain or tactile stimulation and were tested behaviorally for mechanical withdrawal thresholds of the paws and gait alterations, after 15 (P15) or 180 (P180) days of life. Brains from rats on P15 and P180 were immunostained for glial markers (GFAP, MCP-1, OX-42) and the following cortical areas were analyzed for immunoreactivity density: prefrontal, anterior insular, anterior cingulated, somatosensory and motor cortices. Withdrawal thresholds of the stimulated paw remained decreased on P180 after neonatal pain when compared to controls. Neonatal pain animals showed increased density for both GFAP and MCP-1 staining, but not for OX-42, in all investigated cortical areas on both experimental times (P15 and P180). Painful stimuli in the neonatal period produced pain behaviors immediately after injury that persisted in adult life, and was accompanied by increase in the glial markers density in cortical areas that process and interpret pain. Thus, long-lasting changes in cortical glial activity could be, at least in part, responsible for the persistent hyperalgesia in adult rats that suffered from neonatal pain. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Chronic prostatitis/chronic pelvic pain syndrome impairs erectile function through increased endothelial dysfunction, oxidative stress, apoptosis, and corporal fibrosis in a rat model.

PubMed

Hu, Y; Niu, X; Wang, G; Huang, J; Liu, M; Peng, B

2016-11-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an independent risk factor for the development of erectile dysfunction (ED). But the molecular mechanisms underlying the relationship between CP/CPPS and ED are still unclear. The aim of this study was to investigate the effect of CP/CPPS on erectile function in a rat model and the possible mechanisms. A rat model of experimental autoimmune prostatitis (EAP) was established to mimic human CP⁄CPPS. Then twenty 2-month-old male Sprague-Dawley rats were divided into EAP group and control group. Intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured during cavernous nerve electrostimulation, the ratio of max ICP/MAP was calculated. Blood was collected to measure the levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and testosterone, respectively. The expression of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in corpus cavernosum were detected. We also evaluated the smooth muscle/collagen ratio and apoptotic index (AI). The ratio of max ICP/MAP in EAP group were significantly lower than that in control group. The levels of serum CRP, TNF-α, IL-1β, and IL-6 in EAP group were all significantly higher than these in control group. The expression of eNOS and cGMP levels in corpus cavernosum of EAP rats were significantly downregulated. Furthermore, decreased SOD activity and smooth muscle/collagen ratio, increased MDA levels and AI were found in corpus cavernosum of EAP rats. In conclusion, CP/CPPS impaired penile erectile function in a rat model. The declines of eNOS expression and cGMP levels in corpus cavernosum may be an important mechanism of CP/CPPS-induced ED. CP/CPPS also increased oxidative stress, cell apoptosis and decreased smooth muscle/collagen ratio in corpus cavernosum of rats, which were all important for erectile function. © 2016 American Society of Andrology and European Academy of Andrology.

Estrogen rapidly enhances incisional pain of ovariectomized rats primarily through the G protein-coupled estrogen receptor.

PubMed

An, Guanghui; Li, Wenhui; Yan, Tao; Li, Shitong

2014-06-11

It has become increasingly apparent that the pain threshold of females and males varies in an estrogen dependent manner. To investigate the modulation of pain by estrogen and the molecular mechanisms involved in this process. A total of 48 rats were ovariectomized (OVX). At 14 and 20 days after OVX, rats were divided into eight groups: groups 1-4 were administered drugs intravenously (IV); groups 5-8 were administered through intrathecal (IT) catheter. Hind paw incision was made in all animals to determine incisional pain. Paw withdraw threshold (PWT) was tested prior to and 24 h after incision. The test drugs were applied 24 h after the incision. Rats were either IV or IT administered with: 17-β-estradiol (E2), G protein-coupled estrogen receptor (GPER)-selective agonist (G1), GPER-selective antagonist (G15) and E2 (G15+E2), or solvent. Before and 30 min after IV drug administration and 20 min during the IT catheter administration, PWT was tested and recorded. 24 h after incisional surgery, the PWT of all rats significantly decreased. Both in the IV group and IT group: administration of E2 and G1 significantly decreased PWT. Neither administration of G15+E2 nor solvent significantly changed PWT. Estrogen causes rapid reduction in the mechanical pain threshold of OVX rats via GPER.

Membrane protein Nav1.7 contributes to the persistent post-surgical pain regulated by p-p65 in dorsal root ganglion (DRG) of SMIR rats model.

PubMed

Li, Zhisong; Li, Yaru; Cao, Jing; Han, Xuemin; Cai, Weihua; Zang, Weidong; Xu, Jitian; Zhang, Wei

2017-11-07

Persistent post-surgical pain is a difficult clinical problem. In this study, we intend to explore the mechanism underlying the persistent post-surgical pain in SMIR (skin/muscle incision and retraction) rats. First of all, the expression of membrane protein Nav1.7 and p-p65 (Phosphorylation of p65) were detected in ipsilateral L4-6 DRGs of SMIR rats by western-blot and immunostaining. Then with ProTx-II (Nav1.7 blocker) or PDTC (p65 inhibitor) were intrathecally injected while the change of Nav1.7 expression and mechanical withdrawal threshold were detected. Finally chromatin immunoprecipitation assay method was used to detect whether could p-p65 bind in the Nav1.7 gene promoter region directly. The results shows that mechanical hyperalgesia occurs following SMIR model, from 5 day (d) and lasted more than 20d after surgery. Meanwhile, the expression of Nav1.7 was up-regulated at 10d, 15d and 20d after surgery compared with naïve group. The expression of p-p65 was up-regulated at 10d and 15d compared with incision group. The mechanical hyperalgesia induced by SMIR was reversed after blocking Nav1.7 or inhibiting p65. Furthermore, Nav1.7 expression was down-regulated when p-p65 was inhibited and p-p65 could combine with the Nav1.7 gene promoter region directly. Membrane protein Nav1.7 could participate in the peripheral sensitization of persistent post-surgical pain, which may be regulated by p-p65.

Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study

PubMed Central

Wodarski, Rachel; Delaney, Ada; Ultenius, Camilla; Morland, Rosie; Andrews, Nick; Baastrup, Catherine; Bryden, Luke A.; Caspani, Ombretta; Christoph, Thomas; Gardiner, Natalie J.; Huang, Wenlong; Kennedy, Jeffrey D.; Koyama, Suguru; Li, Dominic; Ligocki, Marcin; Lindsten, Annika; Machin, Ian; Pekcec, Anton; Robens, Angela; Rotariu, Sanziana M.; Voß, Sabrina; Segerdahl, Marta; Stenfors, Carina; Svensson, Camilla I.; Treede, Rolf-Detlef; Uto, Katsuhiro; Yamamoto, Kazumi; Rutten, Kris; Rice, Andrew S.C.

2016-01-01

Abstract Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats (Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP—all animals allocated to treatment; n = 249) and a selected population (SP—TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding “poor” burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of −374 g (−479 to −269 g) for TP and −498 g (−609 to −386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future. PMID:27643836

Blockade of dopamine D2 receptors disrupts intrahippocampal connectivity and enhances pain-related working memory deficits in neuropathic pain rats.

PubMed

Cardoso-Cruz, H; Dourado, M; Monteiro, C; Galhardo, V

2018-05-01

Dopamine (DA) is thought to be important to local hippocampal networks integrity during spatial working memory (sWM) processing. Chronic pain may contribute to deficient dopaminergic signalling, which may in turn affect cognition. However, the neural mechanisms that determine this impairment are poorly understood. Here, we evaluated whether the sWM impairment characteristic of animal models of chronic pain is dependent on DA D2 receptor (D2r) activity. To address this issue, we implanted multichannel arrays of electrodes in the dorsal and ventral hippocampal CA1 field (dvCA1) of rats and recorded the neuronal activity during a classical delayed food-reinforced T-maze sWM task. Within-subject behavioural performance and patterns of dorsoventral neural activity were assessed before and after the onset of persistent neuropathic pain using the spared nerve injury (SNI) model. Our results show that the peripheral nerve lesion caused a disruption in sWM and hippocampus spike activity and that disruption was maximized by the systemic administration of the D2r antagonist raclopride. These deficits are strictly correlated with a selective disruption of hippocampal theta-oscillations. Particularly, we found a significant decrease in intrahippocampal CA1 field connectivity level. Together, these results suggest that disruption of the dopaminergic balance in the intrahippocampal networks may be important for the development of cognitive deficits experienced during painful conditions. This study provides new insights into the role of D2r in the manifestation of pain-related sWM deficits. Our findings support that selective blockade of D2r produces a significant decrease in intrahippocampal connectivity mediated by theta-oscillations, and amplifies pain-related sWM deficits. These results suggest that further characterization of intrahippocampal dopaminergic modulation may be clinically relevant for the understanding of cognitive impairments that accompanies nociceptive stressful conditions. © 2018 European Pain Federation - EFIC®.

Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.

PubMed

Yang, Yang; Huang, Jianying; Mis, Malgorzata A; Estacion, Mark; Macala, Lawrence; Shah, Palak; Schulman, Betsy R; Horton, Daniel B; Dib-Hajj, Sulayman D; Waxman, Stephen G

2016-07-13

Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.7 produce several pain syndromes, including inherited erythromelalgia (IEM), a disorder in which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning pain triggered by warmth, the effects of increased temperature on DRG neurons expressing mutant Nav1.7 channels have not been well documented. Here, using structural modeling, voltage-clamp, current-clamp, and multielectrode array recordings, we have studied a newly identified Nav1.7 mutation, Ala1632Gly, from a multigeneration family with IEM. Structural modeling suggests that Ala1632 is a molecular hinge and that the Ala1632Gly mutation may affect channel gating. Voltage-clamp recordings revealed that the Nav1.7-A1632G mutation hyperpolarizes activation and depolarizes fast-inactivation, both gain-of-function attributes at the channel level. Whole-cell current-clamp recordings demonstrated increased spontaneous firing, lower current threshold, and enhanced evoked firing in rat DRG neurons expressing Nav1.7-A1632G mutant channels. Multielectrode array recordings further revealed that intact rat DRG neurons expressing Nav1.7-A1632G mutant channels are more active than those expressing Nav1.7 WT channels. We also showed that physiologically relevant thermal stimuli markedly increase the mean firing frequencies and the number of active rat DRG neurons expressing Nav1.7-A1632G mutant channels, whereas the same thermal stimuli only increase these parameters slightly in rat DRG neurons expressing Nav1.7 WT channels. The response of DRG neurons expressing Nav1.7-A1632G mutant channels upon increase in temperature suggests a cellular basis for warmth-triggered pain in IEM. Inherited erythromelalgia (IEM), a severe pain syndrome characterized by episodes of intense burning pain triggered by warmth, is caused by mutations in sodium channel Nav1.7, which are preferentially expressed in sensory and sympathetic neurons. More than 20 gain-of-function Nav1.7 mutations have been identified from IEM patients, but the question of how warmth triggers episodes of pain in IEM has not been well addressed. Combining multielectrode array, voltage-clamp, and current-clamp recordings, we assessed a newly identified IEM mutation (Nav1.7-A1632G) from a multigeneration family. Our data demonstrate gain-of-function attributes at the channel level and differential effects of physiologically relevant thermal stimuli on the excitability of DRG neurons expressing mutant and WT Nav1.7 channels, suggesting a cellular mechanism for warmth-triggered pain episodes in IEM patients. Copyright © 2016 the authors 0270-6474/16/367512-12$15.00/0.

Electroacupuncture Reduces the Effects of Acute Noxious Stimulation on the Electrical Activity of Pain-Related Neurons in the Hippocampus of Control and Neuropathic Pain Rats

PubMed Central

Wang, Jun-Ying; Chen, Renbo; Feng, Xiu-Mei; Yan, Yaxia; Lippe, Irmgard Th.

2016-01-01

To study the effects of acupuncture analgesia on the hippocampus, we observed the effects of electroacupuncture (EA) and mitogen-activated protein kinase (MEK) inhibitor on pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal area CA1 of sham or chronic constrictive injury (CCI) rats. The animals were randomly divided into a control, a CCI, and a U0126 (MEK1/2 inhibitor) group. In all experiments, we briefly (10-second duration) stimulated the sciatic nerve electrically and recorded the firing rates of PENs and PINs. The results showed that in both sham and CCI rats brief sciatic nerve stimulation significantly increased the electrical activity of PENs and markedly decreased the electrical activity of PINs. These effects were significantly greater in CCI rats compared to sham rats. EA treatment reduced the effects of the noxious stimulus on PENs and PINs in both sham and CCI rats. The effects of EA treatment could be inhibited by U0126 in sham-operated rats. The results suggest that EA reduces effects of acute sciatic nerve stimulation on PENs and PINs in the CA1 region of the hippocampus of both sham and CCI rats and that the ERK (extracellular regulated kinase) signaling pathway is involved in the modulation of EA analgesia. PMID:27833763

Long-Term Antihyperalgesic and Opioid-Sparing Effects of 5-Day Ketamine and Morphine Infusion ("Burst Ketamine") in Diabetic Neuropathic Rats.

PubMed

Mak, Plato; Broadbear, Jillian H; Kolosov, Anton; Goodchild, Colin S

2015-09-01

"Burst ketamine" (BK) is the long-term infusion of subanesthetic ketamine in combination with an opioid. It is used clinically with mixed success to provide long-term pain relief and improve opioid response in patients. BK has not been simulated preclinically, therefore, its effectiveness was investigated in an animal model of neuropathic pain--streptozotocin-induced diabetic neuropathy. Diabetic neuropathic rats were randomized to receive a subcutaneous infusion of ketamine 20 mg/kg/day plus morphine 20 mg/kg/day (BK), either drug alone at the same dose, or sham treatment. Drugs were administered continuously over 5 days via osmotic minipump. Antihyperalgesic effects and antinociceptive responsiveness to morphine (0.625-10 mg/kg, i.p.) were assessed at 2, 4, 6, and 12 weeks post-treatment using paw withdrawal latency (PWL) from noxious heat (thermal hyperalgesia) and mechanical touch (tactile allodynia). Antihyperalgesic effects with significant increases in PWL from noxious heat occurred following BK and ketamine-only infusion, persisting 12 and 4 weeks, respectively. Opioid-sparing effects from noxious heat with increased sensitivity to morphine analgesia also occurred for 6 weeks after BK and 2 weeks after ketamine treatment; acute treatment with the maximum nonsedating dose of morphine (5 mg/kg) produced an antinociceptive effect in these two groups, but not in sham-treated rats. In morphine-only infusion rats, hyperalgesia and opioid insensitivity were both increased. This is the first preclinical study to use a model of neuropathic pain to demonstrate the utility of the BK procedure for delivering a long-lasting reduction in hyperalgesia and improved antinociceptive responsiveness to opioids. Wiley Periodicals, Inc.

Local analgesic effect of tramadol is mediated by opioid receptors in late postoperative pain after plantar incision in rats.

PubMed

de Oliveira Junior, José Oswaldo; de Freitas, Milena Fernandes; Bullara de Andrade, Carolina; Chacur, Marucia; Ashmawi, Hazem Adel

2016-01-01

Tramadol is a drug used to treat moderate to severe pain. It is known to present a peripheral effect, but the local mechanisms underlying its actions remain unclear. The role of peripheral opioid receptors in postoperative pain is not well understood. In the present study, we examined the peripheral opioid receptors to determine the local effect of tramadol in a plantar incision pain model. Rats were subjected to plantar incision and divided into four groups on postoperative day (POD) 1: SF_SF, 0.9% NaCl injected into the right hindpaw; SF_TraI, 0.9% NaCl and tramadol injected into the right hindpaw; SF_TraC, 0.9% NaCl and tramadol injected into the contralateral hindpaw; and Nal_Tra, naloxone and tramadol injected into the ipsilateral hindpaw. To determine the animals' nociceptive threshold, mechanical hyperalgesia was measured before incision, on POD1 before treatment and at 15, 30, 45, and 60 minutes after the incision. The same procedure was repeated on the POD2. The expression levels of μ-opioid receptor (MOR) and δ-opioid receptor (DOR) were obtained through immunoblotting assays in the lumbar dorsal root ganglia (L3-L6) in naïve rats and 1, 2, 3, and 7 days after the incision. Our results showed that the plantar incision was able to cause an increase in mechanical hyperalgesia and that tramadol reversed this hyperalgesia on POD1 and POD2. Tramadol injections in the contralateral paw did not affect the animals' nociceptive threshold. Naloxone was able to antagonize the tramadol effect partially on POD1 and completely on POD2. The DOR expression increased on POD2, POD3, and POD7, whereas the MOR expression did not change. Together, our results show that tramadol promoted a local analgesic effect in the postoperative pain model that was antagonized by naloxone in POD2, alongside the increase of DOR expression.

Participation of pro- and anti-nociceptive interleukins in botulinum toxin A-induced analgesia in a rat model of neuropathic pain.

PubMed

Zychowska, Magdalena; Rojewska, Ewelina; Makuch, Wioletta; Luvisetto, Siro; Pavone, Flaminia; Marinelli, Sara; Przewlocka, Barbara; Mika, Joanna

2016-11-15

Botulinum neurotoxin serotype A (BoNT/A) shows antinociceptive properties, and its clinical applications in pain therapy are continuously increasing. BoNT/A specifically cleaves SNAP-25, which results in the formation of a non-functional SNARE complex, thereby potently inhibiting the release of neurotransmitters and neuropeptides, including those involved in nociception. The aim of the present study was to determine the effects of BoNT/A (300pg/paw) on pain-related behavior and the levels of glial markers and interleukins in the spinal cord and dorsal root ganglia (DRG) after chronic constriction injury (CCI) to the sciatic nerve in rats. Glial activity was also examined after repeated intraperitoneal injection of minocycline combined with a single BoNT/A injection. Our results show that a single intraplantar BoNT/A injection did not influence motor function but strongly diminished pain-related behaviors in naïve and CCI-exposed rats. Additionally, microglial inhibition using minocycline enhanced the analgesic effects of BoNT/A. Western blotting results suggested that CCI induces the upregulation of the pronociceptive proteins IL-18, IL-6 and IL-1β in the ipsilateral lumbar spinal cord and DRG, but no changes in the levels of the antinociceptive proteins IL-18BP, IL-1RA and IL-10 were observed. Interestingly, BoNT/A injection suppressed the CCI-induced upregulation of IL-18 and IL-1β in the spinal cord and/or DRG and increased the levels of IL-10 and IL-1RA in the DRG. In summary, our results suggest that BoNT/A significantly attenuates pain-related behavior and microglial activation and restores the neuroimmune balance in a CCI model by decreasing the levels of pronociceptive factors (IL-1β and IL-18) and increasing the levels of antinociceptive factors (IL-10 and IL-1RA) in the spinal cord and DRG. Copyright © 2016 Elsevier B.V. All rights reserved.

