Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia.

PubMed

Matsuura, Wataru; Harada, Shinichi; Tokuyama, Shogo

2016-01-01

Central post-stroke pain (CPSP), a potential sequela of stroke, is classified as neuropathic pain. Although we recently established a CPSP-like model in mice, the effects of adjuvant analgesics as therapeutic drugs for neuropathic pain in this model are unknown. Hence, the aim of the present study was to assess the usefulness of our model by evaluating the effects of adjuvant analgesics used for treating neuropathic pain in this mouse model of CPSP. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical allodynia was measured after BCAO using the von Frey test. The mechanical allodynia was significantly increased on day 3 after BCAO compared with that during the pre-BCAO assessment. BCAO-induced mechanical allodynia was significantly decreased by intraperitoneal injections of imipramine (a tricyclic antidepressant), mexiletine (an antiarrhythmic), gabapentin (an antiepileptic), or a subcutaneous injection of morphine (an opioid receptor agonist) compared with that following vehicle treatment in BCAO-mice. By contrast, milnacipran (a serotonin and norepinephrine reuptake inhibitor), paroxetine (selective serotonin reuptake inhibitor), carbamazepine (antiepileptic), and indomethacin (nonsteroidal anti-inflammatory drug) did not affect the BCAO-induced mechanical allodynia. Our results show that BCAO in mice may be useful as an animal model of CPSP. In addition, BCAO-induced mechanical allodynia may be suppressed by some adjuvant analgesics used to treat neuropathic pain.

Gastrodin Inhibits Allodynia and Hyperalgesia in Painful Diabetic Neuropathy Rats by Decreasing Excitability of Nociceptive Primary Sensory Neurons

PubMed Central

Ye, Xin; Han, Wen-Juan; Wang, Wen-Ting; Luo, Ceng; Hu, San-Jue

2012-01-01

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus and adversely affects the patients’ quality of life. Evidence has accumulated that PDN is associated with hyperexcitability of peripheral nociceptive primary sensory neurons. However, the precise cellular mechanism underlying PDN remains elusive. This may result in the lacking of effective therapies for the treatment of PDN. The phenolic glucoside, gastrodin, which is a main constituent of the Chinese herbal medicine Gastrodia elata Blume, has been widely used as an anticonvulsant, sedative, and analgesic since ancient times. However, the cellular mechanisms underlying its analgesic actions are not well understood. By utilizing a combination of behavioral surveys and electrophysiological recordings, the present study investigated the role of gastrodin in an experimental rat model of STZ-induced PDN and to further explore the underlying cellular mechanisms. Intraperitoneal administration of gastrodin effectively attenuated both the mechanical allodynia and thermal hyperalgesia induced by STZ injection. Whole-cell patch clamp recordings were obtained from nociceptive, capsaicin-sensitive small diameter neurons of the intact dorsal root ganglion (DRG). Recordings from diabetic rats revealed that the abnormal hyperexcitability of neurons was greatly abolished by application of GAS. To determine which currents were involved in the antinociceptive action of gastrodin, we examined the effects of gastrodin on transient sodium currents (I NaT) and potassium currents in diabetic small DRG neurons. Diabetes caused a prominent enhancement of I NaT and a decrease of potassium currents, especially slowly inactivating potassium currents (I AS); these effects were completely reversed by GAS in a dose-dependent manner. Furthermore, changes in activation and inactivation kinetics of I NaT and total potassium current as well as I AS currents induced by STZ were normalized by GAS. This study provides a

Crosstalk between Activated Microglia and Neurons in the Spinal Dorsal Horn Contributes to Stress-induced Hyperalgesia

PubMed Central

Qi, Jian; Chen, Chen; Meng, Qing-Xi; Wu, Yan; Wu, Haitao; Zhao, Ting-Bao

2016-01-01

Stress has been shown to enhance pain sensitivity resulting in stress-induced hyperalgesia. However, the underlying mechanisms have yet to be elucidated. Using single-prolonged stress combined with Complete Freund’s Adjuvant injection model, we explored the reciprocal regulatory relationship between neurons and microglia, which is critical for the maintenance of posttraumatic stress disorder (PTSD)-induced hyperalgesia. In our assay, significant mechanical allodynia was observed. Additionally, activated neurons in spinal dorsal horn were observed by analysis of Fos expression. And, microglia were also significantly activated with the presence of increased Iba-1 expression. Intrathecal administration of c-fos antisense oligodeoxynucleotides (ASO) or minocycline (a specific microglia inhibitor) attenuated mechanical allodynia. Moreover, intrathecal administration of c-fos ASO significantly suppressed the activation of neurons and microglia. Interestingly, inhibition of microglia activation by minocycline significantly suppressed the activation of both neurons and microglia in spinal dorsal horn. P38 inhibitor SB203580 suppressed IL-6 production, and inhibition of IL-6 receptor (IL-6R) activation by tocilizumab suppressed Fos expression. Together, our data suggest that the presence of a “crosstalk” between activated microglia and neurons in the spinal dorsal horn, which might contribute to the stress-induced hyperactivated state, leading to an increased pain sensitivity. PMID:27995982

A role for Piezo2 in EPAC1-dependent mechanical allodynia

PubMed Central

Eijkelkamp, N; Linley, J.E.; Torres, J.M.; Bee, L.; Dickenson, A.H.; Gringhuis, M.; Minett, M.S.; Hong, G.S.; Lee, E.; Oh, U.; Ishikawa, Y.; Zwartkuis, F.J.; Cox, J.J.; Wood, J.N.

2013-01-01

Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia. Dorsal root ganglia Epac1 mRNA levels increase during neuropathic pain, and nerve damage-induced allodynia is reduced in Epac1−/− mice. The Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents in sensory neurons. Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton. In vivo, 8-pCPT induces long-lasting allodynia that is prevented by the knockdown of Epac1 and attenuated by mouse Piezo2 knockdown. Piezo2 knockdown also enhanced thresholds for light touch. Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres. These data indicate that the Epac1–Piezo2 axis has a role in the development of mechanical allodynia during neuropathic pain. PMID:23575686

Sulfasalazine Blocks the Development of Tactile Allodynia in Diabetic Rats

PubMed Central

Berti-Mattera, Liliana N.; Kern, Timothy S.; Siegel, Ruth E.; Nemet, Ina; Mitchell, Rochanda

2008-01-01

OBJECTIVE—Diabetic neuropathy is manifested either by loss of nociception (painless syndrome) or by mechanical hyperalgesia and tactile allodynia (pain in response to nonpainful stimuli). While therapies with vasodilators or neurotrophins reverse some functional and metabolic abnormalities in diabetic nerves, they only partially ameliorate neuropathic pain. The reported link between nociception and targets of the anti-inflammatory drug sulfasalazine prompted us to investigate its effect on neuropathic pain in diabetes. RESEARCH DESIGN AND METHODS—We examined the effects of sulfasalazine, salicylates, and the poly(ADP-ribose) polymerase-1 inhibitor PJ34 on altered nociception in streptozotocin-induced diabetic rats. We also evaluated the levels of sulfasalazine targets in sciatic nerves and dorsal root ganglia (DRG) of treated animals. Finally, we analyzed the development of tactile allodynia in diabetic mice lacking expression of the sulfasalazine target nuclear factor-κB (NF-κB) p50. RESULTS—Sulfasalazine completely blocked the development of tactile allodynia in diabetic rats, whereas relatively minor effects were observed with other salicylates and PJ34. Along with the behavioral findings, sciatic nerves and DRG from sulfasalazine-treated diabetic rats displayed a decrease in NF-κB p50 expression compared with untreated diabetic animals. Importantly, the absence of tactile allodynia in diabetic NF-κB p50−/− mice supported a role for NF-κB in diabetic neuropathy. Sulfasalazine treatment also increased inosine levels in sciatic nerves of diabetic rats. CONCLUSIONS—The complete inhibition of tactile allodynia in experimental diabetes by sulfasalazine may stem from its ability to regulate both NF-κB and inosine. Sulfasalazine might be useful in the treatment of nociceptive alterations in diabetic patients. PMID:18633115

Weight bearing of the limb as a confounding factor in assessment of mechanical allodynia in the rat.

PubMed

Kauppila, T; Kontinen, V K; Pertovaara, A

1998-01-01

Effect of weight bearing of the hindlimbs on the assessment of mechanically-induced hindlimb withdrawal threshold was determined in intact rats and in rats with various pathophysiological conditions causing allodynia or hyperalgesia. Hindlimb withdrawal was elicited by applying a series of calibrated monofilaments to the plantar or the dorsal surface of the paw. During testing the rat was either in a restraint tube with hindlimbs hanging semi-extended without weight bearing or it was standing on a metal grid (bearing its own weight). In intact rats, the withdrawal thresholds were significantly lower when the stimulus site was the dorsal hairy skin rather than the plantar glabrous skin. Also, thresholds were significantly lower when the hindlimbs were not bearing weight. Following carrageenan-induced unilateral inflammation of the plantar paw or a tibial nerve cut there was a marked threshold decrease to test stimuli applied to plantar or dorsal paw, respectively, ipsilateral to the pathological condition in standing rats. However, when the hindlimbs were not weight bearing the unilateral threshold decrease was markedly attenuated (carrageenan-treated rats) or completely abolished (tibial cut). In contrast, in rats with a unilateral spinal nerve ligation the threshold decrease ipsilateral to the nerve lesion was highly significant independent of the weight bearing of the hindlimbs. The results indicate that weight bearing of hindlimbs is an important confounding factor in the assessment of tactile allodynia in rats.

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.

Sex differences in mechanical allodynia: how can it be preclinically quantified and analyzed?

PubMed Central

Nicotra, Lauren; Tuke, Jonathan; Grace, Peter M.; Rolan, Paul E.; Hutchinson, Mark R.