Role of Sigma-1 Receptor/p38 MAPK Inhibition in Acupoint Catgut Embedding-Mediated Analgesic Effects in Complete Freund's Adjuvant-Induced Inflammatory Pain.

PubMed

Du, Kairong; Wang, Xue; Chi, Laiting; Li, Wenzhi

2017-08-01

The endoplasmic reticulum chaperone protein Sigma-1 receptor (Sig-1 R) and mitogen-activated protein kinases (MAPKs) are involved in the mechanism of pain. Acupoint stimulation exerts an exact antihyperalgesic effect in inflammatory pain. However, whether Sig-1 R and MAPKs are associated with the acupoint stimulation-induced analgesic effects is not clear. This study investigated the analgesic effect of acupoint catgut embedding (ACE) and the inhibition of Sig-1 R and MAPKs in ACE analgesia. Rats were prepared with intrathecal catheter implantation. ACE was applied to bilateral "Kunlun" (BL60), "Zusanli" (ST36), and "Sanyinjiao" (SP6) acupoints in the rat model of inflammatory pain (complete Freund's adjuvant [CFA] intraplantar injection). Then, Sig-1R agonist PRE084 or saline was intrathecally given daily. The paw withdrawal thresholds and paw edema were measured before CFA injection and at 1, 3, and 5 day after CFA injection. Western bolt was used to evaluate the protein expression of spinal Sig-1R, p38MAPK, and extracellular signal-regulated kinase (ERK), and immunohistochemistry of Sig-1R was detected at 1, 3, and 5 days after CFA injection. ACE exhibited specific analgesic effects. ACE increased paw withdrawal thresholds and markedly decreased CFA-induced paw edema at 1, 3, and 5 days. ACE downregulated the protein expression of Sig-1R, which was increased significantly at 1, 3, and 5 days after CFA injection. ACE decreased the expression of p38 MAPK and ERK at 1 and 3 days but not at 5 days. However, an injection of Sig-1R agonist PRE084 markedly reversed these alterations, except ERK expression. The present study demonstrated that ACE exhibited antihyperalgesic effects via the inhibition of the Sig-1R that modulated p38 MAPK, but not ERK, expression in the CFA-induced inflammatory pain model in rats.

Anti-nociceptive effects of Tanshinone IIA (TIIA) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain.

PubMed

Sun, Shukai; Yin, Yue; Yin, Xin; Cao, Fale; Luo, Daoshu; Zhang, Ting; Li, Yunqing; Ni, Longxing

2012-09-01

Inflammatory pain is an important clinical symptom. The levels of extracellular signal-regulated kinases (ERKs) and the levels of cytokines such as interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play important roles in inflammatory pain. Tanshinone IIA (TIIA) is an important component of Danshen, a traditional Chinese medicine that has been commonly used to treat cardiovascular disease. In this study, we investigated the potential anti-inflammatory nociceptive effects of TIIA on complete Freund's adjuvant (CFA)-induced inflammation and inflammatory pain in rats. The effects of TIIA on CFA-induced thermal and mechanical hypersensitivity were investigated using behavioral tests. The levels of ERKs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transient receptor potential vanilloid 1 (TRPV1) in the fifth segment of the lumbar spinal cord (L5) ganglia were detected by Western blot, and the levels of mRNA and protein production of IL1-β, IL-6 and TNF-α were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immuno sorbent assay (ELISA). In this study, we found that TIIA attenuates the development of CFA-induced mechanical and thermal hypersensitivity. In addition, p-ERK and NF-κB expression levels were inhibited by TIIA, and the levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced. Finally, we found that the expression level of TRPV1 was significantly decreased after TIIA injection. This study demonstrated that TIIA has significant anti-nociceptive effects in a rat model of CFA-induced inflammatory pain. TIIA can inhibit the activation of ERK signaling pathways and the expression of pro-inflammatory cytokines. These results suggest that TIIA may be a potential anti-inflammatory and anti-nociceptive drug. Copyright © 2012 Elsevier Inc. All rights reserved.

Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.

PubMed

Xiao, Xing; Zhao, Xiao-Tao; Xu, Ling-Chi; Yue, Lu-Peng; Liu, Feng-Yu; Cai, Jie; Liao, Fei-Fei; Kong, Jin-Ge; Xing, Guo-Gang; Yi, Ming; Wan, You

2015-04-01

Transient receptor potential vanilloid 1 (TRPV1) receptors are expressed in nociceptive neurons of rat dorsal root ganglions (DRGs) and mediate inflammatory pain. Nonspecific inhibition of protein-tyrosine phosphatases (PTPs) increases the tyrosine phosphorylation of TRPV1 and sensitizes TRPV1. However, less is known about tyrosine phosphorylation's implication in inflammatory pain, compared with that of serine/threonine phosphorylation. Src homology 2 domain-containing tyrosine phosphatase 1 (Shp-1) is a key phosphatase dephosphorylating TRPV1. In this study, we reported that Shp-1 colocalized with and bound to TRPV1 in nociceptive DRG neurons. Shp-1 inhibitors, including sodium stibogluconate and PTP inhibitor III, sensitized TRPV1 in cultured DRG neurons. In naive rats, intrathecal injection of Shp-1 inhibitors increased both TRPV1 and tyrosine-phosphorylated TRPV1 in DRGs and induced thermal hyperalgesia, which was abolished by pretreatment with TRPV1 antagonists capsazepine, BCTC, or AMG9810. Complete Freund's adjuvant (CFA)-induced inflammatory pain in rats significantly increased the expression of Shp-1, TRPV1, and tyrosine-phosphorylated TRPV1, as well as the colocalization of Shp-1 and TRPV1 in DRGs. Intrathecal injection of sodium stibogluconate aggravated CFA-induced inflammatory pain, whereas Shp-1 overexpression in DRG neurons alleviated it. These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.

Attenuation of pCREB and Egr1 expression in the insular and anterior cingulate cortices associated with enhancement of CFA-evoked mechanical hypersensitivity after repeated forced swim stress.

PubMed

Imbe, Hiroki; Kimura, Akihisa

2017-09-01

The perception and response to pain are severely impacted by exposure to stressors. In some animal models, stress increases pain sensitivity, which is termed stress-induced hyperalgesia (SIH). The insular cortex (IC) and anterior cingulate cortex (ACC), which are typically activated by noxious stimuli, affect pain perception through the descending pain modulatory system. In the present study, we examined the expression of phospho-cAMP response element-binding protein (pCREB) and early growth response 1 (Egr1) in the IC and ACC at 3h (the acute phase of peripheral tissue inflammation) after complete Freund's adjuvant (CFA) injection in naïve rats and rats preconditioned with forced swim stress (FS) to clarify the effect of FS, a stressor, on cortical cell activities in the rats showing SIH induced by FS. The CFA injection into the hindpaw induced mechanical hypersensitivity and increased the expression of the pCREB and Egr1 in the IC and ACC at 3h after the injection. FS (day 1, 10min; days 2-3, 20min) prior to the CFA injection enhanced the CFA-induced mechanical hypersensitivity and attenuated the increase in the expression of pCREB and Egr1 in the IC and ACC. These findings suggested that FS modulates the CFA injection-induced neuroplasticity in the IC and ACC to enhance the mechanical hypersensitivity. These findings are thought to signify stressor-induced dysfunction of the descending pain modulatory system. Copyright © 2017 Elsevier Inc. All rights reserved.

Neural tissue engineering scaffold with sustained RAPA release relieves neuropathic pain in rats.

PubMed

Ding, Tan; Zhu, Chao; Kou, Zhen-Zhen; Yin, Jun-Bin; Zhang, Ting; Lu, Ya-Cheng; Wang, Li-Ying; Luo, Zhuo-Jing; Li, Yun-Qing

2014-09-01

To investigate the effect of locally slow-released rapamycin (RAPA) from bionic peripheral nerve stent to reduce the incidence of neuropathic pain or mitigate the degree of pain after nerve injury. We constructed a neural tissue engineering scaffold with sustained release of RAPA to repair 20mm defects in rat sciatic nerves. Four presurgical and postsurgical time windows were selected to monitor the changes in the expression of pain-related dorsal root ganglion (DRG) voltage-gated sodium channels 1.3 (Nav1.3), 1.7 (Nav1.7), and 1.8 (Nav1.8) through immunohistochemistry (IHC) and Western Blot, along with the observation of postsurgical pathological pain in rats by pain-related behavior approaches. Relatively small upregulation of DRG sodium channels was observed in the experimental group (RAPA+poly(lactic-co-glycolic acid) (PLGA)+stent) after surgery, along with low degrees of neuropathic pain and anxiety, which were similar to those in the Autologous nerve graft group. Autoimmune inflammatory response plays a leading role in the occurrence of post-traumatic neuropathic pain, and that RAPA significantly inhibits the abnormal upregulation of sodium channels to reduce pain by alleviating inflammatory response. Copyright © 2014 Elsevier Inc. All rights reserved.

The effects of levetiracetam, sumatriptan, and caffeine in a rat model of trigeminal pain: interactions in 2-component combinations.

PubMed

Tomić, Maja A; Pecikoza, Uroš B; Micov, Ana M; Popović, Božidar V; Stepanović-Petrović, Radica M

2015-06-01

Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain. Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis. Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test. Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically.

Effects of fentanyl on pain and motor behaviors following a collagenase-induced intracerebral hemorrhage in rats

PubMed Central

Saine, Laurence; Hélie, Pierre; Vachon, Pascal

2016-01-01

Purpose Intracerebral hemorrhage (IH) and cephalalgia are common consequences of traumatic brain injury. One of the primary obstacles for patient recovery is the paucity of treatments to support an appropriate analgesic protocol. The present study aimed to assess pain and motor behaviors following different doses of fentanyl on a rat model of IH. Methods Twenty-one male Sprague Dawley rats underwent a stereotaxic surgery to produce a collagenase-induced IH in the right caudoputamen nucleus. The control group (n=6) received saline subcutaneously (SC), and experimental groups received either 5 (n=6), 10 (n=6), or 20 (n=3) µg/kg of fentanyl SC, 2 hours following surgery and on 2 subsequent days. Only 3 animals received 20 µg/kg because this dose caused catalepsy for 15–20 minutes following the injection. The rat grimace scale, a neurological examination, balance beam test, and rotarod test were performed for 5 consecutive days postoperatively to evaluate pain and motor performance. At the end of the experimentation, the brains were evaluated to determine hematoma volume, and the number of reactive astrocytes and necrotic neurons. Results When compared to controls, the grimace scale showed that 5 µg/kg fentanyl significantly alleviated pain on day 2 only (P<0.01) and that 10 µg/kg alleviated pain on days 1 (P<0.01), 2 (P<0.001), and 3 (P<0.01). For the rotarod test, only the 10 µg/kg group showed significant decreases in performance on days 5 (P<0.05) and 6 (P<0.02). The neurological examination was not significantly different between the groups, but only the hopping test showed poor recuperation for the 5 and 10 µg/kg fentanyl group when compared to saline (P<0.01). No differences were found between the groups for the balance beam test, the histopathological results. Conclusion Fentanyl, at a dose of 10 µg/kg SC, provides substantial analgesia following a collagenase-induced IH in rats; however, it can alter motor performance following analgesic treatments. PMID:27895509

The antinociceptive effect of intravenous imipramine in colorectal distension-induced visceral pain in rats: the role of serotonergic and noradrenergic receptors.

PubMed

İlkaya, Fatih; Bilge, S Sırrı; Bozkurt, Ayhan; Baş, Duygu B; Erdal, Arzu; Çiftçioğlu, Engin; Kesim, Yüksel

2014-07-01

It has been shown that imipramine, a tricyclic antidepressant (TCA), is a potent analgesic agent. However, the effect of imipramine on visceral pain has not been extensively investigated. In the current study, our aim was to characterise the putative analgesic effect of intravenous imipramine on visceral pain in rats. Our second aim was to assess the involvement of serotonergic (5-HT₂,₃,₄) and noradrenergic (α(2A, 2B, 2C)) receptor subtypes in this putative antinociceptive effect of imipramine. Male Sprague Dawley rats (250-300 g) were implanted with venous catheters for drug administration and implanted with enamelled nichrome electrodes for electromyography of the external oblique muscles. Noxious visceral stimulation was applied via by colorectal distension (CRD). The visceromotor responses (VMRs) to CRD were quantified electromyographically before and after imipramine administration at 5, 15, 30, 60, 90 and 120 min. In the antagonist groups, the agents were administered 10 min before imipramine. The administration of imipramine (5-40 mg/kg) produced a dose-dependent reduction in VMR. The administration of yohimbine (a nonselective α₂-adrenoceptor antagonist, 1 mg/kg), BRL-44408 (an α(2A)-adrenoceptor antagonist, 1 mg/kg) or MK-912 (an α2C-adrenoceptor antagonist, 300 μg/kg) but not imiloxan (an α(2B)-adrenoceptor antagonist, 1 mg/kg) inhibited the antinociceptive effect of imipramine (20 mg/kg). Additionally, ketanserin (a 5-HT₂ receptor antagonist, 0.5, 1, and 2 mg/kg) and GR113808 (a 5-HT₄ receptor antagonist, 1 mg/kg) enhanced, and ondansetron (a 5-HT₃ receptor antagonist, 0.5, 1, and 2 mg/kg) failed to alter the imipramine-induced antinociceptive effect. Our data demonstrated that, in the CDR-induced rat visceral pain model, intravenous imipramine appeared to have antinociceptive potential and that α(2A)-/α(2C)-adrenoceptors and 5-HT₂/5-HT₄ receptors may be responsible for the antinociceptive effect of imipramine on visceral pain in rats. Copyright © 2014 Elsevier Inc. All rights reserved.

Antinociceptive action of carbamazepine on thermal hypersensitive pain at spinal level in a rat model of adjuvant-induced chronic inflammation.

PubMed

Iwamoto, Tatsushige; Takasugi, Yoshihiro; Higashino, Hideaki; Ito, Hiroyuki; Koga, Yoshihisa; Nakao, Shinichi

2011-02-01

Systemic carbamazepine, a voltage-gated sodium channel blocker, has been reported to dose-dependently reduce inflammatory hyperalgesia. However, the antinociceptive effects of carbamazepine on the spinal cord in inflammatory conditions are unclear. The aim of the present study was to evaluate the antinociceptive effects of carbamazepine on the spinal cord in a chronic inflammatory condition. In Sprague-Dawley rats, a chronic inflammatory condition was induced by complete Freund's adjuvant (CFA) inoculation into the tail. Tail flick (TF) latencies were measured following intraperitoneal carbamazepine, or intrathecal carbamazepine or tetrodotoxin injection in intact rats and in the chronic inflammatory rats. From the values of TF latency at 60 min after drug injection, the effective dose required to produce 50% response (ED(50)) of each drug was derived. Carbamazepine attenuated thermal responses with both systemic and intrathecal administration. The effect was more evident in rats with chronic inflammation than in intact rats; the ED(50s) of intraperitoneal carbamazepine in intact and inflamed rats were 12.39 and 1.54 mg/kg, and those of intrathecal carbamazepine were 0.311 and 0.048 nmol, respectively. Intrathecal tetrodotoxin also clearly inhibited the response, with ED(50s) of 1.006 pmol in intact rats and 0.310 pmol in inflamed rats. The relative potencies of intrathecal carbamazepine versus tetrodotoxin for inhibition were approximately 1:150-1:300 in intact and inflamed rats. These results indicate that the inhibition of voltage-gated sodium channels, at least tetrodotoxin-sensitive channels, may contribute to the antinociceptive effect of carbamazepine on CFA-induced inflammatory pain, since lower doses of intrathecal carbamazepine and tetrodotoxin attenuated thermal responses to a greater extent in inflamed rats than in intact rats.

Role of opioid system in verapamil-induced antinociception in a rat model of orofacial pain

PubMed Central

Tamaddonfard, Esmaeal; Erfanparast, Amir; Taati, Mina; Dabbaghi, Milad

2014-01-01

Calcium, through its various channels involves in local, spinal and supra-spinal transmission of pain. In the present study, we investigated the separate and combined treatment effects of verapamil (a calcium channel blocker), morphine (an opioid agonist) and naloxone (an opioid antagonist) on pain in the orofacial region of rats. Orofacial pain was induced by subcutaneous (SC) injection of formalin (50 µL, 1.5%) into the left upper lip side, and the time durations spent face rubbing with epsilateral forepaw were recorded in three min blocks for a period of 45 min. Formalin induced a biphasic pattern (first phase: 0-3 min; second phase: 15-33 min) of pain. Intraperitoneal (IP) injections of verapamil (2 and 8 mg kg-1) and morphine (2 and 4 mg kg-1) suppressed orofacial pain. Co-administration of sub-analgesic doses of verapamil (0.5 mg kg-1) and morphine (1 mg kg-1) produced second phase analgesia. Both phases of formalin-induced pain were suppressed when an analgesic dose (2 mg kg-1) of verapamil co-administered with a sub-analgesic dose (1 mg kg-1) of morphine. The SC injection of naloxone (2 mg kg-1) alone with no effect on pain intensity, prevented the antinociceptive effects induced by morphine (2 mg kg-1), but not verapamil (2 mg kg-1). The obtained results showed antinociceptive effects for verapamli and morphine on orofacial pain. Co-administrations of verapamil and morphine produced antinociceptive effects. It seems that opioid analgesic system may not have a role in the verapamil-induced antinociception. PMID:25568692

Gait analysis and weight bearing in pre-clinical joint pain research.

PubMed

Ängeby Möller, Kristina; Svärd, Heta; Suominen, Anni; Immonen, Jarmo; Holappa, Johanna; Stenfors, Carina

2018-04-15

There is a need for better joint pain treatment, but development of new medication has not been successful. Pre-clinical models with readouts that better reflect the clinical situation are needed. In patients with joint pain, pain at rest and pain at walking are two major complaints. We describe a new way of calculating results from gait analysis using the CatWalk™ setup. Rats with monoarthritis induced by injection of Complete Freund's Adjuvant (CFA) intra-articularly into the ankle joint of one hind limb were used to assess gait and dynamic weight bearing. The results show that dynamic weight bearing was markedly reduced for the injected paw. Gait parameters such as amount of normal step sequences, walking speed and duration of step placement were also affected. Treatment with naproxen (an NSAID commonly used for inflammatory pain) attenuated the CFA-induced effects. Pregabalin, which is used for neuropathic pain, had no effect. Reduced dynamic weight bearing during locomotion, assessed and calculated in the way we present here, showed a dose-dependent and lasting normalization after naproxen treatment. In contrast, static weight bearing while standing (Incapacitance tester) showed a significant effect for a limited time only. Mechanical sensitivity (von Frey Optihairs) was completely normalized by naproxen, and the window for testing pharmacological effect disappeared. Objective and reproducible effects, with an endpoint showing face validity compared to pain while walking in patients with joint pain, are achieved by a new way of calculating dynamic weight bearing in monoarthritic rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Enhanced excitability of small dorsal root ganglion neurons in rats with bone cancer pain

PubMed Central

2012-01-01

Background Primary and metastatic cancers that affect bone are frequently associated with severe and intractable pain. The mechanisms underlying the development of bone cancer pain are largely unknown. The aim of this study was to determine whether enhanced excitability of primary sensory neurons contributed to peripheral sensitization and tumor-induced hyperalgesia during cancer condition. In this study, using techniques of whole-cell patch-clamp recording associated with immunofluorescent staining, single-cell reverse-transcriptase PCR and behavioral test, we investigated whether the intrinsic membrane properties and the excitability of small-sized dorsal root ganglion (DRG) neurons altered in a rat model of bone cancer pain, and whether suppression of DRG neurons activity inhibited the bone cancer-induced pain. Results Our present study showed that implantation of MRMT-1 tumor cells into the tibial canal in rats produced significant mechanical and thermal hyperalgesia in the ipsilateral hind paw. Moreover, implantation of tumor cells provoked spontaneous discharges and tonic excitatory discharges evoked by a depolarizing current pulse in small-sized DRG neurons. In line with these findings, alterations in intrinsic membrane properties that reflect the enhanced neuronal excitability were observed in small DRG neurons in bone cancer rats, of which including: 1) depolarized resting membrane potential (RMP); 2) decreased input resistance (Rin); 3) a marked reduction in current threshold (CT) and voltage threshold (TP) of action potential (AP); 4) a dramatic decrease in amplitude, overshot, and duration of evoked action potentials as well as in amplitude and duration of afterhyperpolarization (AHP); and 5) a significant increase in the firing frequency of evoked action potentials. Here, the decreased AP threshold and increased firing frequency of evoked action potentials implicate the occurrence of hyperexcitability in small-sized DRG neurons in bone cancer rats. In addiotion, immunofluorescent staining and single-cell reverse-transcriptase PCR revealed that in isolated small DRG neurons, most neurons were IB4-positive, or expressed TRPV1 or CGRP, indicating that most recorded small DRG neurons were nociceptive neurons. Finally, using in vivo behavioral test, we found that blockade of DRG neurons activity by TTX inhibited the tumor-evoked mechanical allodynia and thermal hyperalgesia in bone cancer rats, implicating that the enhanced excitability of primary sensory neurons underlied the development of bone cancer pain. Conclusions Our present results suggest that implantation of tumor cells into the tibial canal in rats induces an enhanced excitability of small-sized DRG neurons that is probably as results of alterations in intrinsic electrogenic properties of these neurons. Therefore, alterations in intrinsic membrane properties associated with the hyperexcitability of primary sensory neurons likely contribute to the peripheral sensitization and tumor-induced hyperalgesia under cancer condition. PMID:22472208

The effects of alpha2-adrenoceptor agents on anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain.

PubMed

Vucković, Sonja M; Tomić, Maja A; Stepanović-Petrović, Radica M; Ugresić, Nenad; Prostran, Milica S; Bosković, Bogdan

2006-11-01

In this study, the effects of yohimbine (alpha2-adrenoceptor antagonist) and clonidine (alpha2-adrenoceptor agonist) on anti-hyperalgesia induced by carbamazepine and oxcarbazepine in a rat model of inflammatory pain were investigated. Carbamazepine (10-40 mg/kg; i.p.) and oxcarbazepine (40-160 mg/kg; i.p.) caused a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A, intraplantarly) in a paw pressure test in rats. Yohimbine (1-3 mg/kg; i.p.) significantly depressed the anti-hyperalgesic effects of carbamazepine and oxcarbazepine, in a dose- and time-dependent manner. Both drug mixtures (carbamazepine-clonidine and oxcarbazepine-clonidine) administered in fixed-dose fractions of the ED50 (1/2, 1/4 and 1/8) caused significant and dose-dependent reduction of the hyperalgesia induced by Con A. Isobolographic analysis revealed a significant synergistic (supra-additive) anti-hyperalgesic effect of both combinations tested. These results indicate that anti-hyperalgesic effects of carbamazepine and oxcarbazepine are, at least partially, mediated by activation of adrenergic alpha2-receptors. In addition, synergistic interaction for anti-hyperalgesia between carbamazepine and clonidine, as well as oxcarbazepine and clonidine in a model of inflammatory hyperalgesia, was demonstrated.

Design, synthesis, and biological evaluation of 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors.

PubMed

Ramnauth, Jailall; Speed, Joanne; Maddaford, Shawn P; Dove, Peter; Annedi, Subhash C; Renton, Paul; Rakhit, Suman; Andrews, John; Silverman, Sarah; Mladenova, Gabriela; Zinghini, Salvatore; Nair, Sheela; Catalano, Concettina; Lee, David K H; De Felice, Milena; Porreca, Frank

2011-08-11

Neuronal nitric oxide synthase (nNOS) inhibitors are effective in preclinical models of many neurological disorders. In this study, two related series of compounds, 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline, containing a 6-substituted thiophene amidine group were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). A structure-activity relationship (SAR) study led to the identification of a number of potent and selective nNOS inhibitors. Furthermore, a few representative compounds were shown to possess druglike properties, features that are often difficult to achieve when designing nNOS inhibitors. Compound (S)-35, with excellent potency and selectivity for nNOS, was shown to fully reverse thermal hyperalgesia when given to rats at a dose of 30 mg/kg intraperitonieally (ip) in the L5/L6 spinal nerve ligation model of neuropathic pain (Chung model). In addition, this compound reduced tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in a rat model of dural inflammation relevant to migraine pain.

Manual therapy as an effective treatment for fibrosis in a rat model of upper extremity overuse injury

PubMed Central

Bove, Geoffrey M.; Harris, Michele Y; Zhao, Huaqing; Barbe, Mary F.

2016-01-01

Key clinical features of carpal tunnel syndrome and other types of cumulative trauma disorders of the hand and wrist include pain and functional disabilities. Mechanistic details remain under investigation but may involve tissue inflammation and/or fibrosis. We examined the effectiveness of modeled manual therapy (MMT) as a treatment for sensorimotor behavior declines and increased fibrogenic processes occurring in forearm tissues of rats performing an high repetition high force (HRHF) reaching and grasping task for 12 weeks. Young adult, female rats were examined: food restricted control rats (FRC, n=12); rats that were trained for 6 weeks before performing the HRHF task for 12 weeks with no treatment (HRHF-CON, n=11); and HRHF task rats received modeled manual therapy (HRHF-MMT, n=5) for 5 days/week for the duration of the 12-week of task. Rats receiving the MMT expressed fewer discomfort-related behaviors, and performed progressively better in the HRHF task. Grip strength, while decreased after training, improved following MMT. Fibrotic nerve and connective tissue changes (increased collagen and TGF-β1 deposition) present in 12-week HRHF-CON rats were significantly decreased in 12-week HRHF-MMT rats. These observations support the investigation of manual therapy as a preventative for repetitive motion disorders. PMID:26810536

Episodic Dural Stimulation in Awake Rats: A Model for Recurrent Headache

PubMed Central

Oshinsky, Michael L.; Gomonchareonsiri, Sumittra

2014-01-01

Objectives To model, in rats, the development of chronic trigeminal nociceptive hypersensitivity seen in patients with recurrent headache. Background Pathophysiology studies suggest that patients with recurrent migraine headache experience repeated bouts of dural nociceptor activation. In some patients, the severity and frequency of headache attacks increase over time. Patients with recurrent headache are hypersensitive to nitric oxide donors, such as glyceryl trinitrate (GTN). Current trigeminal pain models do not reflect the repeated episodic nature of dural nociceptor activation in patients with recurrent headache. Repeated nociceptor activation creates long-lasting changes in the periphery and brain due to activity-dependent neuronal plasticity. An animal model of repeated activation of dural nociceptors will facilitate the study of the physiological changes caused by repeated, episodic pain and the factors important for the transition of episodic to chronic migraine. Methods We induced dural inflammation by infusing an inflammatory soup (IS) through a cannula on the dura in awake behaving rats. This was repeated 3 times per week for up to 4 weeks. Periorbital pressure sensory testing was used to monitor the change in trigeminal sensitivity. Rats were challenged with GTN to test the hypothesis that many dural stimulations are required to model the hypersensitivity of migraine patients. Quantitative trigeminal sensory testing and microdialysis in the trigeminal nucleus caudalis (TNC) were used to measure GTN hypersensitivity. Results Multiple infusions of IS (>8), over weeks, induced a long-lasting decrease in periorbital pressure thresholds that lasted >3 weeks after the last infusion. In contrast, IS infusion in IS-naive rats and those that received 3 IS infusions produced only short-lasting decreases in periorbital pressure thresholds. Rats that received more than 8 IS infusions showed a marked increase in their neurochemical and behavioral responses to GTN. In these rats, GTN induced a decrease in periorbital von Frey thresholds that lasted >5 hours. In contrast, in rats that received only 3 IS infusions, GTN caused a threshold decrease for 1.5 hour. In vivo microdialysis in the TNC showed that GTN increased extracellular glutamate levels in rats with more than 8 IS infusions to 7.7 times the basal levels. In IS-naive rats and those that received only 3 IS infusions, the extracellular glutamate levels rose to only 1.7 and 1.9 times the basal level, respectively. Conclusions Repeated IS stimulation of the dura produces a chronic state of trigeminal hypersensitivity and potentiates the response to GTN. This hyperresponsiveness outlasts the last IS infusion and is the basis of our rat model of recurrent headache. This model can be used to study the changes in the brain and periphery induced by repeated trigeminovascular nociceptor activation and has the potential to elucidate the mechanisms for the transition of episodic to chronic headache. PMID:17635594

Evaluation of phenoxybenzamine in the CFA model of pain following gene expression studies and connectivity mapping.

PubMed

Chang, Meiping; Smith, Sarah; Thorpe, Andrew; Barratt, Michael J; Karim, Farzana

2010-09-16

We have previously used the rat 4 day Complete Freund's Adjuvant (CFA) model to screen compounds with potential to reduce osteoarthritic pain. The aim of this study was to identify genes altered in this model of osteoarthritic pain and use this information to infer analgesic potential of compounds based on their own gene expression profiles using the Connectivity Map approach. Using microarrays, we identified differentially expressed genes in L4 and L5 dorsal root ganglia (DRG) from rats that had received intraplantar CFA for 4 days compared to matched, untreated control animals. Analysis of these data indicated that the two groups were distinguishable by differences in genes important in immune responses, nerve growth and regeneration. This list of differentially expressed genes defined a "CFA signature". We used the Connectivity Map approach to identify pharmacologic agents in the Broad Institute Build02 database that had gene expression signatures that were inversely related ('negatively connected') with our CFA signature. To test the predictive nature of the Connectivity Map methodology, we tested phenoxybenzamine (an alpha adrenergic receptor antagonist) - one of the most negatively connected compounds identified in this database - for analgesic activity in the CFA model. Our results indicate that at 10 mg/kg, phenoxybenzamine demonstrated analgesia comparable to that of Naproxen in this model. Evaluation of phenoxybenzamine-induced analgesia in the current study lends support to the utility of the Connectivity Map approach for identifying compounds with analgesic properties in the CFA model.

Pavlovian second-order conditioned analgesia.

PubMed

Ross, R T

1986-01-01

Three experiments with rat subjects assessed conditioned analgesia in a Pavlovian second-order conditioning procedure by using inhibition of responding to thermal stimulation as an index of pain sensitivity. In Experiment 1, rats receiving second-order conditioning showed longer response latencies during a test of pain sensitivity in the presence of the second-order conditioned stimulus (CS) than rats receiving appropriate control procedures. Experiment 2 found that extinction of the first-order CS had no effect on established second-order conditioned analgesia. Experiment 3 evaluated the effects of post second-order conditioning pairings of morphine and the shock unconditioned stimulus (US). Rats receiving paired morphine-shock presentations showed significantly shorter response latencies during a hot-plate test of pain sensitivity in the presence of the second-order CS than did groups of rats receiving various control procedures; second-order analgesia was attenuated. These data extend the associative account of conditioned analgesia to second-order conditioning situations and are discussed in terms of the mediation of both first- and second-order analgesia by an association between the CS and a representation or expectancy of the US, which may directly activate endogenous pain inhibition systems.

Role of peripheral sigma-1 receptors in ischaemic pain: Potential interactions with ASIC and P2X receptors.

PubMed

Kwon, S G; Roh, D H; Yoon, S Y; Choi, S R; Choi, H S; Moon, J Y; Kang, S Y; Kim, H W; Han, H J; Beitz, A J; Oh, S B; Lee, J H

2016-04-01

The role of peripheral sigma-1 receptors (Sig-1Rs) in normal nociception and in pathologically induced pain conditions has not been thoroughly investigated. Since there is mounting evidence that Sig-1Rs modulate ischaemia-induced pathological conditions, we investigated the role of Sig-1Rs in ischaemia-induced mechanical allodynia (MA) and addressed their possible interaction with acid-sensing ion channels (ASICs) and P2X receptors at the ischaemic site. We used a rodent model of hindlimb thrombus-induced ischaemic pain (TIIP) to investigate their role. Western blot was performed to observe changes in Sig-1R expression in peripheral nervous tissues. MA was measured after intraplantar (i.pl.) injections of antagonists for the Sig-1, ASIC and P2X receptors in TIIP rats or agonists of each receptor in naïve rats. Sig-1R expression significantly increased in skin, sciatic nerve and dorsal root ganglia at 3 days post-TIIP surgery. I.pl. injections of the Sig-1R antagonist, BD-1047 on post-operative days 0-3 significantly attenuated the development of MA during the induction phase, but had no effect on MA when given during the maintenance phase (days 3-6 post-surgery). BD-1047 synergistically increased amiloride (an ASICs blocker)- and TNP-ATP (a P2X antagonist)-induced analgesic effects in TIIP rats. In naïve rats, i.pl. injection of Sig-1R agonist PRE-084 alone did not produce MA; but it did induce MA when co-administered with either an acidic pH solution or a sub-effective dose of αβmeATP. Peripheral Sig-1Rs contribute to the induction of ischaemia-induced MA via facilitation of ASICs and P2X receptors. Thus, peripheral Sig-1Rs represent a novel therapeutic target for the treatment of ischaemic pain. © 2015 European Pain Federation - EFIC®

Antinociceptive interaction between spinal clonidine and lidocaine in the rat formalin test: an isobolographic analysis.

PubMed

Hao, S; Takahata, O; Iwasaki, H

2001-03-01

Clinical and basic science studies suggest that spinal alpha-2-adrenergic receptor agonists and local anesthetics produce analgesia, but interaction between alpha-2-adrenergic receptor agonists and local anesthetics in the persistent pain model has not been examined. In the present study, using isobolographic analysis, we investigated the antinociceptive interaction of intrathecal clonidine and lidocaine in the rat formalin test. Sprague-Dawley rats were implanted with chronic lumbar intrathecal catheters, and were tested for paw flinch by formalin injection. Biphasic painful behavior was counted. Intrathecal clonidine (3-12 nmol) was administered 15 min before formalin, and intrathecal lidocaine (375-1850 nmol) was administered 5 min before formalin. To examine the interaction of intrathecal clonidine and lidocaine, an isobolographic design was used. Spinal administration of clonidine produced dose-dependent suppression of the biphasic responses in the formalin test. Spinal lidocaine resulted in dose-dependent transient motor dysfunction and the motor dysfunction recovered to normal at 10-15 min after administration. Spinal lidocaine produced dose-dependent suppression of phase-2 activity in the formalin test. Isobolographic analysis showed that the combination of intrathecal clonidine and lidocaine synergistically reduced Phase-2 activity. We conclude that intrathecal clonidine synergistically interacts with lidocaine in reducing the nociceptive response in the formalin test. Preformalin administration of intrathecal clonidine and lidocaine dose-dependently produced antinociception in the formalin test. The combination of clonidine and lidocaine, synergistically produced suppression of nociceptive response in the persistent pain model.

Cerebrolysin Attenuates Heat Shock Protein (HSP 72 KD) Expression in the Rat Spinal Cord Following Morphine Dependence and Withdrawal: Possible New Therapy for Pain Management

PubMed Central

Sharma, Hari S; Ali, Syed F; Patnaik, Ranjana; Zimmermann-Meinzingen, Sibilla; Sharma, Aruna; Muresanu, Dafin F

2011-01-01

The possibility that pain perception and processing in the CNS results in cellular stress and may influence heat shock protein (HSP) expression was examined in a rat model of morphine dependence and withdrawal. Since activation of pain pathways result in exhaustion of growth factors, we examined the influence of cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,) on morphine induced HSP expression. Rats were administered morphine (10 mg/kg, s.c. /day) for 12 days and the spontaneous withdrawal symptoms were developed by cessation of the drug administration on day 13th that were prominent on day 14th and continued up to day 15th (24 to 72 h periods). In a separate group of rats, cerebrolysin was infused intravenously (5 ml/kg) once daily from day one until day 15th. In these animals, morphine dependence and withdrawal along with HSP immunoreactivity was examined using standard protocol. In untreated group mild HSP immunoreaction was observed during morphine tolerance, whereas massive upregulation of HSP was seen in CNS during withdrawal phase that correlated well with the withdrawal symptoms and neuronal damage. Pretreatment with cerebrolysin did not affect morphine tolerance but reduced the HSP expression during this phase. Furthermore, cerebrolysin reduced the withdrawal symptoms on day 14th to 15th. Taken together these observations suggest that cellular stress plays an important role in morphine induced pain pathology and exogenous supplement of growth factors, i.e. cerebrolysin attenuates HSP expression in the CNS and induce neuroprotection. This indicates a new therapeutic role of cerebrolysin in the pathophysiology of drugs of abuse, not reported earlier. PMID:21886595

Moringa oleifera, a species with potential analgesic and anti-inflammatory activities.