2014-01-01

Translating promising preclinical drug discoveries to successful clinical trials remains a significant hurdle in pain research. Although animal models have significantly contributed to understanding chronic pain pathophysiology, the majority of research has focused on male rodents using testing procedures that produce sex difference data that do not align well with comparable clinical experiences. Additionally, the use of animal pain models presents ongoing ethical challenges demanding continuing refinement of preclinical methods. To this end, this study sought to test a quantitative allodynia assessment technique and associated statistical analysis in a modified graded nerve injury pain model with the aim to further examine sex differences in allodynia. Graded allodynia was established in male and female Sprague Dawley rats by altering the number of sutures placed around the sciatic nerve and quantified by the von Frey test. Linear mixed effects modeling regressed response on each fixed effect (sex, oestrus cycle, pain treatment). On comparison with other common von Frey assessment techniques, utilizing lower threshold filaments than those ordinarily tested, at 1 s intervals, appropriately and successfully investigated female mechanical allodynia, revealing significant sex and oestrus cycle difference across the graded allodynia that other common behavioral methods were unable to detect. Utilizing this different von Frey approach and graded allodynia model, a single suture inflicting less allodynia was sufficient to demonstrate exaggerated female mechanical allodynia throughout the phases of dioestrus and pro-oestrus. Refining the von Frey testing method, statistical analysis technique and the use of a graded model of chronic pain, allowed for examination of the influences on female mechanical nociception that other von Frey methods cannot provide. PMID:24592221

Peripheral Receptor Mechanisms Underlying Orofacial Muscle Pain and Hyperalgesia

NASA Astrophysics Data System (ADS)

Saloman, Jami L.

Musculoskeletal pain conditions, particularly those associated with temporomandibular joint and muscle disorders (TMD) are severely debilitating and affect approximately 12% of the population. Identifying peripheral nociceptive mechanisms underlying mechanical hyperalgesia, a prominent feature of persistent muscle pain, could contribute to the development of new treatment strategies for the management of TMD and other muscle pain conditions. This study provides evidence of functional interactions between ligand-gated channels, P2X3 and TRPV1/TRPA1, in trigeminal sensory neurons, and proposes that these interactions underlie the development of mechanical hyperalgesia. In the masseter muscle, direct P2X3 activation, via the selective agonist αβmeATP, induced a dose- and time-dependent hyperalgesia. Importantly, the αβmeATP-induced hyperalgesia was prevented by pretreatment of the muscle with a TRPV1 antagonist, AMG9810, or the TRPA1 antagonist, AP18. P2X3 was co-expressed with both TRPV1 and TRPA1 in masseter muscle afferents confirming the possibility for intracellular interactions. Moreover, in a subpopulation of P2X3 /TRPV1 positive neurons, capsaicin-induced Ca2+ transients were significantly potentiated following P2X3 activation. Inhibition of Ca2+-dependent kinases, PKC and CaMKII, prevented P2X3-mechanical hyperalgesia whereas blockade of Ca2+-independent PKA did not. Finally, activation of P2X3 induced phosphorylation of serine, but not threonine, residues in TRPV1 in trigeminal sensory neurons. Significant phosphorylation was observed at 15 minutes, the time point at which behavioral hyperalgesia was prominent. Similar data were obtained regarding another nonselective cation channel, the NMDA receptor (NMDAR). Our data propose P2X3 and NMDARs interact with TRPV1 in a facilitatory manner, which could contribute to the peripheral sensitization underlying masseter hyperalgesia. This study offers novel mechanisms by which individual pro-nociceptive ligand

Effect of Mas-related gene (Mrg) receptors on hyperalgesia in rats with CFA-induced inflammation via direct and indirect mechanisms.

PubMed

Jiang, Jianping; Wang, Dongmei; Zhou, Xiaolong; Huo, Yuping; Chen, Tingjun; Hu, Fenjuan; Quirion, Rémi; Hong, Yanguo

2013-11-01

Mas oncogene-related gene (Mrg) receptors are exclusively distributed in small-sized neurons in trigeminal and dorsal root ganglia (DRG). We investigated the effects of MrgC receptor activation on inflammatory hyperalgesia and its mechanisms. A selective MrgC receptor agonist, bovine adrenal medulla peptide 8-22 (BAM8-22) or melanocyte-stimulating hormone (MSH) or the μ-opioid receptor (MOR) antagonist CTAP was administered intrathecally (i.t.) in rats injected with complete Freund's adjuvant (CFA) in one hindpaw. Thermal and mechanical nociceptive responses were assessed. Neurochemicals were measured by immunocytochemistry, Western blot, ELISA and RT-PCR. CFA injection increased mRNA for MrgC receptors in lumbar DRG. BAM8-22 or MSH, given i.t., generated instant short and delayed long-lasting attenuations of CFA-induced thermal hyperalgesia, but not mechanical allodynia. These effects were associated with decreased up-regulation of neuronal NOS (nNOS), CGRP and c-Fos expression in the spinal dorsal horn and/or DRG. However, i.t. administration of CTAP blocked the induction by BAM8-22 of delayed anti-hyperalgesia and inhibition of nNOS and CGRP expression in DRG. BAM8-22 also increased mRNA for MORs and pro-opiomelanocortin, along with β-endorphin content in the lumbar spinal cord and/or DRG. MrgC receptors and nNOS were co-localized in DRG neurons. Activation of MrgC receptors suppressed up-regulation of pronociceptive mediators and consequently inhibited inflammatory pain, because of the activation of up-regulated MrgC receptors and subsequent endogenous activity at MORs. The uniquely distributed MrgC receptors could be a novel target for relieving inflammatory pain. © 2013 The British Pharmacological Society.

Evaluation of aqueous and ethanolic extracts of saffron, Crocus sativus L., and its constituents, safranal and crocin in allodynia and hyperalgesia induced by chronic constriction injury model of neuropathic pain in rats.

PubMed

Amin, Bahareh; Hosseinzadeh, Hossein

2012-07-01

The current study was designed to evaluate therapeutic potential of systemically administered ethanolic and aqueous extracts of saffron as well as its bioactive ingredients, safranal and crocin, in chronic constriction injury (CCI)-induced neuropathic pain in rats. The von Frey filaments, acetone drop, and radiant heat test were performed to assess the degree of mechanical allodynia, thermal allodynia and thermal hyperalgesia respectively, at different time intervals, i.e., one day before surgery and 3, 5, 7 and 10 days post surgery. The ambulatory behavior was evaluated using the open field test. A 7-day treatment with the ethanolic and aqueous extracts (50,100 and 200 mg/kg, i.p.) and safranal (0.025, 0.05 and 0.1 mg/kg, i.p.), attenuated the behavioral symptoms of neuropathic pain in a dose dependent manner. Crocin even at the high dose (50 mg/kg) failed to produce any protective role. However, gabapentine (100 mg/kg) as a reference drug significantly alleviated all behavioral manifestations of neuropathic pain compared to control group. In conclusion, the results of this study suggest that ethanolic and aqueous extracts of saffron as well as safranal could be useful in treatment of different kinds of neuropathic pains and as an adjuvant to conventional medicines. Copyright © 2012 Elsevier B.V. All rights reserved.

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.

Ultraviolet-B-induced mechanical hyperalgesia: A role for peripheral sensitisation.

PubMed

Bishop, Thomas; Marchand, Fabien; Young, Antony R; Lewin, Gary R; McMahon, Stephen B

2010-07-01

Ultraviolet (UV) induced cutaneous inflammation is emerging as a model of pain with a novel sensory phenotype. A UVB dose of 1000mJ/cm2 produces a highly significant thermal and mechanical hypersensitivity. Here we examined the properties and mechanisms of such hyperalgesia in rats. Significantly, the mechanical hyperalgesia (with approximately 60% change in withdrawal thresholds) was restricted to the lesion site with no changes in mechanical threshold in adjacent non-irradiated skin (i.e. no secondary hypersensitivity), suggesting a peripheral mechanism. Consistent with this, we found that primary mechanical hypersensitivity showed no significant changes after intrathecal treatment with 10microg of the NMDA-receptor antagonist MK-801. Using an in vitro skin-nerve preparation, in the presence and absence of UVB-inflammation, suprathreshold responses to skin displacement stimuli of 6-768microm of 103 peripheral nociceptors were recorded. At the peak of UVB-induced hyperalgesia we observed that mechanical response properties of Adelta-nociceptors recorded from UVB-inflamed skin (n=19) were significantly diminished, by approximately 50%, compared to those recorded from naïve skin (n=13). The mechanical response properties of heat-sensitive C-nociceptors were unchanged while their heat responses were significantly increased, by approximately 75%, in UVB-inflamed (n=26) compared to naïve skin (n=12). Heat-insensitive C-nociceptors, however, demonstrated significantly enhanced (by approximately 60%) response properties to mechanical stimulation in UVB-inflamed (n=21) compared to naïve skin (n=12). Notably alteration in mechanical responses of Adelta- and heat-insensitive C-nociceptors were particular to stronger stimuli. Spontaneous activity was not induced by this dose of UVB. We conclude that UVB-induced mechanical hyperalgesia may be explained by a net shift in peripheral nociceptor response properties. Copyright 2010 International Association for the Study of

Preemptive application of QX-314 attenuates trigeminal neuropathic mechanical allodynia in rats.

PubMed

Yoon, Jeong-Ho; Son, Jo-Young; Kim, Min-Ji; Kang, Song-Hee; Ju, Jin-Sook; Bae, Yong-Chul; Ahn, Dong-Kuk

2018-05-01

The aim of the present study was to examine the effects of preemptive analgesia on the development of trigeminal neuropathic pain. For this purpose, mechanical allodynia was evaluated in male Sprague-Dawley rats using chronic constriction injury of the infraorbital nerve (CCI-ION) and perineural application of 2% QX-314 to the infraorbital nerve. CCI-ION produced severe mechanical allodynia, which was maintained until postoperative day (POD) 30. An immediate single application of 2% QX-314 to the infraorbital nerve following CCI-ION significantly reduced neuropathic mechanical allodynia. Immediate double application of QX-314 produced a greater attenuation of mechanical allodynia than a single application of QX-314. Immediate double application of 2% QX-314 reduced the CCI-ION-induced upregulation of GFAP and p-p38 expression in the trigeminal ganglion. The upregulated p-p38 expression was co-localized with NeuN, a neuronal cell marker. We also investigated the role of voltage-gated sodium channels (Navs) in the antinociception produced by preemptive application of QX-314 through analysis of the changes in Nav expression in the trigeminal ganglion following CCI-ION. Preemptive application of QX-314 significantly reduced the upregulation of Nav1.3, 1.7, and 1.9 produced by CCI-ION. These results suggest that long-lasting blockade of the transmission of pain signaling inhibits the development of neuropathic pain through the regulation of Nav isoform expression in the trigeminal ganglion. Importantly, these results provide a potential preemptive therapeutic strategy for the treatment of neuropathic pain after nerve injury.