PubMed

Martínez-González, Claudia Lizbeth; Martínez, Laura; Martínez-Ortiz, Efraín J; González-Trujano, María Eva; Déciga-Campos, Myrna; Ventura-Martínez, Rosa; Díaz-Reval, Irene

2017-03-01

Moringa oleifera has long been used in large demand in folk medicine to treat pain. The present study was undertaken to examine the antinociceptive and anti-inflammatory spectrum of M. oleifera leaf extracts discriminating the constituents' nature by using different kind of experimental models in rats. Pharmacological evaluation of a non-polar and/or polar extracts at several doses (30-300mg/kg, p.o.) was explored through experimental nociception using formalin test, carrageenan-induced paw edema and arthritis with subcutaneous injection of collagen in rats. Basic morphology characterization was done by scanning electronic microscopy and laser scanning confocal microscopy. Not only polar (from 30 or 100mg/kg, p.o.) but also non-polar extract produced significant inhibition of the nociceptive behavior with major efficacy in the inflammatory response in different assessed experimental models. This antinociceptive activity involved constituents of different nature and depended on the intensity of the induced painful stimulus. Phytochemical analysis showed the presence of kaempferol-3-glucoside in the polar extract and fatty acids like chlorogenic acid, among others, in the non-polar extract. Data obtained with M. oleifera leaf extracts give evidence of its potential for pain treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Evaluation of a Postoperative Pain-Like State on Motivated Behavior in Rats: Effects of Plantar Incision on Progressive-Ratio Food-Maintained Responding.

PubMed

Warner, Emily; Krivitsky, Rebecca; Cone, Katherine; Atherton, Phillip; Pitre, Travis; Lanpher, Janell; Giuvelis, Denise; Bergquist, Ivy; King, Tamara; Bilsky, Edward J; Stevenson, Glenn W

2015-12-01

There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional postoperative pain manipulation on food-maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hr, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior. © 2015 Wiley Periodicals, Inc.

Evaluation of a post-operative pain-like state on motivated behavior in rats: Effects of plantar incision on progressive-ratio food-maintained responding

PubMed Central

Warner, Emily; Krivitsky, Rebecca; Cone, Katherine; Atherton, Phillip; Pitre, Travis; Lanpher, Janell; Giuvelis, Denise; Bergquist, Ivy; King, Tamara; Bilsky, Edward J.; Stevenson, Glenn W.

2015-01-01

There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional post-operative pain manipulation on food-maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hrs, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior. PMID:26494422

Preclinical characterization of three transient receptor potential vanilloid receptor 1 antagonists for early use in human intradermal microdose analgesic studies.

PubMed

Sjögren, E; Halldin, M M; Stålberg, O; Sundgren-Andersson, A K

2018-05-01

The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel involved in the mediation of peripheral pain to the central nervous system. As such, the TRPV1 is an accessible molecular target that lends itself well to the understanding of nociceptive signalling. This study encompasses preclinical investigations of three molecules with the prospect to establish them as suitable analgesic model compounds in human intradermal pain relief studies. The inhibitory effectiveness was evaluated by means of in vitro assays, TRPV1 expressing Chinese hamster ovary cells (CHO-K1) and rat dorsal root ganglion cultures in fluorescent imaging plate reader and whole cell patch clamp systems, as well as in vivo by capsaicin-evoked pain-related behavioural response studies in rat. Secondary pharmacology, pharmacokinetics and preclinical safety were also assessed. In vitro, all three compounds were effective at inhibiting capsaicin-activated TRPV1. The concentration producing 50% inhibition (IC 50 ) determined was in the range of 3-32 nmol/L and 10-501 nmol/L using CHO-K1 and dorsal root ganglion cultures, respectively. In vivo, all compounds showed dose-dependent reduction in capsaicin-evoked pain-related behavioural responses in rat. None of the three compounds displayed any significant activity on any of the secondary targets tested. The compounds were also shown to be safe from a toxicological, drug metabolism and pharmacokinetic perspective, for usage in microgram doses in the human skin. The investigated model compounds displayed ideal compound characteristics as pharmacological and translational tools to address efficacy on the human native TRPV1 target in human skin in situ. This work details the pharmaceutical work-up of three TRPV1-active investigational compounds, to obtain regulatory approval, for subsequent use in humans. This fast and cost-effective preclinical development path may impact research beyond the pain management area, as it allows human target engagement information gathering early in drug development. © 2018 European Pain Federation - EFIC®.

Transcutaneous electrical nerve stimulation attenuates postsurgical allodynia and suppresses spinal substance P and proinflammatory cytokine release in rats.

PubMed

Chen, Yu-Wen; Tzeng, Jann-Inn; Lin, Min-Fei; Hung, Ching-Hsia; Wang, Jhi-Joung

2015-01-01

Transcutaneous electrical nerve stimulation (TENS) is often used for management of chronic pain. The purpose of this study was to investigate whether TENS altered postincisional allodynia, substance P, and proinflammatory cytokines in a rat model of skin-muscle incision and retraction (SMIR). This was an experimental study. High-frequency (100-Hz) TENS therapy began on postoperative day 3 and was administered for 20 minutes daily to SMIR-operated rats by self-adhesive electrodes delivered to skin innervated via the ipsilateral dorsal rami of lumbar spinal nerves L1-L6 for the next 27 days. The expressions of substance P, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1β) in the spinal cord and mechanical sensitivity to von Frey stimuli (4g and 10g) were evaluated. The SMIR-operated rats displayed a marked hypersensitivity to von Frey stimuli on postoperative day 3. In contrast to the SMIR-operated rats, SMIR-operated rats after TENS administration showed a quick recovery of mechanical hypersensitivity. On postoperative days 3, 16, and 30, SMIR-operated rats exhibited an upregulation of substance P and cytokines (TNF-α, IL-6, and IL-1β) in the spinal cord, whereas SMIR-operated rats after TENS therapy inhibited that upregulation. By contrast, the placebo TENS following SMIR surgery did not alter mechanical hypersensitivity and the levels of spinal substance P, TNF-α, IL-6, and IL-1β. The experimental data are limited to animal models and cannot be generalized to postoperative pain in humans. The results revealed that TENS attenuates prolonged postoperative allodynia following SMIR surgery. Increased levels of spinal substance P and proinflammatory cytokines, activated after SMIR surgery, are important in the processing of persistent postsurgical allodynia. The protective effect of TENS may be related to the suppression of spinal substance P and proinflammatory cytokines in SMIR-operated rats. © 2015 American Physical Therapy Association.

Curcumin attenuates mechanical and thermal hyperalgesia in chronic constrictive injury model of neuropathic pain.

PubMed

Di, Yu Xiang; Hong, Cao; Jun, Li; Renshan, Ge; Qinquan, Lian

2014-06-01

The aim of this study was to observe the effect of stress caused by neuropathic pain on serum cortisol concentration and expression of 11β-hydroxysteroid dehydrogenase type I enzyme (11βHSD1) in spinal cord and dorsal root ganglions (DRG) and investigate the role and mechanism of curcumin in the neuropathic pain of stressful rats. Neuropathic pain is a prevalent disease that greatly impairs the patients' quality of life. A lack of the understanding of its etiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of the newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect of curcumin and its effect on expression of 11β-hydroxysteroid dehydrogenase type I enzyme (11βHSD1) in spinal dorsal horn and DRG in chronic constriction injury (CCI) mode of neuropathic pain of rats. Seventy-two male Sprague-Dawley rats were randomized into four groups with 18 rats in each: sham operation group (Sham), chronic constrictive injury group (CCI), solvent contrast group (SC), and curcumin-treated group (Cur100). Curcumin, 100 mg/kg/day intraperitoneal, was given for 14 days starting from the first day after operation in the Cur100 group. Paw thermal withdrawal latency (PTWL) and paw mechanical withdrawal threshold (PMWT) of rats were measured 2 days pre-operative, and 1, 3, 5, 7, 10, and 14 days post-operative. The animals were deeply anesthetized and blood was taken from the heart, the lumbar segment (L4, 5) of the spinal cord and DRG were dissected out and homogenized. The change of cortisol was measured by enzyme-linked immunosorbent assay and the change of 11βHSD1 expression was determined by immunochemistry and Western blot. Compared with sham group, PTWL and PMWT significantly decrease after operation in the CCI group; serum cortisol concentration was significantly increased and the expression of 11βHSD1 was significantly increased in the CCI group. Comparing with CCI group, the PMWT and PTWL were increased and the serum cortisol concentration was decreased and the expression of 11βHSD1 was inhibited in Cur100 group. Stress caused by neuropathic pain triggers release of cortisol to the blood and expression of 11βHSD1 would increase at the same time. Curcumin could alleviate thermal and mechanical hyperalgesia induced by CCI and inhibit the serum cortisol concentration and expression of 11βHSD1 in the spinal cord and DRG.

Andrographis Paniculata shows anti-nociceptive effects in an animal model of sensory hypersensitivity associated with migraine

PubMed Central

Greco, Rosaria; Siani, Francesca; Demartini, Chiara; Zanaboni, Annamaria; Nappi, Giuseppe; Davinelli, Sergio; Scapagnini, Giovanni; Tassorelli, Cristina

2016-01-01

Administration of nitroglycerin (NTG) to rats induces a hyperalgesic condition and neuronal activation of central structures involved in migraine pain. In order to identify therapeutic strategies for migraine pain, we evaluated the anti-nociceptive activity of Andrographis Paniculata (AP), a herbaceous plant, in the hyperalgesia induced by NTG administration in the formalin test. We also analyzed mRNA expression of cytokines in specific brain areas after AP treatment. Male Sprague-Dawley rats were pre-treated with AP extract 30 minutes before NTG or vehicle injection. The data show that AP extract significantly reduced NTG-induced hyperalgesia in phase II of the test, 4 hours after NTG injection. In addition, AP extract reduced IL-6 mRNA expression in the medulla and mesencephalon and also mRNA levels of TNF-alpha in the mesencephalic region. These findings suggest that AP extract may be a potential therapeutic approach in the treatment of general pain, and possibly of migraine. PMID:27027895

Andrographis Paniculata shows anti-nociceptive effects in an animal model of sensory hypersensitivity associated with migraine.

PubMed

Greco, Rosaria; Siani, Francesca; Demartini, Chiara; Zanaboni, Annamaria; Nappi, Giuseppe; Davinelli, Sergio; Scapagnini, Giovanni; Tassorelli, Cristina

2016-01-01

Administration of nitroglycerin (NTG) to rats induces a hyperalgesic condition and neuronal activation of central structures involved in migraine pain. In order to identify therapeutic strategies for migraine pain, we evaluated the anti-nociceptive activity of Andrographis Paniculata (AP), a herbaceous plant, in the hyperalgesia induced by NTG administration in the formalin test. We also analyzed mRNA expression of cytokines in specific brain areas after AP treatment. Male Sprague-Dawley rats were pre-treated with AP extract 30 minutes before NTG or vehicle injection. The data show that AP extract significantly reduced NTG-induced hyperalgesia in phase II of the test, 4 hours after NTG injection. In addition, AP extract reduced IL-6 mRNA expression in the medulla and mesencephalon and also mRNA levels of TNFalpha in the mesencephalic region. These findings suggest that AP extract may be a potential therapeutic approach in the treatment of general pain, and possibly of migraine.

Upregulation of the sodium channel NaVβ4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local DRG inflammation

PubMed Central

Xie, Wenrui; Tan, Zhi-Yong; Barbosa, Cindy; Strong, Judith A.; Cummins, Theodore R.; Zhang, Jun-Ming

2016-01-01

High frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all the isoforms in adult DRG, NaV1.6 is the main carrier of TTX-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA mediated knockdown of NaVβ4 to examine its role in the DRG inflammation model. NaVβ4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRGs showed that NaVβ4 siRNA blocked the inflammation-induced increase in spontaneous activity of Aβ neurons, and reduced repetitive firing and other measures of excitability. NaVβ4 was preferentially expressed in larger diameter cells; DRG inflammation increased its expression and this was reversed by NaVβ4 siRNA, based on immunohistochemistry and Western blotting. NaVβ4 siRNA also reduced immunohistochemical NaV1.6 expression. Patch clamp recordings of TTX-sensitive Na currents in acutely cultured medium diameter DRG neurons showed that DRG inflammation increased transient and especially resurgent current; effects blocked by NaVβ4 siRNA. NaVβ4 may represent a more specific target for pain conditions that depend on myelinated neurons expressing NaV1.6. PMID:26785322

AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain

PubMed Central

Su, Chen; Lin, Hau Yeuh; Yang, Runtao; Xu, Duo; Lee, Michelle; Pawlak, Natalie; Norcini, Monica; Sideris, Alexandra; Recio-Pinto, Esperanza; Huang, Dong; Wang, Jing

2016-01-01

Background AMPAkines augment the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the brain to increase excitatory outputs. These drugs are known to relieve persistent pain. However, their role in acute pain is unknown. Furthermore, a specific molecular and anatomic target for these novel analgesics remains elusive. Methods We studied the analgesic role of an AMPAkine, CX546, in a rat paw incision (PI) model of acute postoperative pain. We measured the effect of AMPAkines on sensory as well as depressive symptoms of pain using mechanical hypersensitivity and forced swim tests. We asked whether AMPA receptors in the nucleus accumbens (NAc), a key node in the brain's reward and pain circuitry, can be a target for AMPAkine analgesia. Results Systemic administration of CX546 (n=13), compared with control (n=13), reduced mechanical hypersensitivity (50% withdrawal threshold of 6.05±1.30g (mean±SEM) vs. 0.62±0.13g), and it reduced depressive features of pain by decreasing immobility on the forced swim test in PI-treated rats (89.0±15.5s vs. 156.7±18.5s). Meanwhile, CX546 delivered locally into the NAc provided pain-relieving effects in both PI (50% withdrawal threshold of 6.81±1.91g vs. 0.50±0.03g; control n=6, CX546 n=8) and persistent postoperative pain (spared nerve injury – SNI) models (50% withdrawal threshold of 3.85±1.23g vs. 0.45±0.00g; control n=7, CX546 n=11). Blocking AMPA receptors in the NAc with 3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2, 3-dione (NBQX) inhibited these pain-relieving effects (50% withdrawal threshold of 7.18±1.52g vs. 1.59±0.66g; n=8 for PI groups; 10.70±3.45g vs. 1.39±0.88g; n=4 for SNI groups). Conclusions AMPAkines relieves postoperative pain by activating AMPA receptors in the NAc. PMID:27627816

AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain.

PubMed

Su, Chen; Lin, Hau Yeuh; Yang, Runtao; Xu, Duo; Lee, Michelle; Pawlak, Natalie; Norcini, Monica; Sideris, Alexandra; Recio-Pinto, Esperanza; Huang, Dong; Wang, Jing

2016-11-01

AMPAkines augment the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the brain to increase excitatory outputs. These drugs are known to relieve persistent pain. However, their role in acute pain is unknown. Furthermore, a specific molecular and anatomic target for these novel analgesics remains elusive. The authors studied the analgesic role of an AMPAkine, CX546, in a rat paw incision (PI) model of acute postoperative pain. The authors measured the effect of AMPAkines on sensory and depressive symptoms of pain using mechanical hypersensitivity and forced swim tests. The authors asked whether AMPA receptors in the nucleus accumbens (NAc), a key node in the brain's reward and pain circuitry, can be a target for AMPAkine analgesia. Systemic administration of CX546 (n = 13), compared with control (n = 13), reduced mechanical hypersensitivity (50% withdrawal threshold of 6.05 ± 1.30 g [mean ± SEM] vs. 0.62 ± 0.13 g), and it reduced depressive features of pain by decreasing immobility on the forced swim test in PI-treated rats (89.0 ± 15.5 vs. 156.7 ± 18.5 s). Meanwhile, CX546 delivered locally into the NAc provided pain-relieving effects in both PI (50% withdrawal threshold of 6.81 ± 1.91 vs. 0.50 ± 0.03 g; control, n = 6; CX546, n = 8) and persistent postoperative pain (spared nerve injury) models (50% withdrawal threshold of 3.85 ± 1.23 vs. 0.45 ± 0.00 g; control, n = 7; CX546, n = 11). Blocking AMPA receptors in the NAc with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione inhibited these pain-relieving effects (50% withdrawal threshold of 7.18 ± 1.52 vs. 1.59 ± 0.66 g; n = 8 for PI groups; 10.70 ± 3.45 vs. 1.39 ± 0.88 g; n = 4 for spared nerve injury groups). AMPAkines relieve postoperative pain by acting through AMPA receptors in the NAc.

Rat Models and Identification of Candidate Early Serum Biomarkers of Battlefield Traumatic Brain Injury

DTIC Science & Technology

2007-07-31

brain injury) All surgeries were performed using aseptic technique. Animals were checked for pain /distress immediately prior to anesthesia/surgery... Pain /distress checks were performed at 3, 6, 12, 24, 36, 48, 60, and 72 hours post-injury. Fluid Percussion Injury (FPI) For animals in the...NIH), and Neurobehavioral Scale (NBS). The criteria used to obtain the scores are detailed in Tables 2 and 3. As an additional endpoint, we also

Development of Novel Combinatorial Treatment to Prevent Chemotherapeutic Resistance and Enhance Efficacy of Riluzole in a Rodent Model of SCI

DTIC Science & Technology

2016-10-01

site as well as in the cervical and lumbar cords out to at least 10 months post-injury. While our rodent study was ongoing, a multi-center clinical...lead to a preservation of motor function and an attenuation in long-term pathologies like neuropathic pain in rats following an acute therapeutic...chemotherapeutic resistance, mass spectrometry, riluzole, licofelone, neuropathic pain , locomotor, bioavailability 11 University of Mississippi

Duloxetine and 8-OH-DPAT, but not fluoxetine, reduce depression-like behaviour in an animal model of chronic neuropathic pain.

PubMed

Hu, Bing; Doods, Henri; Treede, Rolf-Detlef; Ceci, Angelo

2016-04-21

The current study assessed whether antidepressant and/or antinociceptive drugs, duloxetine, fluoxetine as well as (±)-8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), are able to reverse depression-like behaviour in animals with chronic neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve in rats was selected as neuropathic pain model. Mechanical hypersensitivity and depression-like behaviour were evaluated 4 weeks after surgery by "electronic algometer" and forced swimming test (FST), which measured the time of immobility, and active behaviours climbing and swimming. The selective noradrenergic and serotonergic uptake blocker duloxetine (20mg/kg) and the selective 5-HT1A agonist 8-OH-DPAT (0.5mg/kg) significantly reversed both mechanical hypersensitivity and depression-like behaviour in CCI animals. Duloxetine significantly reversed depression-like behaviour in CCI rats by increasing the time of climbing and swimming, while 8-OH-DPAT attenuated depression-like behaviour mainly by increasing the time of swimming. However, the selective serotonergic uptake blocker fluoxetine (20mg/kg) failed to attenuate mechanical hypersensitivity and depression-like behaviour, possibly due to confounding pro-nociceptive actions at 5-HT3 receptors. These data suggest to target noradrenergic and 5-HT1A receptors for treatment of chronic pain and its comorbidity depression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain

PubMed Central

Bridges, Daniel; Ahmad, Kamran; Rice, Andrew S C

2001-01-01

The analgesic properties of the synthetic cannabinoid WIN55,212-2 were investigated in a model of neuropathic pain. In male Wistar rats, bilateral hind limb withdrawal thresholds to cold, mechanical and noxious thermal stimuli were measured. Following this, unilateral L5 spinal nerve ligation was performed. Seven days later, sensory thresholds were reassessed and the development of allodynia to cold and mechanical stimuli and hyperalgesia to a noxious thermal stimulus confirmed.The effect of WIN55,212-2 (0.1 – 5.0 mg kg−1, i.p.) on the signs of neuropathy was then determined; there was a dose related reversal of all three signs of painful neuropathy at doses which did not generally alter sensory thresholds in the contralateral unligated limb. This effect was prevented by co-administration of the CB1 receptor antagonist SR141716a, but not by co-administration of the CB2 receptor antagonist SR144528, suggesting this action of WIN55,212-2 is mediated via the CB1 receptor. Administration of SR141716a alone had no affect on the observed allodynia and hyperalgesia, which does not support the concept of an endogenous analgesic tone.These data indicate that cannabinoids may have therapeutic potential in neuropathic pain, and that this effect is mediated through the CB1 receptor. PMID:11399676

Ameliorative effect of Vernonia cinerea in vincristine-induced painful neuropathy in rats.

PubMed

Thiagarajan, Venkata Rathina Kumar; Shanmugam, Palanichamy; Krishnan, Uma Maheswari; Muthuraman, Arunachalam

2014-10-01

The present study was designed to investigate the antinociceptive potential of Vernonia cinerea (VC) on vincristine-induced painful neuropathy in rats. A chemotherapeutic agent, vincristine (50 μg/kg intraperitoneally for 10 consecutive days), was administered for the induction of neuropathic pain in rats. The painful behavioral changes were assessed using hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests to assess the degree of hyperalgesic and allodynic pain sensation in paw and tail. Tissue biomarker changes including thiobarbituric acid reactive substances (TBARSs), reduced glutathione (GSH) and total calcium levels were estimated in sciatic nerve tissue samples to assess the degree of oxidative stress. Histopathological changes were also observed in transverse sections of rat sciatic nerve tissue. Ethanolic extract of VC leaves and pregabalin were administered for 14 consecutive days from day 0 (day of surgery). Pregabalin served as a positive control in the present study. Vincristine administration resulted in a significant reduction in painful behavioral changes along with a rise in the levels of TBARS, total calcium and decrease in GSH levels when compared with the normal control group. Furthermore, significant histopathological changes were also observed. Pretreatment with VC significantly attenuated vincristine-induced development of painful behavioral, biochemical and histological changes in a dose-dependent manner, which is similar to that of pregabalin-pretreated group. The attenuating effect of VC in vincristine-induced nociceptive painful sensation may be due to its potential of antioxidative, neuroprotective and calcium channel inhibitory action. © The Author(s) 2012.

The changing balance of brainstem–spinal cord modulation of pain processing over the first weeks of rat postnatal life

PubMed Central

Hathway, G J; Koch, S; Low, L; Fitzgerald, M

2009-01-01

Brainstem–spinal cord connections play an essential role in adult pain processing, and the modulation of spinal pain network excitability by brainstem nuclei is known to contribute to hyperalgesia and chronic pain. Less well understood is the role of descending brainstem pathways in young animals when pain networks are more excitable and exposure to injury and stress can lead to permanent modulation of pain processing. Here we show that up to postnatal day 21 (P21) in the rat, the rostroventral medulla of the brainstem (RVM) exclusively facilitates spinal pain transmission but that after this age (P28 to adult), the influence of the RVM shifts to biphasic facilitation and inhibition. Graded electrical microstimulation of the RVM at different postnatal ages revealed a robust shift in the balance of descending control of both spinal nociceptive flexion reflex EMG activity and individual dorsal horn neuron firing properties, from excitation to inhibition, beginning after P21. The shift in polarity of descending control was also observed following excitotoxic lesions of the RVM in adult and P21 rats. In adults, RVM lesions decreased behavioural mechanical sensory reflex thresholds, whereas the same lesion in P21 rats increased thresholds. These data demonstrate, for the first time, the changing postnatal influence of the RVM in spinal nociception and highlight the central role of descending brainstem control in the maturation of pain processing. PMID:19403624

Blocking mammalian target of rapamycin alleviates bladder hyperactivity and pain in rats with cystitis.

PubMed

Liang, Simin; Li, Jie; Gou, Xin; Chen, Daihui

2016-01-01

Bladder disorders associated with interstitial cystitis are frequently characterized by increased contractility and pain. The purposes of this study were to examine (1) the effects of blocking mammalian target of rapamycin (mTOR) on the exaggerated bladder activity and pain evoked by cystitis and (2) the underlying mechanisms responsible for the role of mTOR in regulating cystic sensory activity. The expression of p-mTOR, mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4 E-binding protein 4 (p-4 E-BP1), as well as phosphatidylinositide 3-kinase (p-PI3K) pathway were amplified in cyclophosphamide rats as compared with control rats. Blocking mTOR by intrathecal infusion of rapamycin attenuated bladder hyperactivity and pain. In addition, blocking PI3K signal pathway attenuated activities of mTOR, which was accompanied with decreasing bladder hyperactivity and pain. Inhibition of either mTOR or PI3K blunted the enhanced spinal substance P and calcitonin gene-related peptide in cyclophosphamide rats. The data for the first time revealed specific signaling pathways leading to cyclophosphamide-induced bladder hyperactivity and pain, including the activation of mTOR and PI3K. Inhibition of these pathways alleviates cystic pain. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of overactive bladder and pain often observed in cystitis. © The Author(s) 2016.

Ablating spinal NK1-bearing neurons eliminates the development of pain & reduces spinal neuronal hyperexcitability & inflammation from mechanical joint injury in the rat

PubMed Central

Weisshaar, Christine L.; Winkelstein, Beth A.

2014-01-01

The facet joint is a common source of pain especially from mechanical injury. Although chronic pain is associated with altered spinal glial and neuronal responses, the contribution of specific spinal cells to joint pain are not understood. This study used the neurotoxin [Sar9,Met(O2)11]-substance P-saporin (SSP-SAP) to selectively eliminate spinal cells expressing neurokinin-1 receptor (NK1R) in a rat model of painful facet joint injury to determine the role of those spinal neurons in pain from facet injury. Following spinal administration of SSP-SAP or its control (blank-SAP), a cervical facet injury was imposed and behavioral sensitivity assessed. Spinal extracellular recordings were made on day 7 to classify neurons and quantify evoked firing. Spinal glial activation and IL1α expression also were evaluated. SSP-SAP prevented the development of mechanical hyperalgesia that is induced by joint injury and reduced NK1R expression and mechanically-evoked neuronal firing in the dorsal horn. SSP-SAP also prevented a shift toward wide dynamic range neurons that is seen after injury. Spinal astrocytic activation and IL1α expression were reduced to sham levels with SSP-SAP treatment. These results suggest that spinal NK1R-bearing cells are critical in initiating spinal nociception and inflammation associated with a painful mechanical joint injury. Perspective Results demonstrate that cells expressing NK1R in the spinal cord are critical for the development of joint pain and spinal neuroplasticity and inflammation after trauma to the joint. These findings have utility for understanding mechanisms of joint pain and developing potential targets to treat pain. PMID:24389017

The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat.

PubMed

McKernan, D P; Fitzgerald, P; Dinan, T G; Cryan, J F

2010-09-01

Irritable bowel syndrome (IBS) is characterized by recurrent abdominal pain and altering bowel habit with a high percentage of patients displaying comorbid anxiety. Growing clinical and preclinical evidence suggests that probiotic agents may restore the altered brain-gut communication in IBS. In this study, we evaluated the efficacy of repeated treatment with three different probiotics in reducing visceral pain in visceral normosensitive (Sprague-Dawley [SD]) and visceral hypersensitive (Wistar-Kyoto [WKY]) rat strains. Following 14 days oral gavage of Lactobacillus salivarius UCC118, Bifidobacterium infantis 35624, or Bifidobacterium breve UCC2003 both SD and WKY rats were exposed to a novel stress, the open field arena and their behavior was recorded. Subsequently, the effects of probiotics on visceral nociceptive responses were analyzed by recording pain behaviors during colorectal distension (CRD). It was found that there was a difference in the open field behavior between strains but none of the probiotic treatment altered behavior within each strain. Interestingly, the probiotic B. infantis 35624 but not others tested significantly reduced CRD-induced visceral pain behaviors in both rat strains. It significantly increased the threshold pressure of the first pain behavior and also reduced the total number pain behaviors during CRD. These data confirm that probiotics such as B. infantis 35624 are effective in reducing visceral pain and may be effective in treating certain symptoms of IBS.

Injured nerve-derived COX2/PGE2 contributes to the maintenance of neuropathic pain in aged rats.

PubMed

Ma, Weiya; Chabot, Jean-Guy; Vercauteren, Freya; Quirion, Remi

2010-07-01

Neuropathic pain (NeP) is a debilitating disease afflicting mostly the aged population. Inflammatory responses in injured nerves play a pivotal role in the pathogenesis of NeP. Injured nerve derived cyclooxygenase 2/prostaglandin E2 (COX2/PGE2) contributes to the genesis of NeP at the early stage in young rats. Here we show that COX2/PGE2 is involved in the maintenance of NeP at a chronic stage in aged rats. Eighteen months after partial sciatic nerve ligation (PSNL), NeP remained prominent in aged rats. COX2 expressing macrophages and PGE2 levels were increased in injured nerves. PGE2 receptors (EP1 and EP4) and pain-related ion channel transient receptor potential vanilloid-1 (TRPV1) were increased in the ipsilateral dorsal root ganglion (DRG) neurons of aged PSNL rats. Perineural injection of a selective COX2 inhibitor NS-398 relieved NeP, reversed PSNL increased expression of EP1, EP4 and TRPV1 and suppressed the levels of pain-related peptide substance P and calcitonin gene-related peptide in DRG neurons. These data suggest that injured nerve-derived PGE2 contributes to the maintenance of NeP at the chronic stage in aged rats. Chronically facilitating the synthesis of pain-related molecules in nociceptive DRG neurons is a novel mechanism underpinning the contribution of PGE2. Copyright 2008 Elsevier Inc. All rights reserved.

Disruption of δ-opioid receptor phosphorylation at threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity.

PubMed

Chen, Hai-Jing; Xie, Wei-Yan; Hu, Fang; Zhang, Ying; Wang, Jun; Wang, Yun

2012-04-01

Our previous study identified Threonine 161 (Thr-161), located in the second intracellular loop of the δ-opioid receptor (DOR), as the only consensus phosphorylation site for cyclin-dependent kinase 5 (Cdk5). The aim of this study was to assess the function of DOR phosphorylation by Cdk5 in complete Freund's adjuvant (CFA)-induced inflammatory pain and morphine tolerance. Dorsal root ganglion (DRG) neurons of rats with CFA-induced inflammatory pain were acutely dissociated and the biotinylation method was used to explore the membrane localization of phosphorylated DOR at Thr-161 (pThr-161-DOR), and paw withdrawal latency was measured after intrathecal delivery of drugs or Tat-peptide, using a radiant heat stimulator in rats with CFA-induced inflammatory pain. Both the total amount and the surface localization of pThr-161-DOR were significantly enhanced in the ipsilateral DRG following CFA injection. Intrathecal delivery of the engineered Tat fusion-interefering peptide corresponding to the second intracellular loop of DOR (Tat-DOR-2L) increased inflammatory hypersensitivity, and inhibited DOR- but not µ-opioid receptor-mediated spinal analgesia in CFA-treated rats. However, intrathecal delivery of Tat-DOR-2L postponed morphine antinociceptive tolerance in rats with CFA-induced inflammatory pain. Phosphorylation of DOR at Thr-161 by Cdk5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain, while disruption of the phosphorylation of DOR at Thr-161 attenuates morphine tolerance.

Orofacial neuropathic pain reduces spontaneous burrowing behavior in rats.

PubMed

Deseure, K; Hans, G

2018-07-01

It was recently reported that spontaneous burrowing behavior is decreased after tibial nerve transection, spinal nerve transection and partial sciatic nerve ligation. It was proposed that spontaneous burrowing could be used as a measure of the impact of neuropathic pain after peripheral nerve injury. It has remained unclear whether the reduction in burrowing behavior is caused directly by pain or hypersensitivity in the affected limbs, making it more difficult to perform burrowing, or by a pain induced decrease in the general wellbeing, thus reducing the motivation to burrow. We studied burrowing behavior after infraorbital nerve injury, a model of orofacial neuropathic pain that does not affect the limbs. Burrowing behavior was significantly reduced after infraorbital nerve injury. Isolated face grooming and responsiveness to mechanical von Frey stimulation of the infraorbital nerve territory were significantly increased after infraorbital nerve injury, indicative, respectively, of spontaneous pain and mechanical allodynia. It is concluded that spontaneous burrowing may provide a measure of the global impact of pain on the animal's wellbeing after peripheral nerve injury and incorporation of this behavioral assay in preclinical drug testing may improve the predictive validity of currently used pain models. Copyright © 2018 Elsevier Inc. All rights reserved.

A bacosides containing Bacopa monnieri extract alleviates allodynia and hyperalgesia in the chronic constriction injury model of neuropathic pain in rats.

PubMed

Shahid, Muhammad; Subhan, Fazal; Ahmad, Nisar; Ullah, Ihsan

2017-06-05

The current therapy of neuropathic pain is inadequate and is limited by the extent of pain relief and the occurrence of dose dependant side effects. Insufficient control of pain with conventional medications prompts the use of complementary and alternative medicine therapies by patients with neuropathic pain. This study therefore investigated a standardized methanolic extract of Bacopa monnieri, a widely reputed nootropic plant, for prospective antinociceptive effect in the chronic constriction injury (CCI) model of neuropathic pain. Placement of four loose ligatures around the sciatic nerve produced partial denervation of the hindpaw in rats. Bacopa monnieri (40 and 80 mg/kg, p.o) and the positive control, gabapentin (75 mg/kg, i.p), were administered daily after CCI or sham surgery and the behavioral paradigms of static- and dynamic-allodynia (paw withdrawal threshold to von Frey filament stimulation [PWT] and paw withdrawal latency to light-brushing [PWL]), cold-allodynia (paw withdrawal duration [PWD] to acetone), heat- (PWL to heat-stimulus) and punctate-hyperalgesia (PWD to pin-prick) were assessed on days 3, 7, 14 and 21. CCI consistently generated static- (days 3-21), dynamic- (days 14-21) and cold-allodynia (days 3-21) plus heat- and mechano-hyperalgesia (days 3-21). The tested doses of Bacopa monnieri significantly attenuated the CCI-induced allodynia and hyperalgesia, exemplified by increased PWT (days 7-21), PWL to light brushing (days 14-21) and heat (days 7-21) as well as decreased PWD to pin prick and cold stimuli (days 3-21). The extract also counterbalanced the CCI-induced aberrations in the nociceptive behaviors by increasing the pain threshold to that of pre-surgery baseline. Gabapentin also afforded analogous beneficial behavioral profile but of higher magnitude. Our findings suggest that Bacopa monnieri can be used as adjuvant therapy for neuropathic pain conditions afflicted with allodynia and hyperalgesia.

Tramadol and propentofylline coadministration exerted synergistic effects on rat spinal nerve ligation-induced neuropathic pain.

PubMed

Zhang, Jin; Wu, Dan; Xie, Cheng; Wang, Huan; Wang, Wei; Zhang, Hui; Liu, Rui; Xu, Li-Xian; Mei, Xiao-Peng

2013-01-01

Neuropathic pain is an intractable clinical problem. Drug treatments such as tramadol have been reported to effectively decrease neuropathic pain by inhibiting the activity of nociceptive neurons. It has also been reported that modulating glial activation could also prevent or reverse neuropathic pain via the administration of a glial modulator or inhibitor, such as propentofylline. Thus far, there has been no clinical strategy incorporating both neuronal and glial participation for treating neuropathic pain. Therefore, the present research study was designed to assess whether coadministration of tramadol and propentofylline, as neuronal and glial activation inhibitors, respectively, would exert a synergistic effect on the reduction of rat spinal nerve ligation (SNL)-induced neuropathic pain. Rats underwent SNL surgery to induce neuropathic pain. Pain behavioral tests were conducted to ascertain the effect of drugs on SNL-induced mechanical allodynia with von-Frey hairs. Proinflammatory factor interleukin-1β (IL-1β) expression was also detected by Real-time RT-PCR. Intrathecal tramadol and propentofylline administered alone relieved SNL-induced mechanical allodynia in a dose-dependent manner. Tramadol and propentofylline coadministration exerted a more potent effect in a synergistic and dose dependent manner than the intrathecal administration of either drug alone. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn after the lesion, which was significantly decreased by tramadol and propentofylline coadministration. Inhibiting proinflammatory factor IL-1β contributed to the synergistic effects of tramadol and propentofylline coadministration on rat peripheral nerve injury-induced neuropathic pain. Thus, our study provided a rationale for utilizing a novel strategy for treating neuropathic pain by blocking the proinflammatory factor related pathways in the central nervous system.