Mechanisms mediating Nitroglycerin-induced Delayed Onset Hyperalgesia in the Rat

PubMed Central

Ferrari, Luiz F.; Levine, Jon D.; Green, Paul G.

2016-01-01

Nitroglycerin (glycerol trinitrate, GTN) induces headache in migraineurs, an effect that has been used both diagnostically and in the study of the pathophysiology of this neurovascular pain syndrome. An important feature of this headache is a delay from the administration of GTN to headache onset that, because of GTN’s very rapid metabolism, cannot be due to its pharmacokinetic profile. It has recently been suggested that activation of perivascular mast cells, which has been implicated in the pathophysiology of migraine, may contribute to this delay. We reported that hyperalgesia induced by intradermal GTN has a delay to onset of ~30 min in male and ~45 min in female rats. This hyperalgesia was greater in females, was prevented by pretreatment with the anti-migraine drug, sumatriptan, as well as by chronic pretreatment with the mast cell degranulator, compound 48/80. The acute administration of GTN and compound 48/80 both induced hyperalgesia that was prevented by pretreatment with octoxynol-9, which attenuates endothelial function, suggesting that GTN and mast cell-mediated hyperalgesia are endothelial cell-dependent. Furthermore, A-317491, a P2X3 antagonist, which inhibits endothelial cell-dependent hyperalgesia, also prevents GTN and mast cell-mediated hyperalgesia. We conclude that delayed onset mechanical hyperalgesia induced by GTN is mediated by activation of mast cells, which in turn release mediators that stimulate endothelial cells to release ATP, to act on P2X3, a ligand-gated ion channel, in perivascular nociceptors. A role of the mast and endothelial cell in GTN-induced hyperalgesia suggest potential novel risk factors and targets for the treatment of migraine. PMID:26779834

Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat.

PubMed

Ferrari, L F; Levine, J D; Green, P G

2016-03-11

Nitroglycerin (glycerol trinitrate, GTN) induces headache in migraineurs, an effect that has been used both diagnostically and in the study of the pathophysiology of this neurovascular pain syndrome. An important feature of this headache is a delay from the administration of GTN to headache onset that, because of GTN's very rapid metabolism, cannot be due to its pharmacokinetic profile. It has recently been suggested that activation of perivascular mast cells, which has been implicated in the pathophysiology of migraine, may contribute to this delay. We reported that hyperalgesia induced by intradermal GTN has a delay to onset of ∼ 30 min in male and ∼ 45 min in female rats. This hyperalgesia was greater in females, was prevented by pretreatment with the anti-migraine drug, sumatriptan, as well as by chronic pretreatment with the mast cell degranulator, compound 48/80. The acute administration of GTN and compound 48/80 both induced hyperalgesia that was prevented by pretreatment with octoxynol-9, which attenuates endothelial function, suggesting that GTN and mast cell-mediated hyperalgesia are endothelial cell-dependent. Furthermore, A-317491, a P2X3 antagonist, which inhibits endothelial cell-dependent hyperalgesia, also prevents GTN and mast cell-mediated hyperalgesia. We conclude that delayed-onset mechanical hyperalgesia induced by GTN is mediated by activation of mast cells, which in turn release mediators that stimulate endothelial cells to release ATP, to act on P2X3, a ligand-gated ion channel, in perivascular nociceptors. A role of the mast and endothelial cell in GTN-induced hyperalgesia suggests potential novel risk factors and targets for the treatment of migraine. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

CXCL13 regulates the trafficking of GluN2B-containing NMDA receptor via IL-17 in the development of remifentanil-induced hyperalgesia in rats.

PubMed

Zhu, M; Yuan, S T; Yu, W L; Jia, L L; Sun, Y

2017-05-01

This study aimed to investigate whether CXCL13 modulated the trafficking of NMDA receptor via interleukin (IL)-17 in a rat model of remifentanil-induced hyperalgesia (RIH).Although chemokines are crucial regulators of neuroinflammation, spinal N-methyl-d-aspartate (NMDA) receptor activation, and development of hypernociceptive process, little is known about specific pathogenesis and effective treatment. Inflammatory mediators are required for excitatory synaptic transmission in pathologic pain. A neutralizing antibody against CXCL13 (anti-CXCL13), antiserum against IL-17 (anti-IL-17), and recombinant CXCL13 and IL-17 were administered intrathecally to explore the roles of CXCL13, IL-17, and NMDA receptor, as well as the prevention of hyperalgesia. Paw withdrawal threshold and paw withdrawal latency were employed to record mechanical allodynia and thermal hyperalgesia. Reverse transcriptase quantitative polymerase chain reaction was used to evaluate the levels of CXCL13/CXCR5 and IL-17/IL-17RA in the spinal dorsal horn. The trafficking of spinal GluN2B-containing NMDA receptor was assessed by Western blot after nociceptive testing. This study found mechanical allodynia and thermal hyperalgesia with a remarkable increase in the expression of spinal CXCL13/CXCR5 and IL-17/IL-17RA and trafficking of GluN2B-containing NMDA receptor after remifentanil exposure. Behavioral RIH and elevated GluN2B trafficking were dampened by intrathecal anti-CXCL13 and anti-IL-17, respectively. The delivery of exogenous CXCL13 dose-dependently generated a rapid nociceptive hypersensitivity in naïve rats, which was prevented by coadministering anti-IL-17. CXCL13-induced IL-17RA overproduction and GluN2B trafficking were reversed by anti-IL-17 treatment. GluN2B antagonist also blocked CXCL13, and IL-17 directly induced hyperalgesia. This study highlighted the contribution of IL-17 pathway in the trafficking of CXCL13-induced GluN2B-containing NMDA receptor in the pathogenesis of RIH

Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles

PubMed Central

Baron, Ralf; Maier, Christoph; Attal, Nadine; Binder, Andreas; Bouhassira, Didier; Cruccu, Giorgio; Finnerup, Nanna B.; Haanpää, Maija; Hansson, Per; Hüllemann, Philipp; Jensen, Troels S.; Freynhagen, Rainer; Kennedy, Jeffrey D.; Magerl, Walter; Mainka, Tina; Reimer, Maren; Rice, Andrew S.C.; Segerdahl, Märta; Serra, Jordi; Sindrup, Sören; Sommer, Claudia; Tölle, Thomas; Vollert, Jan; Treede, Rolf-Detlef

2016-01-01

Abstract Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders. PMID:27893485

Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles.

PubMed

Baron, Ralf; Maier, Christoph; Attal, Nadine; Binder, Andreas; Bouhassira, Didier; Cruccu, Giorgio; Finnerup, Nanna B; Haanpää, Maija; Hansson, Per; Hüllemann, Philipp; Jensen, Troels S; Freynhagen, Rainer; Kennedy, Jeffrey D; Magerl, Walter; Mainka, Tina; Reimer, Maren; Rice, Andrew S C; Segerdahl, Märta; Serra, Jordi; Sindrup, Sören; Sommer, Claudia; Tölle, Thomas; Vollert, Jan; Treede, Rolf-Detlef

2017-02-01

Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.

Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: Engagement of antioxidant mechanisms and spinal GABAA receptors.

PubMed

Zhao, Xin; Li, Xin-Lin; Liu, Xin; Wang, Chuang; Zhou, Dong-Sheng; Ma, Qing; Zhou, Wen-Hua; Hu, Zhen-Yu

2015-12-01

Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Fisetin, a naturally occurring flavonoid, has been reported to exert antidepressant-like effect in previous studies. As antidepressant drugs are employed clinically to treat neuropathic pain, this work aimed to investigate whether fisetin possess beneficial effect on diabetic neuropathic pain and explore the mechanism(s). We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (200mg/kg), and von Frey test or Hargreaves test was used to assess mechanical allodynia or thermal hyperalgesia, respectively. Chronic treatment of diabetic mice with fisetin not only ameliorated the established symptoms of thermal hyperalgesia and mechanical allodynia, but also arrested the development of neuropathic pain when given at low doses. Although chronic fisetin administration did not impact on the symptom of hyperglycemia in diabetic mice, it reduced exacerbated oxidative stress in tissues of spinal cord, dorsal root ganglion (DRG) and sciatic verve. Furthermore, the analgesic actions of fisetin were abolished by repetitive co-treatment with the reactive oxygen species (ROS) donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the ROS scavenger phenyl-N-tert-butylnitrone (PBN). Finally, acute blockade of spinal GABAA receptors by bicuculline totally counteracted such fisetin analgesia. These findings indicate that chronic fisetin treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the present fisetin analgesia may be associated with its antioxidant activity, and spinal GABAA receptors are likely rendered as downstream targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Suppression of Pax2 attenuates allodynia and hyperalgesia through ET-1-ETAR-NFAT5 signaling in a rat model of neuropathic pain.

PubMed

Tai, Lydia Wai; Pan, Zhiqiang; Sun, Liting; Li, Haobo; Gu, Pan; Wong, Stanley Sau Ching; Chung, Sookja K; Cheung, Chi Wai

2018-05-27

Endothelin-1 (ET-1) and its receptors (ETAR/ETBR) emerge to be a key signaling axis in neuropathic pain processing and are recognized as new therapeutic targets. Yet, little is known on the functional regulation of ET-1 axis during neuropathic pain. Bioinformatics analysis indicated that paired box gene 2 (Pax2) or nuclear factor of activated T-cells 5 (NFAT5), two transcription factors involved in the modulation of neurotransmission, may regulate ET-1. Therefore, we hypothesized that ET-1 axis may be regulated by Pax2 or NFAT5 in the development of neuropathic pain. After partial sciatic nerve ligation (pSNL), rats displayed allodynia and hyperalgesia, which was associated with increased mRNA and protein expressions of spinal Pax2, NFAT5, and mRNA levels of ET-1 and ETAR, but not ETBR. Knockdown of Pax2 or NFAT5 with siRNA, or inhibition of ETAR with BQ-123 attenuated pSNL-induced pain-like behaviors. At molecular level, Pax2 siRNA, but not NFAT5 siRNA, downregulated ET-1 and ETAR, while ETAR inhibitor reduced NFAT5, indicating Pax2 in the upstream of ET-1 axis with NFAT5 in the downstream. Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling. These findings demonstrate that Pax2 targeting ET-1-ETAR-NFAT5 is a novel regulatory mechanism underlying neuropathic pain. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

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

Peripherally injected linalool and bergamot essential oil attenuate mechanical allodynia via inhibiting spinal ERK phosphorylation.

PubMed

Kuwahata, Hikari; Komatsu, Takaaki; Katsuyama, Soh; Corasaniti, Maria Tiziana; Bagetta, Giacinto; Sakurada, Shinobu; Sakurada, Tsukasa; Takahama, Kazuo

2013-02-01

Bergamot essential oil (BEO) is one of the most common essential oil containing linalool and linalyl acetate as major volatile components. This study investigated the effect of intraplantar (i.pl.) bergamot essential oil (BEO) or linalool on neuropathic hypersensitivity induced by partial sciatic nerve ligation (PSNL) in mice. The i.pl. injection of BEO or linalool into the ipsilateral hindpaw to PSNL reduced PSNL-induced mechanical allodynia in a dose-dependent manner. Peripheral (i.pl.) injection of BEO or linalool into the contralateral hindpaw did not yield anti-allodynic effects, suggesting a local anti-mechanical allodynic effect of BEO or linalool in PSNL mice. Anti-mechanical hypersensitivity of morphine was enhanced by the combined injection of BEO or linalool at an ineffective dose when injected alone. We also examined the possible involvement of spinal extracellular signal-regulated protein kinase (ERK) in BEO or linalool-induced anti-mechanical allodynia. In western blotting analysis, i.pl. injection of BEO or linalool resulted in a significant blockade of spinal ERK activation induced by PSNL. These results suggest that i.pl. injection of BEO or linalool may reduce PSNL-induced mechanical allodynia followed by decreasing spinal ERK activation. Copyright © 2012 Elsevier Inc. All rights reserved.

Psychosocial factors partially mediate the relationship between mechanical hyperalgesia and self-reported pain.

PubMed

Mason, Kayleigh J; O'Neill, Terence W; Lunt, Mark; Jones, Anthony K P; McBeth, John

2018-01-26

Amplification of sensory signalling within the nervous system along with psychosocial factors contributes to the variation and severity of knee pain. Quantitative sensory testing (QST) is a non-invasive test battery that assesses sensory perception of thermal, pressure, mechanical and vibration stimuli used in the assessment of pain. Psychosocial factors also have an important role in explaining the occurrence of pain. The aim was to determine whether QST measures were associated with self-reported pain, and whether those associations were mediated by psychosocial factors. Participants with knee pain identified from a population-based cohort completed a tender point count and a reduced QST battery of thermal, mechanical and pressure pain thresholds, temporal summation, mechanical pain sensitivity (MPS), dynamic mechanical allodynia (DMA) and vibration detection threshold performed following the protocol by the German Research Network on Neuropathic Pain. QST assessments were performed at the most painful knee and opposite forearm (if pain-free). Participants were asked to score for their global and knee pain intensities within the past month (range 0-10), and complete questionnaire items investigating anxiety, depression, illness perceptions, pain catastrophising, and physical functioning. QST measures (independent variable) significantly correlated (Spearman's rho) with self-reported pain intensity (dependent variable) were included in structural equation models with psychosocial factors (latent mediators). Seventy-two participants were recruited with 61 participants (36 women; median age 64 years) with complete data included in subsequent analyses. Tender point count was significantly correlated with global pain intensity. DMA at the knee and MPS at the most painful knee and opposite pain-free forearm were significantly correlated with both global pain and knee pain intensities. Psychosocial factors including pain catastrophising sub-scales (rumination and

Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice

PubMed Central

Bates, EA; Nikai, T; Brennan, KC; Fu, Y-H; Charles, AC; Basbaum, AI; Ptáček, LJ; Ahn, AH

2016-01-01

The association between the clinical use of nitroglycerin (NTG) and headache has led to the examination of NTG as a model trigger for migraine and related headache disorders, both in humans and laboratory animals. In this study in mice, we hypothesized that NTG could trigger behavioural and physiological responses that resemble a common manifestation of migraine in humans. We report that animals exhibit a dose-dependent and prolonged NTG-induced thermal and mechanical allodynia, starting 30–60 min after intraperitoneal injection of NTG at 5–10 mg/kg. NTG administration also induced Fos expression, an anatomical marker of neuronal activity in neurons of the trigeminal nucleus caudalis and cervical spinal cord dorsal horn, suggesting that enhanced nociceptive processing within the spinal cord contributes to the increased nociceptive behaviour. Moreover, sumatriptan, a drug with relative specificity for migraine, alleviated the NTG-induced allodynia. We also tested whether NTG reduces the threshold for cortical spreading depression (CSD), an event considered to be the physiological substrate of the migraine aura. We found that the threshold of CSD was unaffected by NTG, suggesting that NTG stimulates migraine mechanisms that are independent of the regulation of cortical excitability. PMID:19489890

Neonatal handling (resilience) attenuates water-avoidance stress induced enhancement of chronic mechanical hyperalgesia in the rat

PubMed Central

Alvarez, Pedro; Levine, Jon D.; Green, Paul G.

2015-01-01

Chronic stress is well known to exacerbate pain. We tested the hypothesis that neonatal handling, which induces resilience to the negative impact of stress by increasing the quality and quantity of maternal care, attenuates the mechanical hyperalgesia produced by water-avoidance stress in the adult rat. Neonatal male rats underwent the handling protocol on postnatal days 2–9, weaned at 21 days and tested for muscle mechanical nociceptive threshold at postnatal days 50–75. Decrease in mechanical nociceptive threshold in skeletal muscle in adult rats, produced by exposure to water-avoidance stress, was significantly attenuated by neonatal handling. Neonatal handling also attenuated the mechanical hyperalgesia produced by intramuscular administration of the pronociceptive inflammatory mediator, prostaglandin E2 in rats exposed as adults to water-avoidance stress. Neonatal handling, which induces a smaller corticosterone response in adult rats exposed to a stressor as well as changes in central nervous system neurotransmitter systems, attenuates mechanical hyperalgesia produced by water-avoidance stress and enhanced prostaglandin hyperalgesia in adult animals. PMID:25637700

Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice.

PubMed

Liang, De-Yong; Li, XiangQi; Clark, J David

2013-01-01

Repeated administration of opioids such as morphine induces persistent behavioral changes including opioid-induced hyperalgesia (OIH), tolerance, and physical dependence. In the current work we explored how the balance of histone acetyltransferase (HAT) versus histone deacetylase (HDAC) might regulate these morphine-induced changes. Nociceptive thresholds, analgesia, and physical dependence were assessed during and for a period of several weeks after morphine exposure. To probe the roles of histone acetylation, the HAT inhibitor curcumin or a selective HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was administered daily to groups of animals. Histone acetylation in spinal cord was assessed by Western blot and immunohistochemistry. Concurrent administration of curcumin with morphine for 4 days significantly reduced development of opioid-induced mechanical allodynia, thermal hyperalgesia, tolerance, and physical dependence. Conversely, the HDAC inhibitor SAHA enhanced these responses. Interestingly, SAHA treatment after the termination of opioid administration sustained these behavioral changes for at least 4 weeks. Histone H3 acetylation in the dorsal horn of the spinal cord was increased after chronic morphine treatment, but H4 acetylation was unchanged. Moreover, we observed a decrease in HDAC activity in the spinal cords of morphine-treated mice while overall HAT activity was unchanged, suggesting a shift toward a state of enhanced histone acetylation. The current study indicates that epigenetic mechanisms play a crucial role in opioid-induced long-lasting neuroplasticity. These results provide new sight into understanding the mechanisms of opioid-induced neuroplasticity and suggest new strategies to limit opioid abuse potential and increase the value of these drugs as analgesics. Copyright © 2013 American Pain Society. All rights reserved.

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.

Downregulations of TRPM8 expression and membrane trafficking in dorsal root ganglion mediate the attenuation of cold hyperalgesia in CCI rats induced by GFRα3 knockdown.