Tramadol and Propentofylline Coadministration Exerted Synergistic Effects on Rat Spinal Nerve Ligation-Induced Neuropathic Pain

PubMed Central

Wang, Huan; Wang, Wei; Zhang, Hui; Liu, Rui; Xu, Li-Xian; Mei, Xiao-Peng

2013-01-01

Neuropathic pain is an intractable clinical problem. Drug treatments such as tramadol have been reported to effectively decrease neuropathic pain by inhibiting the activity of nociceptive neurons. It has also been reported that modulating glial activation could also prevent or reverse neuropathic pain via the administration of a glial modulator or inhibitor, such as propentofylline. Thus far, there has been no clinical strategy incorporating both neuronal and glial participation for treating neuropathic pain. Therefore, the present research study was designed to assess whether coadministration of tramadol and propentofylline, as neuronal and glial activation inhibitors, respectively, would exert a synergistic effect on the reduction of rat spinal nerve ligation (SNL)-induced neuropathic pain. Rats underwent SNL surgery to induce neuropathic pain. Pain behavioral tests were conducted to ascertain the effect of drugs on SNL-induced mechanical allodynia with von-Frey hairs. Proinflammatory factor interleukin-1β (IL-1β) expression was also detected by Real-time RT-PCR. Intrathecal tramadol and propentofylline administered alone relieved SNL-induced mechanical allodynia in a dose-dependent manner. Tramadol and propentofylline coadministration exerted a more potent effect in a synergistic and dose dependent manner than the intrathecal administration of either drug alone. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn after the lesion, which was significantly decreased by tramadol and propentofylline coadministration. Inhibiting proinflammatory factor IL-1β contributed to the synergistic effects of tramadol and propentofylline coadministration on rat peripheral nerve injury-induced neuropathic pain. Thus, our study provided a rationale for utilizing a novel strategy for treating neuropathic pain by blocking the proinflammatory factor related pathways in the central nervous system. PMID:24009718

Evidence for spinal N-methyl-d-aspartate receptor involvement in prolonged chemical nociception in the rat.

PubMed

Haley, Jane E; Dickenson, Anthony H

2016-08-15

We used in vivo electrophysiology and a model of more persistent nociceptive inputs to monitor spinal cord neuronal activity in anaesthetised rats to reveal the pharmacology of enhanced pain signalling. The study showed that all responses were blocked by non-selective antagonism of glutamate receptors but a selective and preferential role of the N-methyl-d-aspartate (NMDA) receptor in the prolonged plastic responses was clearly seen. The work lead to many publications, initially preclinical but increasingly from patient studies, showing the importance of the NMDA receptor in central sensitisation within the spinal cord and how this could relate to persistent pain states. This article is part of a Special Issue entitled SI:50th Anniversary Issue. Copyright © 2016 Elsevier B.V. All rights reserved.

Analgesia induced by morphine microinjected into the nucleus raphe magnus: effects on tonic pain.

PubMed

Dualé, Christian; Sierralta, Fernando; Dallel, Radhouane

2007-07-01

One of the possible sites of action of the analgesic effect of morphine is the Nucleus Raphe Magnus, as morphine injected into this structure induces analgesia in transient pain models. In order to test if morphine in the Nucleus Raphe Magnus is also analgesic in a tonic pain model, 5 microg of morphine or saline (control) were microinjected into the Nucleus Raphe Magnus of the rat. Analgesic effects were assessed following nociceptive stimulation using transient heating of the tail (phasic pain) and subcutaneous orofacial injection of 1.5 % formalin (tonic pain). While morphine was strongly analgesic for the tail-flick response (p <0.0001 compared to control), analgesia on the response to formalin was also observed for both early (p = 0.007) and late responses (p = 0.02). However, the response to formalin was not completely blunted. These results suggest that the Nucleus Raphe Magnus is not the exclusive site of action of morphine-induced analgesia in clinical conditions.

Topical Combinations to Treat Microvascular Dysfunction of Chronic Postischemia Pain

PubMed Central

Laferrière, André; Abaji, Rachid; Tsai, Cheng-Yu Mark; Ragavendran, J. Vaigunda; Coderre, Terence J.

2015-01-01

Background Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. Methods Mechanical allodynia was induced in the hind paws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (post-occlusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats. Results Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared to vehicle in CPIP rats (n = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5 to 10 fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (n = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors, were not reproduced by the same treatment of the contralateral hindpaw (n = 28). Topical combinations produced antiallodynic effects lasting up to 6 h (n = 15), and were significantly enhanced by low dose systemic pregabalin in early, but not late, CPIP rats (n = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed post-occlusive reactive hyperemia in CPIP rats (n = 61), and to increase formazan production in postischemic tissues (skin and muscle) (n = 56). Conclusions The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS. PMID:24651238

Depression of home cage wheel running: a reliable and clinically relevant method to assess migraine pain in rats.

PubMed

Kandasamy, Ram; Lee, Andrea T; Morgan, Michael M

2017-12-01

The development of new anti-migraine treatments is limited by the difficulty inassessing migraine pain in laboratory animals. Depression of activity is one of the few diagnostic criteria formigraine that can be mimicked in rats. The goal of the present study was to test the hypothesis thatdepression of home cage wheel running is a reliable and clinically relevant method to assess migraine painin rats. Adult female rats were implanted with a cannula to inject allyl isothiocyanate (AITC) onto the dura to induce migraine pain, as has been shown before. Rats recovered from implantation surgery for 8 days in cages containing a running wheel. Home cage wheel running was recorded 23 h a day. AITC and the migraine medication sumatriptan were administered in the hour prior to onset of the dark phase. Administration of AITC caused a concentration-dependent decrease in wheel running that lasted 3 h. The duration and magnitude of AITC-induced depression of wheel running was consistent following three repeated injections spaced 48 h apart. Administration of sumatriptan attenuated AITC-induced depressionof wheel running when a large dose (1 mg/kg) was administered immediately following AITC administration. Wheel running patterns did not change when sumatriptan was given to naïve rats. These data indicate that home cage wheel running is a sensitive, reliable, and clinically relevant method to assess migraine pain in the rat.

Systemic ketamine inhibits hypersensitivity after surgery via descending inhibitory pathways in rats.

PubMed

Koizuka, Shiro; Obata, Hideaki; Sasaki, Masayuki; Saito, Shigeru; Goto, Fumio

2005-05-01

Systemic ketamine suppresses several types of chronic pain. Although ketamine is used as a general anesthetic agent, the analgesic effect of systemic ketamine for early-stage postoperative pain is not clear. We investigated the efficacy and mechanism of systemic ketamine in a rat model of postoperative pain. An incision was made in the plantar aspect of the left hind paw in male Wistar rats. Mechanical hypersensitivity was measured using calibrated von Frey filaments. The anti-hypersensitivity effect of systemic or intrathecal administration of ketamine was determined every hour after making the incision. We examined the effects of intrathecal pretreatment with yohimbine, an alpha2-adrenoceptor antagonist, and methysergide, a serotonergic receptor antagonist, on the anti-hypersensitivity effect of ketamine. We also examined the effect of systemic ketamine on the c-fos immunoreactivity in the spinal cord. Systemic administration of ketamine at doses from 3 to 30 mg.kg(-1) produced anti-hypersensitivity effects in a dose-dependent manner. Intrathecal administration of ketamine had no effect. There was no significant difference between effects of pre- and post-incisional administration. Intrathecal pretreatment with yohimbine (10 microg) or methysergide (15 microg) completely reversed the anti-hypersensitivity effects of systemic ketamine. Systemic ketamine reduced fos expression in laminae I-II in the dorsal horn of the lumbar spinal cord ipsilateral to the paw incision. The results suggest that systemic administration of ketamine perioperatively suppresses early-stage postoperative pain via monoaminergic descending inhibitory pathways.

The antinociceptive effect of intrathecal administration of epibatidine with clonidine or neostigmine in the formalin test in rats.

PubMed

Hama, A T; Lloyd, G K; Menzaghi, F

2001-03-01

The analgesic effect of intrathecal injection of epibatidine, clonidine and neostigmine, compounds that elevate ACh, was examined in the formalin test, a model of post-injury central sensitization in the rat. The compounds were injected alone and in combination. Intrathecal injection of epibatidine alone did not alter pain behaviors, compared to vehicle-treated rats. Intrathecal injection of clonidine dose-dependently reduced tonic pain behaviors (ED(50)+/-95% confidence limits=6.7+/-4.8 microg). The combination of clonidine and epibatidine (C:E), in the ratio of 26:1, dose-dependently reduced tonic pain behaviors; and the ED(50) of C:E was 1.1+/-0.98 microg a significant 6-fold leftward shift of the dose response curve, compared with clonidine alone. The antinociceptive effect of C:E (26:1) was attenuated by pre-treatment with the nAChR antagonist mecamylamine. Neostigmine dose-dependently reduced tonic pain behaviors (ED(50)=1.5+/-1.3 microg). The combination of neostigmine and epibatidine, in a ratio of 8:1, significantly shifted the dose response curve 4-fold to the left (ED(50)=0.4+/-0.3 microg). The effect is mediated in part by the activation of the nAChR and possibly by the enhanced release of ACh. These data demonstrate significant enhancement of the antinociceptive effects of spinally delivered analgesics by a nAChR agonist, suggesting that this class of compounds may have utility as adjuvants when combined with conventional therapeutics.

Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats

PubMed Central

Todorovic, Slobodan M; Rastogi, A J; Jevtovic-Todorovic, Vesna

2003-01-01

Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage- and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na+ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 μg per 100 μl, respectively. Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. Hill slope coefficients for the tested anticonvulsants indicate that the dose–response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. Our data strongly suggest that cellular targets like voltage-gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na+ and Ca2+ channels may be useful analgesics. PMID:12970103

The Different Dynamic Changes of Nerve Growth Factor in the Dorsal Horn and Dorsal Root Ganglion Leads to Hyperalgesia and Allodynia in Diabetic Neuropathic Pain.

PubMed

Gao, Zhifeng; Feng, Yi; Ju, Hui

2017-05-01

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes and more than half of the patients with DPN have self-reported symptoms referring to painful diabetic neuropathy (PDN). Nerve growth factor (NGF) is a key factor for the nervous system, but the role of it in the neuropathic pain of diabetic patients is unclear. This study aimed to investigate the relationship between the dynamic expression of NGF in dorsal horn and dorsal root ganglion (DRG) of diabetic rats and hyperalgesia and allodynia in diabetic neuropathic pain. It also aimed to explore the effects of exogenous mouse NGF (mNGF) on NGF expression in dorsal horn, DRG, and mechanical pain threshold. Animal research study. Experimental research laboratory. The model of diabetes was established by a single intraperitoneal injection of streptozocin (STZ 55 mg/kg). Firstly, the rats were randomly divided into 2 groups: control group (n = 10) and diabetes group (n = 40). The diabetes group contained 4 subgroups: diabetes week 1 group (DM1, n = 10), diabetes week 2 group (DM2, n = 10), diabetes week 4 group (DM4, n = 10), and diabetes week 8 group (DM8, n = 10). Then, the other rats were randomly divided into 2 groups: control group (n = 10) and treatment group (n = 30). The treatment group contained 3 subgroups: saline group (n = 10), low dose mNGF group (mNGF1, n = 10), and high dose mNGF group (mNGF2, n = 10). Mechanical pain threshold was assessed using Von Frey hairs, before the establishment of the diabetes model and 1, 2, 4, and 8 weeks after the establishment. The NGF expression in dorsal horn and DRG was measured by western blot. The mechanical pain threshold decreased one week after the establishment of the diabetes model, which continued for 8 weeks. The NGF expression in the dorsal horn was reduced 2 weeks after diabetes induction and the decreased NGF expression continued for 4 weeks. However, the NGF expression in DRG was reduced one week after diabetes induction and remained at a low level for 8 weeks. Hyperalgesia occurred when the NGF expression in the DRG decreased and further reduction in the NGF expression in the dorsal horn caused concomitant allodynia. The mechanical pain threshold was significantly elevated 2 weeks after mNGF treatment. The course of diabetes should be much longer and there is not a precise analysis of the quantitative relation between the NGF expression in the dorsal horn/DRG and hyperalgesia/allodynia. In diabetic neuropathic pain, the dynamic changes of the NGF expression in dorsal horn and DRG is involved in the development of hyperalgesia and allodynia respectively. Exogenous mNGF may relieve diabetic neuropathic pain by increasing the NGF expression in dorsal horn and DRG.

Rescue of Impaired mGluR5-Driven Endocannabinoid Signaling Restores Prefrontal Cortical Output to Inhibit Pain in Arthritic Rats.

PubMed

Kiritoshi, Takaki; Ji, Guangchen; Neugebauer, Volker

2016-01-20

The medial prefrontal cortex (mPFC) serves executive functions that are impaired in neuropsychiatric disorders and pain. Underlying mechanisms remain to be determined. Here we advance the novel concept that metabotropic glutamate receptor 5 (mGluR5) fails to engage endocannabinoid (2-AG) signaling to overcome abnormal synaptic inhibition in pain, but restoring endocannabinoid signaling allows mGluR5 to increase mPFC output hence inhibit pain behaviors and mitigate cognitive deficits. Whole-cell patch-clamp recordings were made from layer V pyramidal cells in the infralimbic mPFC in rat brain slices. Electrical and optogenetic stimulations were used to analyze amygdala-driven mPFC activity. A selective mGluR5 activator (VU0360172) increased pyramidal output through an endocannabinoid-dependent mechanism because intracellular inhibition of the major 2-AG synthesizing enzyme diacylglycerol lipase or blockade of CB1 receptors abolished the facilitatory effect of VU0360172. In an arthritis pain model mGluR5 activation failed to overcome abnormal synaptic inhibition and increase pyramidal output. mGluR5 function was rescued by restoring 2-AG-CB1 signaling with a CB1 agonist (ACEA) or inhibitors of postsynaptic 2-AG hydrolyzing enzyme ABHD6 (intracellular WWL70) and monoacylglycerol lipase MGL (JZL184) or by blocking GABAergic inhibition with intracellular picrotoxin. CB1-mediated depolarization-induced suppression of synaptic inhibition (DSI) was also impaired in the pain model but could be restored by coapplication of VU0360172 and ACEA. Stereotaxic coadministration of VU0360172 and ACEA into the infralimbic, but not anterior cingulate, cortex mitigated decision-making deficits and pain behaviors of arthritic animals. The results suggest that rescue of impaired endocannabinoid-dependent mGluR5 function in the mPFC can restore mPFC output and cognitive functions and inhibit pain. Significance statement: Dysfunctions in prefrontal cortical interactions with subcortical brain regions, such as the amygdala, are emerging as important players in neuropsychiatric disorders and pain. This study identifies a novel mechanism and rescue strategy for impaired medial prefrontal cortical function in an animal model of arthritis pain. Specifically, an integrative approach of optogenetics, pharmacology, electrophysiology, and behavior is used to advance the novel concept that a breakdown of metabotropic glutamate receptor subtype mGluR5 and endocannabinoid signaling in infralimbic pyramidal cells fails to control abnormal amygdala-driven synaptic inhibition in the arthritis pain model. Restoring endocannabinoid signaling allows mGluR5 activation to increase infralimbic output hence inhibit pain behaviors and mitigate pain-related cognitive deficits. Copyright © 2016 the authors 0270-6474/16/360837-14$15.00/0.

Psychological Stress Induces Temporary Masticatory Muscle Mechanical Sensitivity in Rats

PubMed Central

Huang, Fei; Zhang, Min; Chen, Yong-Jin; Li, Qiang; Wu, An-Zhen

2011-01-01

To explore the relationship between psychological stress and masticatory muscle pain, we created a communication stress animal model to determine whether psychological stress could induce increased mechanical sensitivity in masticatory muscles and to study the changes of mechanical nociceptive thresholds after stress removal. Forty-eight male Sprague-Dawley rats were divided into a control group (CON), a foot-shocked group (FS, including 3 subgroups recorded as FS-1, FS-2, and FS-3), a psychological stress group (PS), and a drug treatment group (DT). PS and DT rats were confined in a communication box for one hour a day to observe the psychological responses of neighboring FS rats.Measurements of the mechanical nociceptive thresholds of the bilateral temporal and masseter muscles showed a stimulus-response relationship between psychological stress and muscle mechanical sensitivity. The DT rats, who received a diazepam injection, showed almost the same mechanical sensitivity of the masticatory muscles to that of the control in response to psychological stress. Fourteen days after the psychological stressor was removed, the mechanical nociceptive thresholds returned to normal. These findings suggest that psychological stress is directly related to masticatory muscle pain. Removal of the stressor could be a useful method for relieving mechanical sensitivity increase induced by psychological stress. PMID:21331360

Injury-Dependent and Disability-Specific Lumbar Spinal Gene Regulation following Sciatic Nerve Injury in the Rat

PubMed Central

Denyer, Gareth S.; Keay, Kevin A.

2015-01-01

Allodynia, hyperalgesia and spontaneous pain are cardinal sensory signs of neuropathic pain. Clinically, many neuropathic pain patients experience affective-motivational state changes, including reduced familial and social interactions, decreased motivation, anhedonia and depression which are severely debilitating. In earlier studies we have shown that sciatic nerve chronic constriction injury (CCI) disrupts social interactions, sleep-wake-cycle and endocrine function in one third of rats, a subgroup reliably identified six days after injury. CCI consistently produces allodynia and hyperalgesia, the intensity of which was unrelated either to the altered social interactions, sleep-wake-cycle or endocrine changes. This decoupling of the sensory consequences of nerve injury from the affective-motivational changes is reported in both animal experiments and human clinical data. The sensory changes triggered by CCI are mediated primarily by functional changes in the lumbar dorsal horn, however, whether lumbar spinal changes may drive different affective-motivational states has never been considered. In these studies, we used microarrays to identify the unique transcriptomes of rats with altered social behaviours following sciatic CCI to determine whether specific patterns of lumbar spinal adaptations characterised this subgroup. Rats underwent CCI and on the basis of reductions in dominance behaviour in resident-intruder social interactions were categorised as having Pain & Disability, Pain & Transient Disability or Pain alone. We examined the lumbar spinal transcriptomes two and six days after CCI. Fifty-four ‘disability-specific’ genes were identified. Sixty-five percent were unique to Pain & Disability rats, two-thirds of which were associated with neurotransmission, inflammation and/or cellular stress. In contrast, 40% of genes differentially regulated in rats without disabilities were involved with more general homeostatic processes (cellular structure, transcription or translation). We suggest that these patterns of gene expression lead to either the expression of disability, or to resilience and recovery, by modifying local spinal circuitry at the origin of ascending supraspinal pathways. PMID:25905723

Injury-Dependent and Disability-Specific Lumbar Spinal Gene Regulation following Sciatic Nerve Injury in the Rat.