PubMed

Su, Lin; Shu, Ruichen; Song, Chengcheng; Yu, Yonghao; Wang, Guolin; Li, Yazhuo; Liu, Changxiao

2017-10-01

Cold hyperalgesia is an intractable sensory abnormality commonly seen in peripheral neuropathies. Although glial cell line-derived neurotrophic factor family receptor alpha3 (GFRα3) is required for the formation of pathological cold pain has been revealed, potential transduction mechanism is poorly elucidated. We have previously demonstrated the contribution of enhanced activity of transient receptor potential melastatin 8 (TRPM8) to cold hyperalgesia in neuropathic pain using a rat model of chronic constriction injury (CCI) to the sciatic nerve. Recently, the enhancement of TRPM8 activity is attributed to the increased TRPM8 plasma membrane trafficking. In addition, TRPM8 can be sensitized by the activation of GFRα3, leading to increased cold responses in vivo. The aim of this study was to investigate whether GFRα3 could influence cold hyperalgesia of CCI rats via modulating TRPM8 expression and plasma membrane trafficking in dorsal root ganglion (DRG). Mechanical allodynia, cold and heat hyperalgesia were measured on 1day before CCI and the 1st, 4th, 7th, 10th and 14th day after CCI. TRPM8 total expression and membrane trafficking as well as GFRα3 expression in DRG were detected by immunofluorescence and western blot. Furthermore, GFRα3 small interfering RNA (siRNA) was intrathecally administrated to reduce GFRα3 expression in DRG, and the effects of GFRα3 knockdown on CCI-induced behavioral sensitization as well as TRPM8 total expression and membrane trafficking in both mRNA and protein levels were investigated, and the change in coexpression of TRPM8 with GFRα3 was also evaluated. Then, the effect of GFRα3 activation with artemin on pain behavior of CCI rats pretreated with the selective TRPM8 antagonist RQ-00203078 was observed. Here we found that TRPM8 total expression and plasma membrane trafficking as well as GFRα3 expression in DRG were initially increased on the 4th day after CCI, and maintained at the peak level from the 10th to the 14th day

Unique action mechanisms of tramadol in global cerebral ischemia-induced mechanical allodynia.

PubMed

Matsuura, Wataru; Kageyama, Erika; Harada, Shinichi; Tokuyama, Shogo

2016-06-15

Central poststroke pain is associated with specific somatosensory abnormalities, such as neuropathic pain syndrome. Although central poststroke pain is a serious condition, details pertaining to underlying mechanisms are not well established, making current standard treatments only partially effective. Here, we assessed the effects of tramadol, an analgesic drug mediated by opioid receptors, using a mouse model of global cerebral ischemia. Ischemia was induced by bilateral carotid artery occlusion (30 min) in male ddY mice. Development of hind-paw mechanical allodynia was measured 3 days after bilateral carotid artery occlusion using the von Frey test. Mechanical allodynia was significantly and dose dependently suppressed by intraperitoneal tramadol (10 or 20 mg/kg). These effects, which peaked at 10 min and continued for at least 60 min, were inhibited by naloxone (nonselective opioid receptor antagonist, 1 mg/kg, intraperitoneal). Tramadol antinociception was significantly negated by β-funaltrexamine (selective μ-opioid receptor antagonist, 20 mg/kg, intraperitoneal), but not naltrindole (selective δ-opioid receptor antagonist, 5 mg/kg, intraperitoneal) or nor-binaltorphimine (selective κ-opioid receptor antagonist, 10 mg/kg, intraperitoneal) after 5 min, by β-funaltrexamine and nor-binaltorphimine but not naltrindole after 10 min, and by all selective opioid receptor antagonists at 15 and 30 min after tramadol treatment. These results suggested that antinociception induced by tramadol through various opioid receptors was time dependent. Furthermore, it is possible that the opioid receptors involved in tramadol-induced antinociception change over time with the metabolism of this drug.

The pattern and time course of somatosensory changes in the human UVB sunburn model reveal the presence of peripheral and central sensitization.

PubMed

Gustorff, Burkhard; Sycha, Thomas; Lieba-Samal, Doris; Rolke, Roman; Treede, Rolf-Detlef; Magerl, Walter

2013-04-01

The ultraviolet B (UVB) sunburn model was characterized with a comprehensive battery of quantitative sensory testing (QST). Primary hyperalgesia in UVB-irradiated skin and secondary hyperalgesia in adjacent nonirradiated skin were studied in 22 healthy subjects 24h after irradiation with UVB at 3-fold minimal erythema dose of a skin area 5 cm in diameter at the thigh and compared to mirror-image contralateral control areas. The time course of hyperalgesia over 96 h was studied in a subgroup of 12 subjects. Within the sunburn area, cold hyperesthesia (P=.01), profound generalized hyperalgesia to heat (P<.001), cold (P<.05), pinprick and pressure (P<.001), and mild dynamic mechanical allodynia (P<.001) were present. The finding of cold hyperalgesia and cold hyperesthesia is new in this model. The sunburn was surrounded by large areas of pinprick hyperalgesia (mean±SEM, 218±32 cm(2)) and a small rim of dynamic mechanical allodynia but no other sensory changes. Although of smaller magnitude, secondary hyperalgesia and dynamic mechanical allodynia adjacent to the UVB-irradiated area were statistically highly significant. Primary and secondary hyperalgesia developed in parallel within hours, peaked after 24-32 h, and lasted for more than 96 h. These data reveal that the UVB sunburn model activates a broad spectrum of peripheral and central sensitization mechanisms and hence is a useful human surrogate model to be used as a screening tool for target engagement in phases 1 and 2a of drug development. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Mechanical allodynia in human glabrous skin mediated by low-threshold cutaneous mechanoreceptors with unmyelinated fibres.

PubMed

Nagi, Saad S; Mahns, David A

2013-11-01

We recently showed that C-tactile fibres (CTs) in human hairy skin (anterior leg) mediate crossover between innocuous touch and noxious touch, i.e. mechanical allodynia. Although there is no evidence for existence of a phenotypically identical class of CTs in human glabrous skin, the 'qualia' of affective stimuli are comparable across skin types. In 42 healthy subjects, muscle pain was induced by infusing hypertonic saline (5 %) into flexor carpi ulnaris muscle. Concurrently, sinusoidal vibration (200 Hz-200 μm) was applied to glabrous skin of little finger. The neural substrate of allodynia was determined by employing conduction blocks of myelinated (ulnar nerve compression) and unmyelinated (low-dose intra-dermal anaesthesia) fibres. In order to compare the expression of allodynia across spinal segments and skin types, vibration was also applied to glabrous skin of index finger and hairy skin of dorsal forearm. In addition, high-precision brushing stimuli were applied at speeds of 1.0 and 3.0 cm s(-1) to digital glabrous skin with absent myelinated fibres. During muscle pain, vibration caused a significant and reproducible increase in pain (allodynia). This effect persisted during blockade of myelinated fibres, but was abolished by inactivation of unmyelinated cutaneous fibres. The vibration-evoked effects were found to be comparable across spinal segments and skin types. Furthermore, brushing produced a near-identical expression of C-fibre-mediated allodynia. Prior to induction and upon cessation of muscle pain, vibration and brushing were reported as non-painful. Based on these results, we postulate that a functional homologue of the CTs (hairy skin) mediates allodynia in human glabrous skin.

Tactile allodynia in patients with lumbar radicular pain (sciatica).

PubMed

Defrin, Ruth; Devor, Marshall; Brill, Silviu

2014-12-01

We report a novel symptom in many patients with low back pain (LBP) that sheds new light on the underlying pain mechanism. By means of quantitative sensory testing, we compared patients with radicular LBP (sciatica), axial LBP (LBP without radiation into the leg), and healthy controls, searching for cutaneous allodynia in response to weak tactile and cooling stimuli on the leg and low back. Most patients with radicular pain (~60%) reported static and dynamic tactile allodynia, as well as cooling allodynia, on the leg, often extending into the foot. Some also reported allodynia on the low back. In axial LBP, allodynia was almost exclusively on the back. The degree of dynamic tactile allodynia correlated with the degree of background pain. The presence of allodynia suggests that the peripheral nerve generators of background leg and back pain have also induced central sensitization. The distal (foot) location of the allodynia in patients who have it indicates that the nociceptive drive that maintains the central sensitization arises paraspinally (ectopically) in injured ventral ramus afferents; this is not an instance of somatic referred pain. The presence of central sensitization also provides the first cogent account of shooting pain in sciatica as a wave of activity sweeping vectorially across the width of the sensitized dorsal horn. Finally, the results endorse leg allodynia as a pain biomarker in animal research on LBP, which is commonly used but has not been previously validated. In addition to informing the underlying mechanism of LBP, bedside mapping of allodynia might have practical implications for prognosis and treatment. How can you tell whether pain radiating into the leg in a patient with sciatica is neuropathic, ie, due to nerve injury? Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. 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

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

Secoisolariciresinol diglycoside, a flaxseed lignan, exerts analgesic effects in a mouse model of type 1 diabetes: Engagement of antioxidant mechanism.

PubMed

Hu, Pei; Mei, Qi-Yong; Ma, Li; Cui, Wu-Geng; Zhou, Wen-Hua; Zhou, Dong-Sheng; Zhao, Qing; Xu, Dong-Ying; Zhao, Xin; Lu, Qin; Hu, Zhen-Yu

2015-11-15

Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Secoisolariciresinol diglycoside (SDG), a predominant lignan in flaxseed, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential analgesic efficacy of SDG against diabetic neuropathic pain in a mouse model of type 1 diabetes. We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg), and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic instead of acute SDG treatment (3, 10 or 30 mg/kg, p.o., twice per day for three weeks) ameliorated thermal hyperalgesia and mechanical allodynia in diabetic mice, and these analgesic actions persisted about three days when SDG treatment was terminated. Although chronic treatment of SDG to diabetic mice did not impact on the symptom of hyperglycemia, it greatly attenuated excessive oxidative stress in sciatic nerve and spinal cord tissues, and partially counteracted the condition of weight decrease. Furthermore, the analgesic actions of SDG were abolished by co-treatment with the reactive oxygen species donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the reactive oxygen species scavenger phenyl-N-tert-butylnitrone (PBN). These findings indicate that chronic SDG treatment can correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the analgesic actions of SDG in diabetic mice may be associated with its antioxidant activity. Copyright © 2015. Published by Elsevier B.V.