PubMed

Austin, Paul J; Bembrick, Alison L; Denyer, Gareth S; Keay, Kevin A

2015-01-01

Allodynia, hyperalgesia and spontaneous pain are cardinal sensory signs of neuropathic pain. Clinically, many neuropathic pain patients experience affective-motivational state changes, including reduced familial and social interactions, decreased motivation, anhedonia and depression which are severely debilitating. In earlier studies we have shown that sciatic nerve chronic constriction injury (CCI) disrupts social interactions, sleep-wake-cycle and endocrine function in one third of rats, a subgroup reliably identified six days after injury. CCI consistently produces allodynia and hyperalgesia, the intensity of which was unrelated either to the altered social interactions, sleep-wake-cycle or endocrine changes. This decoupling of the sensory consequences of nerve injury from the affective-motivational changes is reported in both animal experiments and human clinical data. The sensory changes triggered by CCI are mediated primarily by functional changes in the lumbar dorsal horn, however, whether lumbar spinal changes may drive different affective-motivational states has never been considered. In these studies, we used microarrays to identify the unique transcriptomes of rats with altered social behaviours following sciatic CCI to determine whether specific patterns of lumbar spinal adaptations characterised this subgroup. Rats underwent CCI and on the basis of reductions in dominance behaviour in resident-intruder social interactions were categorised as having Pain & Disability, Pain & Transient Disability or Pain alone. We examined the lumbar spinal transcriptomes two and six days after CCI. Fifty-four 'disability-specific' genes were identified. Sixty-five percent were unique to Pain & Disability rats, two-thirds of which were associated with neurotransmission, inflammation and/or cellular stress. In contrast, 40% of genes differentially regulated in rats without disabilities were involved with more general homeostatic processes (cellular structure, transcription or translation). We suggest that these patterns of gene expression lead to either the expression of disability, or to resilience and recovery, by modifying local spinal circuitry at the origin of ascending supraspinal pathways.

Afferent Drive Elicits Ongoing Pain in a Model of Advanced Osteoarthritis

PubMed Central

Okun, Alec; Liu, Ping; Davis, Peg; Ren, Jiyang; Remeniuk, Bethany; Brion, Triza; Ossipov, Michael H.; Xie, Jennifer; Dussor, Gregory O.; King, Tamara; Porreca, Frank

2012-01-01

Osteoarthritis (OA) is a chronic condition characterized by pain during joint movement. Additionally, patients with advanced disease experience pain at rest (i.e., ongoing pain)that is generally resistant to non-steroidal anti-inflammatory drugs (NSAIDs). Injection of monosodium iodoacetate (MIA) into the intra-articular space of the rodent knee is a well-established model of OA that elicits weight-bearing asymmetry and referred tactile and thermal hypersensitivity. Whether ongoing pain is present in this model is unknown. Additionally, the possible relationship of ongoing pain to MIA dose is not known. MIA produced weight asymmetry, joint osteolysis, and cartilage erosion across a range of doses (1, 3, and 4.8 mg). However, only rats treated with the highest dose of MIA showed conditioned place preference to a context paired with intra-articular lidocaine, indicating relief from ongoing pain. Diclofenac blocked the MIA-induced weight asymmetry but failed to block MIA-induced ongoing pain. Systemic AMG9810, a TRPV1 antagonist, effectively blocked thermal hypersensitivity, but failed to block high dose MIA-induced weight asymmetry or ongoing pain. Additionally, systemic or intra-articular HC030031, a TRPA1 antagonist, failed to block high dose MIA-induced weight asymmetry or ongoing pain. Our studies suggest that a high dose of intra-articular MIA induces ongoing pain originating from the site of injury that is dependent on afferent fiber activity but apparently independent of TRPV1 or TRPA1 activation. Identification of mechanisms driving ongoing pain may enable development of improved treatments for patients with severe OA pain and diminish the need for joint replacement surgery. PMID:22387095

ABT-627, an endothelin ET(A) receptor-selective antagonist, attenuates tactile allodynia in a diabetic rat model of neuropathic pain.

PubMed

Jarvis, M F; Wessale, J L; Zhu, C Z; Lynch, J J; Dayton, B D; Calzadilla, S V; Padley, R J; Opgenorth, T J; Kowaluk, E A

2000-01-24

Tactile allodynia, the enhanced perception of pain in response to normally non-painful stimulation, represents a common complication of diabetic neuropathy. The activation of endothelin ET(A) receptors has been implicated in diabetes-induced reductions in peripheral neurovascularization and concomitant endoneurial hypoxia. Endothelin receptor activation has also been shown to alter the peripheral and central processing of nociceptive information. The present study was conducted to evaluate the antinociceptive effects of the novel endothelin ET(A) receptor-selective antagonist, 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627), in the streptozotocin-induced diabetic rat model of neuropathic pain. Rats were injected with 75 mg/kg streptozotocin (i. p.), and drug effects were assessed 8-12 weeks following streptozotocin treatment to allow for stabilization of blood glucose levels (>/=240 mg/dl) and tactile allodynia thresholds (

The antidepressant effects of rosiglitazone on rats with depression induced by neuropathic pain.

PubMed

Zong, Jian; Liao, Xingzhi; Ren, Bingxu; Wang, Zhiping

2018-06-15

A growing number of studies reported that rosiglitazone (a PPARgamma agonist) could ameliorate the painful state and prevent stress-induced depression. However, whether rosiglitazone can prevent pain-induced depression is unclear. This study aimed to explore the antidepressant effects of rosiglitazone in L5 spinal nerve transection (SNT) induced neuropathic pain rats. In addition, AMPK inhibitor (Compound C) and autophagic antagonist (3-methyladenine, 3-MA) were applied to investigate the underlying therapeutic mechanisms. L5 SNT-induced neuropathic pain symptoms and depressive like-behaviors were detected by paw pressure threshold test (PPT), open-field test (OFT), forced swimming test (FST), tail suspension test (TST), sucrose preference test (SPT). Rosiglitazone could ameliorate L5 SNT-induced neuropathic pain symptoms and depressive like-behaviors and the effect could be reversed by Compound C or 3-MA. Compared with the sham group, the levels of BDNF, AMPK, Beclin-1 and LC3B in rats hippocampus significantly decreased in L5 SNT group. On the contrary, rosiglitazone administration significantly up-regulated the levels of AMPK, BDNF, Beclin-1 and LC3B in rats hippocampus. Compared with sham group, the levels of TNF-α, IL-1β, superoxide dismutase (SOD) and malondialdehyde (MDA) in rat hippocampus significantly increased in L5 SNT group. Besides, rosiglitazone administration significantly decreased the levels of TNF-α, IL-1β, SOD and MDA in hippocampus. Compared with rosiglitazone group, 3-MA administration, but not Compound C administration, significantly increased the levels of TNF-α, IL-1β, SOD and MDA in hippocampus. In conclusion, rosiglitazone can counteract down-regulation of AMPK and BDNF induced by L5 SNT rats in hippocampus, and activate autophagic pathway. These effects may contribute to the antidepressant effect of rosiglitazone on the rats with depression induced by L5 SNT. Copyright © 2018 Elsevier Inc. All rights reserved.

Injectable Nanocomposite Analgesic Delivery System for Musculoskeletal Pain Management.

PubMed

Khanal, Manakamana; Gohil, Shalini V; Kuyinu, Emmanuel; Kan, Ho-Man; Knight, Brittany E; Baumbauer, Kyle M; Lo, Kevin W-H; Walker, Joseph; Laurencin, Cato T; Nair, Lakshmi S

2018-05-24

Musculoskeletal pain is a major health issue which results from surgical procedures (i.e. total knee and/ or hip replacements and rotator cuff repairs), as well as from non-surgical conditions (i.e. sympathetically-mediated pain syndrome and occipital neuralgia). Local anesthetics, opioids or corticosteroids are currently used for the pain management of musculoskeletal conditions. Even though local anesthetics are highly preferred, the need for multiple administration presents significant disadvantages. Development of unique delivery systems that can deliver local anesthetics at the injection site for prolonged time could significantly enhance the therapeutic efficacy and patient comfort. The goal of the present study is to evaluate the efficacy of an injectable local anesthetic nanocomposite carrier to provide sustained analgesic effect. The nanocomposite carrier was developed by encapsulating ropivacaine, a local anesthetic, in lipid nanocapsules (LNC-Rop), and incorporating the nanocapsules in enzymatically crosslinked glycol chitosan (0.3GC) hydrogels. Cryo Scanning Electron Microscopic (Cryo SEM) images showed the ability to distribute the LNCs within the hydrogel without adversely affecting their morphology. The study demonstrated the feasibility to achieve sustained release of lipophilic molecules from the nanocomposite carrier in vitro and in vivo. A rat chronic constriction injury (CCI) pain model was used to evaluate the efficacy of the nanocomposite carrier using thermal paw withdrawal latency (TWL). The nanocomposite carriers loaded with ropivacaine and dexamethasone showed significant improvement in pain response compared to the control groups for at least 7 days. The study demonstrated the clinical potential of these nanocomposite carriers for post-operative and neuropathic pain. Acute or chronic pain associated with musculoskeletal conditions is considered a major health issue, with healthcare costs totaling several billion dollars. The opioid crisis presents a pressing clinical need to develop alternative and effective approaches to treat musculoskeletal pain. The goal of this study was to develop a long-acting injectable anesthetic formulation which can sustain a local anesthetic effect for a prolonged time. This in turn could increase the quality of life and rehabilitation outcome of patients, and decrease opioid consumption. The developed injectable nanocomposite demonstrated the feasibility to achieve prolonged pain relief in a rat chronic constriction injury (CCI) model. Copyright © 2018. Published by Elsevier Ltd.

Modelling affective pain in mice: Effects of inflammatory hypersensitivity on place escape/avoidance behaviour, anxiety and hedonic state.

PubMed

Refsgaard, L K; Hoffmann-Petersen, J; Sahlholt, M; Pickering, D S; Andreasen, J T

2016-03-15

The place escape/avoidance paradigm (PEAP) has been used to assess the affective component of pain in rats. Using the Complete Freund's Adjuvant (CFA) model of inflammatory pain, the current study aimed at developing a mouse version of PEAP and investigating the relation between PEAP and other behavioural responses, namely anxiety-like behaviour, locomotor activity, and hedonic state. A novel paradigm assessing the affective component of pain in mice was developed by modifying the setup known from rat studies: Animals were forced to stay 2 × 5 min in the light and the dark area of a box while being stimulated with a suprathreshold filament on the untreated or treated paw, respectively. This was followed by a 30-min test with unrestricted movement. Anxiety-like behaviour, locomotor activity, and hedonic state were assessed with the elevated zero maze (EZM), an open field setup, and a saccharin preference test, respectively, and correlated with the PEAP behaviour to examine potentially confounding parameters of the novel paradigm. In the PEAP, CFA-treated animals spent more time in the light area. CFA also increased anxiety-like behaviour significantly, whereas locomotor activity was unaffected. A significant, albeit modest, reduction in saccharin preference was observed. PEAP responses showed no significant correlations with any other behavioural measure. The PEAP results suggest that this paradigm might be successfully applied in mice to study affective pain. CFA treatment was associated with increased anxiety-like behaviour and anhedonia; however, this appeared unrelated to the PEAP responses. Copyright © 2016 Elsevier B.V. All rights reserved.

Sexually dimorphic effects of unpredictable early life adversity on visceral pain behavior in a rodent model.

PubMed

Chaloner, Aaron; Greenwood-Van Meerveld, Beverley

2013-03-01

Visceral pain is the hallmark feature of irritable bowel syndrome (IBS), a gastrointestinal disorder, which is more commonly diagnosed in women. Female IBS patients frequently report a history of early life adversity (ELA); however, sex differences in ELA-induced visceral pain and the role of ovarian hormones have yet to be investigated. Therefore, we tested the hypothesis that ELA induces visceral hypersensitivity through a sexually dimorphic mechanism mediated via estradiol. As a model of ELA, neonatal rats were exposed to different pairings of an odor and shock to control for trauma predictability. In adulthood, visceral sensitivity was assessed via a visceromotor response to colorectal distension. Following ovariectomy and estradiol replacement in a separate group of rats, the visceral sensitivity was quantified. We found that females that received unpredictable odor-shock developed visceral hypersensitivity in adulthood. In contrast, visceral sensitivity was not significantly different following ELA in adult males. Ovariectomy reversed visceral hypersensitivity following unpredictable ELA, whereas estradiol replacement reestablished visceral hypersensitivity in the unpredictable group. This study is the first to show sex-related differences in visceral sensitivity following unpredictable ELA. Our data highlight the activational effect of estradiol as a pivotal mechanism in maintaining visceral hypersensitivity. This article directly implicates a critical role for ovarian hormones in maintaining visceral hypersensitivity following ELA, specifically identifying the activational effect of estradiol as a key modulator of visceral sensitivity. These data suggest that ELA induces persistent functional abdominal pain in female IBS patients through an estrogen-dependent mechanism. Copyright © 2013 American Pain Society. All rights reserved.

Motor Cortex Stimulation Reverses Maladaptive Plasticity Following Spinal Cord Injury

DTIC Science & Technology

2012-09-01

pp 74–85. Austin: Landes Biosciences. 3. Abstracts o Mechanisms of Pain Relief Following Motor Cortex Stimulation: An fMRI Study. Society for...Neuroscience Meeting. Washington, DC. 2012. o Resting State fMRI in a Rat Model of Spinal Cord Injury Neuropathic Pain: A Longitudinal Study. Society...2601–2610. 16. Stefanacci L, Reber P, Costanza J, Wong E, Buxton R, Zola S, Squire L, Albright T. fMRI of monkey visual cortex. Neuron 1998;20:1051

Use of Polypentapeptides of Elastin to Prevent Postoperative Adhesions: Efficacy in a Contaminated Peritoneal Model

DTIC Science & Technology

1994-02-01

short-gut syndrome, rotomy was conducted to reveal the cranial portion of chronic pain , and female infertility [3, 4]. Many sub- the ileum. The abdominal ...hold the sheets in the proper position. The presence of nal adhesions, chronic abdominal pain , and infertility. Gynecol. suture material acting as a...intra- abdominal landmarks. Opera- of 88 rats were studied with random assignment of ani- tions in this situation are often associated with mals to three

Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons

PubMed Central

Duggett, Natalie A.; Griffiths, Lisa A.; Flatters, Sarah J.L.

2017-01-01

Abstract Painful neuropathy is the major dose-limiting side effect of paclitaxel chemotherapy. Mitochondrial dysfunction and adenosine triphosphate (ATP) deficit have previously been shown in peripheral nerves of paclitaxel-treated rats, but the effects of paclitaxel in the dorsal root ganglia (DRGs) have not been explored. The aim of this study was to determine the bioenergetic status of DRG neurons following paclitaxel exposure in vitro and in vivo. Utilising isolated DRG neurons, we measured respiratory function under basal conditions and at maximal capacity, glycolytic function, and Adenosine diphosphate (ADP)/ATP levels at 3 key behavioural timepoints; prior to pain onset (day 7), peak pain severity and pain resolution. At day 7, maximal respiration and spare reserve capacity were significantly decreased in DRG neurons from paclitaxel-treated rats. This was accompanied by decreased basal ATP levels and unaltered ADP levels. At peak pain severity, respiratory function was unaltered, yet glycolytic function was significantly increased. Reduced ATP and unaltered ADP levels were also observed at the peak pain timepoint. All these effects in DRG neurons had dissipated by the pain resolution timepoint. None of these paclitaxel-evoked changes could be replicated from in vitro paclitaxel exposure to naive DRG neurons, demonstrating the impact of in vivo exposure and the importance of in vivo models. These data demonstrate the nature of mitochondrial dysfunction evoked by in vivo paclitaxel in the DRG for the first time. Furthermore, we have identified paclitaxel-evoked changes in the bioenergetics of DRG neurons, which result in a persistent energy deficit that is causal to the development and maintenance of paclitaxel-induced pain. PMID:28541258

Electrophysiological evidence for voltage-gated calcium channel 2 (Cav2) modulation of mechano- and thermosensitive spinal neuronal responses in a rat model of osteoarthritis.

PubMed

Rahman, W; Patel, R; Dickenson, A H

2015-10-01

Osteoarthritis (OA) remains one of the greatest healthcare burdens in western society, with chronic debilitating pain-dominating clinical presentation yet therapeutic strategies are inadequate in many patients. Development of better analgesics is contingent on improved understanding of the molecular mechanisms mediating OA pain. Voltage-gated calcium channels 2.2 (Cav2.2) play a critical role in spinal nociceptive transmission, therefore blocking Cav2.2 activity represents an attractive opportunity for OA pain treatment, but the only available licensed Cav2.2 antagonist ziconitide (PrilatTM) is of limited use. TROX-1 is an orally available, use dependent and state-selective Cav2 antagonist, exerting its analgesic effect primarily via Cav2.2 blockade, with an improved therapeutic window compared with ziconitide. Using a rat model of monosodium iodoacetate (MIA), 2 mg, induced OA we used in vivo electrophysiology to assess the effects of spinal or systemic administration of TROX-1 on the evoked activity of wide dynamic range spinal dorsal horn neurons in response to electrical, natural mechanical (dynamic brush and von Frey 2, 8, 26 and 6 g) and thermal (40, 45 and 45 °C) stimuli applied to the peripheral receptive field. MIA injection into the knee joint resulted in mechanical hypersensitivity of the ipsilateral hind paw and weight-bearing asymmetry. Spinal administration of TROX-1 (0.1 and 1 μg/50 μl) produced a significant dose-related inhibition of dynamic brush, mechanical (von Frey filament (vF) 8, 26 and 60 g) and noxious thermal-(45 and 48 °C) evoked neuronal responses in MIA rats only. Systemic administration of TROX-1 produced a significant inhibition of the mechanical-(vF 8, 26 and 60 g) evoked neuronal responses in MIA rats. TROX-1 did not produce any significant effect on any neuronal measure in Sham controls. Our in vivo electrophysiological results demonstrate a pathological state-dependent effect of TROX-1, which suggests an increased functional role of Cav2, likely Cav2.2, channels in mediating OA pain. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Electrophysiological evidence for voltage-gated calcium channel 2 (Cav2) modulation of mechano- and thermosensitive spinal neuronal responses in a rat model of osteoarthritis

PubMed Central

Rahman, W.; Patel, R.; Dickenson, A.H.