The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete Freund's adjuvant

PubMed Central

Yu, Lu; Yang, Fei; Luo, Hao; Liu, Feng-Yu; Han, Ji-Sheng; Xing, Guo-Gang; Wan, You

2008-01-01

Background The present study aims to investigate the role of transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons in chronic pain including thermal hyperalgesia and mechanical allodynia. Chronic inflammatory nociception of rats was produced by intraplantar injection of complete Freund's adjuvant (CFA) and data was collected until day 28 following injection. Results Thermal hyperalgesia was evident from day 1 to day 28 with peak at day 7, while mechanical allodynia persisted from day 1 to day 14 and was greatest at day 7. Intrathecal administration of AMG 9810 at day 7, a selective TRPV1 antagonist, significantly reduced thermal hyperalgesia and mechanical allodynia. TRPV1 expression in DRG detected by Western blotting was increased relative to baseline throughout the observation period. Double labeling of TRPV1 with neuronal marker neurofilament 200 (NF200), calcitonin gene-related peptide (CGRP) or isolectin B4 (IB4) was used to distinguish different subtypes of DRG neurons. TRPV1 expression was increased in the medium-sized myelinated A fiber (NF200 positive) neurons and in small non-peptidergic (IB4 positive) neurons from day 1 to day 14 and was increased in small peptidergic (CGRP positive) neurons from day 1 to day 28. Conclusion TRPV1 expression increases in all three types of DRG neurons after CFA injection and plays a role in CFA-induced chronic inflammatory pain including thermal hyperalgesia and mechanical allodynia. PMID:19055783

A novel and selective poly (ADP-ribose) polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy.

PubMed

Ta, Lauren E; Schmelzer, James D; Bieber, Allan J; Loprinzi, Charles L; Sieck, Gary C; Brederson, Jill D; Low, Philip A; Windebank, Anthony J

2013-01-01

Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice. An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment. Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice.

PubMed

Alongkronrusmee, Doungkamol; Chiang, Terrance; van Rijn, Richard M

2016-10-01

As a legal drug, alcohol is commonly abused and it is estimated that 17 million adults in the United States suffer from alcohol use disorder. Heavy alcoholics can experience withdrawal symptoms including anxiety and mechanical allodynia that can facilitate relapse. The molecular mechanisms underlying this phenomenon are not well understood, which stifles development of new therapeutics. Here we investigate whether delta opioid receptors (DORs) play an active role in alcohol withdrawal-induced mechanical allodynia (AWiMA) and if DOR agonists may provide analgesic relief from AWiMA. To study AWiMA, adult male wild-type and DOR knockout C57BL/6 mice were exposed to alcohol by a voluntary drinking model or oral gavage exposure model, which we developed and validated here. We also used the DOR-selective agonist TAN-67 and antagonist naltrindole to examine the involvement of DORs in AWiMA, which was measured using a von Frey model of mechanical allodynia. We created a robust model of alcohol withdrawal-induced anxiety and mechanical allodynia by orally gavaging mice with 3g/kg alcohol for three weeks. AWiMA was exacerbated and prolonged in DOR knockout mice as well as by pharmacological blockade of DORs compared to control mice. However, analgesia induced by TAN-67 was attenuated during withdrawal in alcohol-gavaged mice. DORs appear to play a protective role in the establishment of AWiMA. Our current results indicate that DORs could be targeted to prevent or reduce the development of AWiMA during alcohol use; however, DORs may be a less suitable target to treat AWiMA during active withdrawal. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A combined effect of dextromethorphan and melatonin on neuropathic pain behavior in rats.

PubMed

Wang, Shuxing; Zhang, Lin; Lim, Grewo; Sung, Backil; Tian, Yinghong; Chou, Chiu-Wen; Hernstadt, Hayley; Rusanescu, Gabriel; Ma, Yuxin; Mao, Jianren

2009-09-08

Previous study has shown that administration of melatonin into the anterior cingulate cortex contralateral to peripheral nerve injury prevented exacerbation of mechanical allodynia with a concurrent improvement of depression-like behavior in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats. In the present study, we examined the effect of the individual versus combined treatment of melatonin and/or dextromethorphan (DM), a clinically available N-methyl-d-aspartate (NMDA) receptor antagonist, on pain behaviors in WKY rats with chronic constriction sciatic nerve injury (CCI). Pain behaviors (thermal hyperalgesia and mechanical allodynia) were established at one week after CCI. WKY rats were then treated intraperitoneally with various doses of melatonin, DM or their combination once daily for the following week. At the end of this one-week treatment, behavioral tests were repeated in these same rats. While DM alone was effective in reducing thermal hyperalgesia at three tested doses (15, 30 or 60 mg/kg), it reduced mechanical allodynia only at high doses (30 or 60 mg/kg). By comparison, administration of melatonin alone was effective in reducing thermal hyperalgesia only at the highest dose (120 mg/kg, but not 30 or 60 mg/kg) tested in this experiment. Melatonin alone failed to reverse allodynia at all three tested doses (30, 60 and 120 mg/kg). However, the combined intraperitoneal administration of melatonin (30 mg/kg) and DM (15 mg/kg) effectively reversed both thermal hyperalgesia and mechanical allodynia although each individual dose alone did not reduce pain behaviors. These results suggest that a combination of melatonin with a clinically available NMDA receptor antagonist might be more effective than either drug alone for the treatment of neuropathic pain.

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.

Co-administration of MK-801 and morphine attenuates neuropathic pain in rat.

PubMed

Hamidi, Gholam Ali; Manaheji, Homa; Janahmadi, Mahyar; Noorbakhsh, Sayed Mohammad; Salami, Mahmoud

2006-07-30

Partial peripheral nerve injury often leads to chronic pain states, including allodynia and hyperalgesia. The purpose of this study was to investigate the involvement of the N-methyl-D-aspartate and opioid receptors in the behavioural responses following chronic constriction nerve injury (CCI). The animals were injected a combination of MK-801 (0.3 mg/kg, 20 min before, and 6 h after the operation) and morphine (8 mg/kg, 30 min prior to the operation) and were tested for allodynia and hyperalgesia reactions at 0, 3, 7, 14, 21 and 28 days after CCI. Compound action potentials were also recorded from the injured nerve 2 weeks post-operation to indicate nerve injury state electrophysiologically. Our results indicate that the CCI model importantly influences the behavioural responses to both the thermal and mechanical stimulations. Also, the pre-emptive co-administration of MK-801 and morphine has suppressive effects on the cold allodynia but a slight alleviation on the mechano-allodynia and heat hyperalgesia.

Interleukin-6 mediates low-threshold mechanical allodynia induced by intrathecal HIV-1 envelope glycoprotein gp120

PubMed Central

Schoeniger-Skinner, Diana K.; Ledeboer, Annemarie; Frank, Matthew G.; Milligan, Erin D.; Poole, Stephen; Martin, David; Maier, Steven F.; Watkins, Linda R.

2007-01-01

Spinal cord glia (microglia and astrocytes) contribute to enhanced pain states. One model that has been used to study this phenomenon is intrathecal (i.t.) administration of gp120, an envelope glycoprotein of HIV-1 known to activate spinal cord glia and thereby induce low-threshold mechanical allodynia, a pain symptom where normally innocuous (non-painful) stimuli are perceived as painful. Previous studies have shown that i.t. gp120-induced allodynia is mediated via the release of the glial pro-inflammatory cytokines, tumor necrosis factor-α (TNF), and interleukin-1β (IL-1). As we have recently reported that i.t. gp120 induces the release of interleukin-6 (IL-6), in addition to IL-1 and TNF, the present study tested whether this IL-6 release in spinal cord contributes to gp120-induced mechanical allodynia and/or to gp120-induced increases in TNF and IL-1. An i.t. anti-rat IL-6 neutralizing antibody was used to block IL-6 actions upon its release by i.t. gp120. This IL-6 blockade abolished gp120-induced mechanical allodynia. While the literature predominantly documents the cascade of pro-inflammatory cytokines as beginning with TNF, followed by the stimulation of IL-1, and finally TNF plus IL-1 stimulating the release of IL-6, the present findings indicate that a blockade of IL-6 inhibits the gp120-induced elevations of TNF, IL-1, and IL-6 mRNA in dorsal spinal cord, elevation of IL-1 protein in lumbar dorsal spinal cord, and TNF and IL-1 protein release into the surrounding lumbosacral cerebrospinal fluid. These results would suggest that IL-6 induces pain facilitation, and may do so in part by stimulating the production and release of other proinflammatory cytokines. PMID:17204394

Allodynia and Dysmenorrhea.

PubMed

Jarrell, John; Arendt-Nielsen, Lars

2016-03-01

Cutaneous allodynia (pain from a non-painful stimulus) is a sign that can be observed among women with chronic pelvic pain. Dysmenorrhea is recognized as a common cause of chronic pelvic pain in women. This study was conducted to explore the frequency of allodynia and the relationship between allodynia and severe dysmenorrhea. We enrolled women in this study if they had experienced chronic pelvic pain for more than six months. Women provided information regarding their chronic pelvic pain and menstrual function, specifically the severity of their menstrual pain. In addition to a gynaecological assessment, women were tested for allodynia and pain pressure thresholds. Abdominal allodynia was present in 62.1% of 181 women who participated. Women with allodynia had a significantly greater rate of severe dysmenorrhea and significantly greater duration of severe dysmenorrhea. Pain pressure thresholds were demonstrated to decrease significantly in relation to increasing duration of severe dysmenorrhea. There is a greater frequency of chronic pain among women with a history of severe dysmenorrhea. Women who experienced prolonged severe dysmenorrhea were shown to have a progressive increase in pain sensitivity (reflected in reduced pain pressure thresholds). These findings support efforts to manage dysmenorrhea early in a woman's life with approaches to suppress menstrual function. Copyright © 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.

Topical thermal therapy with hot packs suppresses physical inactivity-induced mechanical hyperalgesia and up-regulation of NGF.

PubMed

Nakagawa, Tatsuki; Hiraga, Shin-Ichiro; Mizumura, Kazue; Hori, Kiyomi; Ozaki, Noriyuki; Koeda, Tomoko

2017-10-12

We focused on the analgesic effect of hot packs for mechanical hyperalgesia in physically inactive rats. Male Wistar rats were randomly divided into four groups: control, physical inactivity (PI), PI + sham treatment (PI + sham), and PI + hot pack treatment (PI + hot pack) groups. Physical inactivity rats wore casts on both hind limbs in full plantar flexed position for 4 weeks. Hot pack treatment was performed for 20 min a day, 5 days a week. Although mechanical hyperalgesia and the up-regulation of NGF in the plantar skin and gastrocnemius muscle were observed in the PI and the PI + sham groups, these changes were significantly suppressed in the PI + hot pack group. The present results clearly demonstrated that hot pack treatment was effective in reducing physical inactivity-induced mechanical hyperalgesia and up-regulation of NGF in plantar skin and gastrocnemius muscle.

Oral Application of Magnesium-L-Threonate Attenuates Vincristine-induced Allodynia and Hyperalgesia by Normalization of Tumor Necrosis Factor-α/Nuclear Factor-κB Signaling.

PubMed

Xu, Ting; Li, Dai; Zhou, Xin; Ouyang, Han-Dong; Zhou, Li-Jun; Zhou, Hang; Zhang, Hong-Mei; Wei, Xu-Hong; Liu, Guosong; Liu, Xian-Guo

2017-06-01

Antineoplastic agents, including vincristine, often induce neuropathic pain and magnesium deficiency clinically, but the causal link between them has not been determined. No drug is available for treating this form of neuropathic pain. Injection of vincristine (0.1 mg · kg · day, intraperitoneally, for 10 days) was used to induce nociceptive sensitization, which was accessed with von Frey hairs and the plantar tester in adult male Sprague-Dawley rats. Magnesium-L- threonate was administered through drinking water (604 mg · kg · day). Extracellular and intracellular free Mg were measured by Calmagite chromometry and flow cytometry. Molecular biologic and electrophysiologic experiments were performed to expose the underlying mechanisms. Vincristine injection induced allodynia and hyperalgesia (n = 12), activated tumor necrosis factor-α/nuclear factor-κB signaling, and reduced free Mg in cerebrospinal fluid by 21.7 ± 6.3% (mean ± SD; n = 13) and in dorsal root ganglion neurons by 27 ± 6% (n = 11). Reducing Mg activated tumor necrosis factor-α/nuclear factor-κB signaling in cultured dorsal root ganglion neurons. Oral application of magnesium-L-threonate prevented magnesium deficiency and attenuated both activation of tumor necrosis factor-α/nuclear factor-κB signaling and nociceptive sensitization (n = 12). Mechanistically, vincristine induced long-term potentiation at C-fiber synapses, up-regulated N-methyl-D-aspartate receptor type 2B subunit of N-methyl-D-aspartate receptor, and led to peptidergic C-fiber sprouting in spinal dorsal horn (n = 6 each). The vincristine-induced pathologic plasticity was blocked by intrathecal injection of nuclear factor-κB inhibitor (n = 6), mimicked by tumor necrosis factor-α, and substantially prevented by oral magnesium-L-threonate (n = 5). Vincristine may activate tumor necrosis factor-α/nuclear factor-κB pathway by reduction of intracellular magnesium, leading to spinal pathologic plasticity and

A COMBINED EFFECT OF DEXTROMETHORPHAN AND MELATONIN ON NEUROPATHIC PAIN BEHAVIOR IN RATS

PubMed Central

Wang, Shuxing; Zhang, Lin; Lim, Grewo; Sung, Backil; Tian, Yinghong; Chou, Chiu-Wen; Hernstadt, Hayley; Rusanescu, Gabriel; Ma, Yuxin; Mao, Jianren

2009-01-01

Previous study has shown that administration of melatonin into the anterior cingulate cortex contralateral to peripheral nerve injury prevented exacerbation of mechanical allodynia with a concurrent improvement of depression-like behavior in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats. In the present study, we examined the effect of the individual versus combined treatment of melatonin and/or dextromethorphan (DM), a clinically available N-methyl-D-aspartate (NMDA) receptor antagonist, on pain behaviors in WKY rats with chronic constriction sciatic nerve injury (CCI). Pain behaviors (thermal hyperalgesia and mechanical allodynia) were established at one week after CCI. WKY rats were then treated intraperitoneally with various doses of melatonin, DM or their combination once daily for the following week. At the end of this one-week treatment, behavioral tests were repeated in these same rats. While DM alone was effective in reducing thermal hyperalgesia at three tested doses (15, 30 or 60 mg/kg), it reduced mechanical allodynia only at high doses (30 or 60 mg/kg). By comparison, administration of melatonin alone was effective in reducing thermal hyperalgesia only at the highest dose (120 mg/kg, but not 30 or 60 mg/kg) tested in this experiment. Melatonin alone failed to reverse allodynia at all three tested doses (30, 60 and 120 mg/kg). However, the combined intraperitoneal administration of melatonin (30 mg/kg) and DM (15 mg/kg) effectively reversed both thermal hyperalgesia and mechanical allodynia although each individual dose alone did not reduce pain behaviors. These results suggest that a combination of melatonin with a clinically available NMDA receptor antagonist might be more effective than either drug alone for the treatment of neuropathic pain. PMID:19595681

FXYD2, a γ subunit of Na+,K+-ATPase, maintains persistent mechanical allodynia induced by inflammation

PubMed Central

Wang, Feng; Cai, Bing; Li, Kai-Cheng; Hu, Xu-Ye; Lu, Ying-Jin; Wang, Qiong; Bao, Lan; Zhang, Xu

2015-01-01

Na+,K+-ATPase (NKA) is required to generate the resting membrane potential in neurons. Nociceptive afferent neurons express not only the α and β subunits of NKA but also the γ subunit FXYD2. However, the neural function of FXYD2 is unknown. The present study shows that FXYD2 in nociceptive neurons is necessary for maintaining the mechanical allodynia induced by peripheral inflammation. FXYD2 interacted with α1NKA and negatively regulated the NKA activity, depolarizing the membrane potential of nociceptive neurons. Mechanical allodynia initiated in FXYD2-deficient mice was abolished 4 days after inflammation, whereas it persisted for at least 3 weeks in wild-type mice. Importantly, the FXYD2/α1NKA interaction gradually increased after inflammation and peaked on day 4 post inflammation, resulting in reduction of NKA activity, depolarization of neuron membrane and facilitation of excitatory afferent neurotransmission. Thus, the increased FXYD2 activity may be a fundamental mechanism underlying the persistent hypersensitivity to pain induced by inflammation. PMID:25633594

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.

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.

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

Comparative Analgesic Efficacy of Pregabalin Administered According to Either a Prevention Protocol or an Intervention Protocol in Rats with Cisplatin-induced Peripheral Neuropathy.

PubMed

Han, F Y; Kuo, A; Nicholson, J R; Corradinni, L; Smith, M T

2018-05-21

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of peripheral neuropathic pain that may be dose-limiting in patients administered potentially curative cancer chemotherapy dosing regimens. In cancer survivors, persistent CIPN adversely affects patient quality of life and so adjuvant drugs (anticonvulsants e.g. pregabalin or antidepressants e.g. amitriptyline) are recommended for the relief of CIPN. However, most studies in rodent models of CIPN involve administration of single bolus doses of adjuvant drugs to assess pain-relieving efficacy. Hence this study was designed to assess the efficacy of pregabalin administered to CIPN-rats according to either a prevention or an intervention protocol. Groups of male Sprague-Dawley rats received four single intraperitoneal bolus doses of cisplatin at 3 mg/kg at once-weekly intervals to induce CIPN. For the prevention protocol, oral pregabalin (or vehicle) was administered to CIPN-rats once-daily for 21 consecutive days from day 0 to day 20 inclusive. For the intervention protocol, oral pregabalin was administered once-daily for 21 consecutive days from day 28 to day 48 inclusive. Mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws were assessed just prior to each dose of cisplatin and at least once-weekly until study completion (day 27, prevention protocol; or day 48, intervention protocol). Mechanical allodynia and mechanical hyperalgesia were also determined at the time of peak effect at ~2 h post- pregabalin/vehicle administration once-weekly until study completion. For the prevention protocol in CIPN-rats, pregabalin alleviated mechanical hyperalgesia but not mechanical allodynia. For the intervention protocol, pregabalin alleviated both mechanical allodynia and mechanical hyperalgesia in the hindpaws. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Molecular Hydrogen Attenuates Neuropathic Pain in Mice

PubMed Central

Kawaguchi, Masanori; Satoh, Yasushi; Otsubo, Yukiko; Kazama, Tomiei

2014-01-01

Neuropathic pain remains intractable and the development of new therapeutic strategies are urgently required. Accumulating evidence indicates that overproduction of oxidative stress is a key event in the pathogenesis of neuropathic pain. However, repeated intra-peritoneal or intrathecal injections of antioxidants are unsuitable for continuous use in therapy. Here we show a novel therapeutic method against neuropathic pain: drinking water containing molecular hydrogen (H2) as antioxidant. The effect of hydrogen on neuropathic pain was investigated using a partial sciatic nerve ligation model in mice. As indicators of neuropathic pain, temporal aspects of mechanical allodynia and thermal hyperalgesia were analysed for 3 weeks after ligation. Mechanical allodynia and thermal hyperalgesia were measured using the von Frey test and the plantar test, respectively. When mice were allowed to drink water containing hydrogen at a saturated level ad libitum after ligation, both allodynia and hyperalgesia were alleviated. These symptoms were also alleviated when hydrogen was administered only for the induction phase (from day 0 to 4 after ligation). When hydrogen was administered only for the maintenance phase (from day 4 to 21 after ligation), hyperalgesia but not allodynia was alleviated. Immunohistochemical staining for the oxidative stress marker, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine, showed that hydrogen administration suppressed oxidative stress induced by ligation in the spinal cord and the dorsal root ganglion. In conclusion, oral administration of hydrogen water may be useful for alleviating neuropathic pain in a clinical setting. PMID:24941001

Intrathecal injection of carbenoxolone, a gap junction decoupler, attenuates the induction of below-level neuropathic pain after spinal cord injury in rats.