2015-01-01

Osteoarthritis (OA) remains one of the greatest healthcare burdens in western society, with chronic debilitating pain-dominating clinical presentation yet therapeutic strategies are inadequate in many patients. Development of better analgesics is contingent on improved understanding of the molecular mechanisms mediating OA pain. Voltage-gated calcium channels 2.2 (Cav2.2) play a critical role in spinal nociceptive transmission, therefore blocking Cav2.2 activity represents an attractive opportunity for OA pain treatment, but the only available licensed Cav2.2 antagonist ziconitide (PrilatTM) is of limited use. TROX-1 is an orally available, use dependent and state-selective Cav2 antagonist, exerting its analgesic effect primarily via Cav2.2 blockade, with an improved therapeutic window compared with ziconitide. Using a rat model of monosodium iodoacetate (MIA), 2 mg, induced OA we used in vivo electrophysiology to assess the effects of spinal or systemic administration of TROX-1 on the evoked activity of wide dynamic range spinal dorsal horn neurons in response to electrical, natural mechanical (dynamic brush and von Frey 2, 8, 26 and 6 g) and thermal (40, 45 and 45 °C) stimuli applied to the peripheral receptive field. MIA injection into the knee joint resulted in mechanical hypersensitivity of the ipsilateral hind paw and weight-bearing asymmetry. Spinal administration of TROX-1 (0.1 and 1 μg/50 μl) produced a significant dose-related inhibition of dynamic brush, mechanical (von Frey filament (vF) 8, 26 and 60 g) and noxious thermal-(45 and 48 °C) evoked neuronal responses in MIA rats only. Systemic administration of TROX-1 produced a significant inhibition of the mechanical-(vF 8, 26 and 60 g) evoked neuronal responses in MIA rats. TROX-1 did not produce any significant effect on any neuronal measure in Sham controls. Our in vivo electrophysiological results demonstrate a pathological state-dependent effect of TROX-1, which suggests an increased functional role of Cav2, likely Cav2.2, channels in mediating OA pain. PMID:26247695

Mechanical hypersensitivity, sympathetic sprouting, and glial activation are attenuated by local injection of corticosteroid near the lumbar ganglion in a rat model of neuropathic pain.

PubMed

Li, Jing-Yi; Xie, Wenrui; Strong, Judith A; Guo, Qu-Lian; Zhang, Jun-Ming

2011-01-01

Inflammatory responses in the lumbar dorsal root ganglion (DRG) play a key role in pathologic pain states. Systemic administration of a common anti-inflammatory corticosteroid, triamcinolone acetonide (TA), reduces sympathetic sprouting, mechanical pain behavior, spontaneous bursting activity, and cytokine and nerve growth factor production in the DRG. We hypothesized that systemic TA effects are primarily due to local effects on the DRG. Male Sprague-Dawley rats were divided into 4 groups: SNL (tight ligation and transection of spinal nerves) and normal with and without a single dose of TA injectable suspension slowly injected onto the surface of DRG and surrounding region at the time of SNL or sham surgery. Mechanical threshold was tested on postoperative days 1, 3, 5, and 7. Immunohistochemical staining examined tyrosine hydroxylase and glial fibrillary acidic protein in DRG and CD11B antibody (OX-42) in spinal cord. Local TA treatment attenuated mechanical sensitivity, reduced sympathetic sprouting in the DRG, and decreased satellite glia activation in the DRG and microglia activation in the spinal cord after SNL. A single injection of corticosteroid in the vicinity of the axotomized DRG can mimic many effects of systemic TA, mitigating behavioral and cellular abnormalities induced by spinal nerve ligation. This provides a further rationale for the use of localized steroid injections clinically and provides further support for the idea that localized inflammation at the level of the DRG is an important component of the spinal nerve ligation model, commonly classified as neuropathic pain model.

Antihyperalgesic Activity of Rhodiola rosea in a Diabetic Rat Model.

PubMed

Déciga-Campos, Myrna; González-Trujano, Maria Eva; Ventura-Martínez, Rosa; Montiel-Ruiz, Rosa Mariana; Ángeles-López, Guadalupe Esther; Brindis, Fernando

2016-02-01

Preclinical Research Rhodiola rosea L. (Crassulaceae) is used for enhancing physical and mental performance. Recent studies demonstrated that R. rosea had anti-inflammatory activity in animal models, for example, carrageenan- and nystatin-induced edema in rats, possibly by inhibiting phospholipase A2 and cyclooxygenases-1 and -2. In addition, R. rosea had antinociceptive activity in thermal and chemical pain tests as well as mechanical hyperalgesia. The purpose of the present study was to assess the antihyperalgesic effect of an ethanol extract of Rhodiola rosea (R. rosea) in a diabetic rat model. Rats were administered a single dose of streptozotocin (STZ; 50 mg/kg, i.p.) and hyperalgesia was evaluated four weeks later. Formalin-evoked (0.5%) flinching was increased in diabetic rats compared with nondiabetic controls Systemic (1-100 mg/kg, i.p.) and local (0.1-10 mg/paw into the dorsal surface of the right hind paw) administration of R. rosea ethanol extract dose-dependently reduced formalin-induced hyperalgesia in diabetic rats. The antihyperalgesic effect of R. rosea was compared with gabapentin. These results suggest that R. rosea ethanol extract may have potential as a treatment for diabetic hyperalgesia. © 2016 Wiley Periodicals, Inc.

Cytotoxic, analgesic and anti-inflammatory properties of Syzygium calophyllifolium bark.

PubMed

Chandran, Rahul; Abrahamse, Heidi; Parimelazhagan, Thangaraj

2018-04-25

The present study explores the effect of Syzygium calophyllifolium bark methanol (SCBM) extract on pain and inflammation as cancer associated symptoms. The anti-proliferative and cell death-inducing ability of the extract was analysed using MCF-7 breast cancer cells. ATP and LDH levels, along with the cell morphology were noted. The anti-proliferative ability of the extract was examined in relation to pain and inflammation. Analgesic activity was determined using a hot plate, acetic acid and formalin-induced pain models in mice. Acute anti-inflammatory activity was observed in carrageenan and egg albumin induced paw oedema in Wistar rats. Chronic inflammation was induced by placing a cotton pellet under the skin at the axial region of rats. Reduced ATP and increased LDH content indicated the cytotoxic effect of the extract. SCBM at 200 mg/kg dose depicted good activity in acetic acid (77.69%) and formalin (80.81%) induced pain models compared to the standard drug indomethacin. However, only a moderate activity was observed in the hot plate method (53.85%). The higher dose of SCBM was equally effective in anti-inflammatory models. The dose (200 mg/kg) significantly reduced the paw oedema in carrageenan (96.71%) and egg albumin models (54.24%) compared to the control. The chronic inflammation was also inhibited upto 70.46% by SCBM. These activities can be attributed to the phenolic compounds detected in HPLC. The outcome of the study states that the extract can reduce both acute and chronic inflammatory conditions and kill the cancer cells, proposing the dual role of SCBM in treating inflammatory pains in cancer. The result of these studies indicated that wild plants like Syzygium calophyllifolium could be taken forward for a detailed study to accomplish the demand for a better treatment against diseases. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

INTRA-ARTICULAR NERVE GROWTH FACTOR REGULATES DEVELOPMENT, BUT NOT MAINTENANCE, OF INJURY-INDUCED FACET JOINT PAIN & SPINAL NEURONAL HYPERSENSITIVITY

PubMed Central

Kras, Jeffrey V.; Kartha, Sonia; Winkelstein, Beth A.

2015-01-01

Objective The objective of the current study is to define whether intra-articular nerve growth factor (NGF), an inflammatory mediator that contributes to osteoarthritic pain, is necessary and sufficient for the development or maintenance of injury-induced facet joint pain and its concomitant spinal neuronal hyperexcitability. Method Male Holtzman rats underwent painful cervical facet joint distraction or sham procedures. Mechanical hyperalgesia was assessed in the forepaws, and NGF expression was quantified in the C6/C7 facet joint. An anti-NGF antibody was administered intra-articularly in additional rats immediately or 1 day following facet distraction or sham procedures to block intra-articular NGF and test its contribution to initiation and/or maintenance of facet joint pain and spinal neuronal hyperexcitability. NGF was injected into the bilateral C6/C7 facet joints in separate rats to determine if NGF alone is sufficient to induce these behavioral and neuronal responses. Results NGF expression increases in the cervical facet joint in association with behavioral sensitivity after that joint’s mechanical injury. Intra-articular application of anti-NGF immediately after a joint distraction prevents the development of both injury-induced pain and hyperexcitability of spinal neurons. Yet, intra-articular anti-NGF applied after pain has developed does not attenuate either behavioral or neuronal hyperexcitability. Intra-articular NGF administered to the facet in naïve rats also induces behavioral hypersensitivity and spinal neuronal hyperexcitability. Conclusion Findings demonstrate that NGF in the facet joint contributes to the development of injury-induced joint pain. Localized blocking of NGF signaling in the joint may provide potential treatment for joint pain. PMID:26521746

Intra-articular nerve growth factor regulates development, but not maintenance, of injury-induced facet joint pain & spinal neuronal hypersensitivity.

PubMed

Kras, J V; Kartha, S; Winkelstein, B A

2015-11-01

The objective of the current study is to define whether intra-articular nerve growth factor (NGF), an inflammatory mediator that contributes to osteoarthritic pain, is necessary and sufficient for the development or maintenance of injury-induced facet joint pain and its concomitant spinal neuronal hyperexcitability. Male Holtzman rats underwent painful cervical facet joint distraction (FJD) or sham procedures. Mechanical hyperalgesia was assessed in the forepaws, and NGF expression was quantified in the C6/C7 facet joint. An anti-NGF antibody was administered intra-articularly in additional rats immediately or 1 day following facet distraction or sham procedures to block intra-articular NGF and test its contribution to initiation and/or maintenance of facet joint pain and spinal neuronal hyperexcitability. NGF was injected into the bilateral C6/C7 facet joints in separate rats to determine if NGF alone is sufficient to induce these behavioral and neuronal responses. NGF expression increases in the cervical facet joint in association with behavioral sensitivity after that joint's mechanical injury. Intra-articular application of anti-NGF immediately after a joint distraction prevents the development of both injury-induced pain and hyperexcitability of spinal neurons. Yet, intra-articular anti-NGF applied after pain has developed does not attenuate either behavioral or neuronal hyperexcitability. Intra-articular NGF administered to the facet in naïve rats also induces behavioral hypersensitivity and spinal neuronal hyperexcitability. Findings demonstrate that NGF in the facet joint contributes to the development of injury-induced joint pain. Localized blocking of NGF signaling in the joint may provide potential treatment for joint pain. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats.

PubMed

Choi, Sheu-Ran; Roh, Dae-Hyun; Yoon, Seo-Yeon; Kang, Suk-Yun; Moon, Ji-Young; Kwon, Soon-Gu; Choi, Hoon-Seong; Han, Ho-Jae; Beitz, Alvin J; Oh, Seog-Bae; Lee, Jang-Hern

2013-08-01

We have recently demonstrated that spinal sigma-1 receptors (Sig-1Rs) mediate pain hypersensitivity in mice and neuropathic pain in rats. In this study, we examine the role of NADPH oxidase 2 (Nox2)-induced reactive oxygen species (ROS) on Sig-1R-induced pain hypersensitivity and the induction of chronic neuropathic pain. Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. Mechanical allodynia and thermal hyperalgesia were evaluated in mice and CCI-rats. Western blotting and dihydroethidium (DHE) staining were performed to assess the changes in Nox2 activation and ROS production in spinal cord, respectively. Direct activation of spinal Sig-1Rs with the Sig-1R agonist, PRE084 induced mechanical allodynia and thermal hyperalgesia, which were dose-dependently attenuated by pretreatment with the ROS scavenger, NAC or the Nox inhibitor, apocynin. PRE084 also induced an increase in Nox2 activation and ROS production, which were attenuated by pretreatment with the Sig-1R antagonist, BD1047 or apocynin. CCI-induced nerve injury produced an increase in Nox2 activation and ROS production in the spinal cord, all of which were attenuated by intrathecal administration with BD1047 during the induction phase of neuropathic pain. Furthermore, administration with BD1047 or apocynin reversed CCI-induced mechanical allodynia during the induction phase, but not the maintenance phase. These findings demonstrate that spinal Sig-1Rs modulate Nox2 activation and ROS production in the spinal cord, and ultimately contribute to the Sig-1R-induced pain hypersensitivity and the peripheral nerve injury-induced induction of chronic neuropathic pain. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of Pulsed Radiofrequency on Rat Sciatic Nerve Chronic Constriction Injury: A Preliminary Study

PubMed Central

Li, Duo-Yi; Meng, Lan; Ji, Nan; Luo, Fang

2015-01-01

Background: Pulsed radiofrequency (PRF) application to the dorsal root ganglia can reduce neuropathic pain (NP) in animal models, but the effect of PRF on damaged peripheral nerves has not been examined. We investigated the effect of PRF to the rat sciatic nerve (SN) on pain-related behavior and SN ultrastructure following chronic constriction injury (CCI). Methods: The analgesic effect was measured by hindpaw mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL). Twenty rats with NP induced by ligating the common SN were then randomly divided into a PRF treatment group and a sham group. The contralateral SN served as a control. The MWT and TWL were determined again 2, 4, 6, 8, 10, 12, and 14 days after the PRF or sham treatment. On day 14, ipsilateral and contralateral common SNs were excised and examined by electron microscopy. Results: Ipsilateral MWT was significantly reduced and TWL significantly shorter compared to the contralateral side 14 days after CCI (both P = 0.000). In the PRF group, MWT was significantly higher and TWL significantly longer 14 days after the PRF treatment compared to before PRF treatment (both P = 0.000), while no such difference was observed in the sham group (P > 0.05). Electron microscopy revealed extensive demyelination and collagen fiber formation in the ipsilateral SN of sham-treated rats but sparse demyelination and some nerve fiber regrowth in the PRF treatment group. Conclusions: Hyperalgesia is relieved, and ultrastructural damage ameliorated after direct PRF treatment to the SN in the CCI rat model of NP. PMID:25673460

Blockade of NMDA receptors decreased spinal microglia activation in bee venom induced acute inflammatory pain in rats.

PubMed

Li, Li; Wu, Yongfang; Bai, Zhifeng; Hu, Yuyan; Li, Wenbin

2017-03-01

Microglial cells in spinal dorsal horn can be activated by nociceptive stimuli and the activated microglial cells release various cytokines enhancing the nociceptive transmission. However, the mechanisms underlying the activation of spinal microglia during nociceptive stimuli have not been well understood. In order to define the role of NMDA receptors in the activation of spinal microglia during nociceptive stimuli, the present study was undertaken to investigate the effect of blockade of NMDA receptors on the spinal microglial activation induced by acute peripheral inflammatory pain in rats. The acute inflammatory pain was induced by subcutaneous bee venom injection to the plantar surface of hind paw of rats. Spontaneous pain behavior, thermal withdrawal latency and mechanical withdrawal threshold were rated. The expression of specific microglia marker CD11b/c was assayed by immunohistochemistry and western blot. After bee venom treatment, it was found that rats produced a monophasic nociception characterized by constantly lifting and licking the injected hind paws, decreased thermal withdrawal latency and mechanical withdrawal threshold; immunohistochemistry displayed microglia with enlarged cell bodies, thickened, extended cellular processes with few ramifications, small spines, and intensive immunostaining; western blot showed upregulated expression level of CD11b/c within the period of hyperalgesia. Prior intrathecal injection of MK-801, a selective antagonist of NMDA receptors, attenuated the pain behaviors and suppressed up-regulation of CD11b/c induced by bee venom. It can be concluded that NMDA receptors take part in the mediation of spinal microglia activation in bee venom induced peripheral inflammatory pain and hyperalgesia in rats.

Harnessing pain heterogeneity and RNA transcriptome to identify blood–based pain biomarkers: a novel correlational study design and bioinformatics approach in a graded chronic constriction injury model

PubMed Central

Grace, Peter M.; Hurley, Daniel; Barratt, Daniel T.; Tsykin, Anna; Watkins, Linda R.; Rolan, Paul E.; Hutchinson, Mark R.

2017-01-01

A quantitative, peripherally accessible biomarker for neuropathic pain has great potential to improve clinical outcomes. Based on the premise that peripheral and central immunity contribute to neuropathic pain mechanisms, we hypothesized that biomarkers could be identified from the whole blood of adult male rats, by integrating graded chronic constriction injury (CCI), ipsilateral lumbar dorsal quadrant (iLDQ) and whole blood transcriptomes, and pathway analysis with pain behavior. Correlational bioinformatics identified a range of putative biomarker genes for allodynia intensity, many encoding for proteins with a recognized role in immune/nociceptive mechanisms. A selection of these genes was validated in a separate replication study. Pathway analysis of the iLDQ transcriptome identified Fcγ and Fcε signaling pathways, among others. This study is the first to employ the whole blood transcriptome to identify pain biomarker panels. The novel correlational bioinformatics, developed here, selected such putative biomarkers based on a correlation with pain behavior and formation of signaling pathways with iLDQ genes. Future studies may demonstrate the predictive ability of these biomarker genes across other models and additional variables. PMID:22697386

Mechanism of Chronic Pain in Rodent Brain Imaging

NASA Astrophysics Data System (ADS)

Chang, Pei-Ching

Chronic pain is a significant health problem that greatly impacts the quality of life of individuals and imparts high costs to society. Despite intense research effort in understanding of the mechanism of pain, chronic pain remains a clinical problem that has few effective therapies. The advent of human brain imaging research in recent years has changed the way that chronic pain is viewed. To further extend the use of human brain imaging techniques for better therapies, the adoption of imaging technique onto the animal pain models is essential, in which underlying brain mechanisms can be systematically studied using various combination of imaging and invasive techniques. The general goal of this thesis is to addresses how brain develops and maintains chronic pain in an animal model using fMRI. We demonstrate that nucleus accumbens, the central component of mesolimbic circuitry, is essential in development of chronic pain. To advance our imaging technique, we develop an innovative methodology to carry out fMRI in awake, conscious rat. Using this cutting-edge technique, we show that allodynia is assoicated with shift brain response toward neural circuits associated nucleus accumbens and prefrontal cortex that regulate affective and cognitive component of pain. Taken together, this thesis provides a deeper understanding of how brain mediates pain. It builds on the existing body of knowledge through maximizing the depth of insight into brain imaging of chronic pain.