PubMed

Roh, Dae-Hyun; Yoon, Seo-Yeon; Seo, Hyoung-Sig; Kang, Suk-Yun; Han, Ho-Jae; Beitz, Alvin J; Lee, Jang-Hern

2010-07-01

The most common type of chronic pain following spinal cord injury (SCI) is central neuropathic pain and SCI patients typically experience mechanical allodynia and thermal hyperalgesia. The present study was designed to examine the potential role of astrocyte gap junction connectivity in the induction and maintenance of "below-level" neuropathic pain in SCI rats. We examined the effect of intrathecal treatment with carbenoxolone (CARB), a gap junction decoupler, on SCI-induced bilateral thermal hyperalgesia and mechanical allodynia during the induction phase (postoperative days 0 to 5) and the maintenance phase (days 15 to 20) following T13 spinal cord hemisection. Immunohistochemistry was performed to determine potential SCI-induced changes in spinal astrocyte activation and phosphorylation of the NMDA receptor NR1 subunit (pNR1). CARB administered during the induction period dose-dependently attenuated the development of bilateral thermal hyperalgesia and mechanical allodynia. Intrathecal CARB also significantly reduced the bilateral SCI-induced increase in GFAP-immunoreactive (ir) staining and the number of pNR1-ir cell profiles in the spinal cord dorsal horn compared to vehicle-treated rats. In contrast, CARB treatment during the maintenance phase had no effect on the established thermal hyperalgesia and mechanical allodynia nor on spinal GFAP expression or the number of pNR1-ir cell profiles. These results indicate that gap junctions play a critical role in the activation of astrocytes distant from the site of SCI and in the subsequent phosphorylation of NMDA receptors in the lumbar spinal cord. Both of these processes appear to contribute to the induction of bilateral below-level pain in SCI rats. Copyright 2010 Elsevier Inc. All rights reserved.

Involvement of endothelin and ET(A) endothelin receptor in mechanical allodynia in mice given orthotopic melanoma inoculation.

PubMed

Fujita, Masahide; Andoh, Tsugunobu; Saiki, Ikuo; Kuraishi, Yasushi

2008-02-01

We investigated whether endothelin (ET) would be involved in skin cancer pain in mice. Orthotopic inoculation of B16-BL6 melanoma cells into the plantar region of the hind paw produced marked mechanical allodynia in C57BL/6 mice. Intraplantar injections of the ET(A)-receptor antagonist BQ-123 (0.3 - 3 nmol/site), but not the ET(B)-receptor antagonist BQ-788 (1 and 3 nmol/site), inhibited mechanical allodynia in mice with grown melanoma. In naive mice, an intraplantar injection of tumor extract (1 and 3 mg/site), which was prepared from the grown melanoma in the paw, produced mechanical allodynia, which was inhibited by BQ-123 and BQ-788 at doses of 3 and 10 nmol/site. An intraplantar injection of ET-1 (1 and 10 pmol/site) elicited licking behavior, which was increased in the melanoma-bearing hind paw. BQ-123 (3 and 10 nmol/site) inhibited licking induced by ET-1 (10 pmol/site). The level of mRNA of ET(A), but not ET(B), receptor, was significantly increased in the dorsal root ganglia on the inoculated side. Cultured B16-BL6 cells contained ET, and the melanoma mass increased the concentration of ET as it grew bigger. These results suggest that ET-1 and ET(A) receptor are at least partly involved in the induction of pain induced by melanoma cell inoculation.

CD4+ αβ T cell infiltration into the leptomeninges of lumbar dorsal roots contributes to the transition from acute to chronic mechanical allodynia after adult rat tibial nerve injuries.

PubMed

Du, Bin; Ding, You-Quan; Xiao, Xia; Ren, Hong-Yi; Su, Bing-Yin; Qi, Jian-Guo

2018-03-15

Antigen-specific and MHCII-restricted CD4+ αβ T cells have been shown or suggested to play an important role in the transition from acute to chronic mechanical allodynia after peripheral nerve injuries. However, it is still largely unknown where these T cells infiltrate along the somatosensory pathways transmitting mechanical allodynia to initiate the development of chronic mechanical allodynia after nerve injuries. Therefore, the purpose of this study was to ascertain the definite neuroimmune interface for these T cells to initiate the development of chronic mechanical allodynia after peripheral nerve injuries. First, we utilized both chromogenic and fluorescent immunohistochemistry (IHC) to map αβ T cells along the somatosensory pathways for the transmission of mechanical allodynia after modified spared nerve injuries (mSNIs), i.e., tibial nerve injuries, in adult male Sprague-Dawley rats. We further characterized the molecular identity of these αβ T cells selectively infiltrating into the leptomeninges of L4 dorsal roots (DRs). Second, we identified the specific origins in lumbar lymph nodes (LLNs) for CD4+ αβ T cells selectively present in the leptomeninges of L4 DRs by two experiments: (1) chromogenic IHC in these lymph nodes for CD4+ αβ T cell responses after mSNIs and (2) fluorescent IHC for temporal dynamics of CD4+ αβ T cell infiltration into the L4 DR leptomeninges after mSNIs in prior lymphadenectomized or sham-operated animals to LLNs. Finally, following mSNIs, we evaluated the effects of region-specific targeting of these T cells through prior lymphadenectomy to LLNs and chronic intrathecal application of the suppressive anti-αβTCR antibodies on the development of mechanical allodynia by von Frey hair test and spinal glial or neuronal activation by fluorescent IHC. Our results showed that during the sub-acute phase after mSNIs, αβ T cells selectively infiltrate into the leptomeninges of the lumbar DRs along the somatosensory pathways

Huperzine A Alleviates Mechanical Allodynia but Not Spontaneous Pain via Muscarinic Acetylcholine Receptors in Mice

PubMed Central

Zuo, Zhen-Xing; Wang, Yong-Jie; Liu, Li; Wang, Yiner; Mei, Shu-Hao; Feng, Zhi-Hui; Wang, Maode; Li, Xiang-Yao

2015-01-01

Chronic pain is a major health issue and most patients suffer from spontaneous pain. Previous studies suggest that Huperzine A (Hup A), an alkaloid isolated from the Chinese herb Huperzia serrata, is a potent analgesic with few side effects. However, whether it alleviates spontaneous pain is unclear. We evaluated the effects of Hup A on spontaneous pain in mice using the conditioned place preference (CPP) behavioral assay and found that application of Hup A attenuated the mechanical allodynia induced by peripheral nerve injury or inflammation. This effect was blocked by atropine. However, clonidine but not Hup A induced preference for the drug-paired chamber in CPP. The same effects occurred when Hup A was infused into the anterior cingulate cortex. Furthermore, ambenonium chloride, a competitive inhibitor of acetylcholinesterase, also increased the paw-withdrawal threshold but failed to induce place preference in CPP. Therefore, our data suggest that acetylcholinesterase in both the peripheral and central nervous systems is involved in the regulation of mechanical allodynia but not the spontaneous pain. PMID:26697233

Knockdown of synaptic scaffolding protein Homer 1b/c attenuates secondary hyperalgesia induced by complete Freund's adjuvant in rats.

PubMed

Yao, Yong-Xing; Jiang, Zhen; Zhao, Zhi-Qi

2011-12-01

Previous studies have demonstrated that Homer 1b/c, a postsynaptic molecular scaffolding protein that binds and clusters metabotropic glutamate receptors at neuronal synapses, has an important role in the metabotropic glutamate receptor signaling process. In the current study, we investigated the possible involvement of Homer 1b/c in secondary hyperalgesia induced by complete Freund's adjuvant (CFA). Chronic inflammation was induced by injecting CFA into the left hind ankle of Wistar rats. Homer 1b/c antisense or missense oligonucleotides were intrathecally administrated (antisense, 10 μg/10 μL, 5 μg/10 μL, or 2.5 μg/10 μL, once a day; missense, 10 μg/10 μL) from 5 to 8 days after the onset of inflammation. The withdrawal threshold and withdrawal latency to mechanical or thermal stimuli were determined before and after the intrathecal administration. The expression and distribution of Homer 1b/c were examined in the spinal cord using immunological techniques. Mechanical allodynia and thermal hyperalgesia were induced within 24 hours and maintained for >2 weeks after the CFA injection. The expression of Homer 1b/c reached the highest level 7 days after inflammation and returned to baseline at day 28. Intrathecal administration of Homer 1b/c antisense oligonucleotides markedly reduced the expression of Homer 1b/c protein in the spinal cord. Additionally, administration of Homer 1b/c antisense oligonucleotides attenuated secondary mechanical hypersensitization on days 2 to 5 and reduced thermal hypersensitization on days 3 to 4. There were no effects of missense oligonucleotides on hypersensitization and the expression of Homer 1b/c. In the naïve rats, Homer 1b/c antisense oligonucleotides did not affect the mechanical and thermal responses or locomotor activity. These novel results demonstrate that Homer 1b/c in the spinal cord contributes to the maintenance of secondary hyperalgesia induced by CFA and suggest that Homer 1b/c may be a novel target for pain

Spinal gap junctions: potential involvement in pain facilitation.

PubMed

Spataro, Leah E; Sloane, Evan M; Milligan, Erin D; Wieseler-Frank, Julie; Schoeniger, Diana; Jekich, Brian M; Barrientos, Ruth M; Maier, Steven F; Watkins, Linda R

2004-09-01

Glia are now recognized as important contributors in pathological pain creation and maintenance. Spinal cord glia exhibit extensive gap junctional connectivity, raising the possibility that glia are involved in the contralateral spread of excitation resulting in mirror image pain. In the present experiments, the gap junction decoupler carbenoxolone was administered intrathecally after induction of neuropathic pain in response to sciatic nerve inflammation (sciatic inflammatory neuropathy) or partial nerve injury (chronic constriction injury). In both neuropathic pain models, a low dose of carbenoxolone reversed mirror image mechanical allodynia, while leaving ipsilateral mechanical allodynia unaffected. Ipsilateral thermal hyperalgesia was briefly attenuated. Critically, blockade of mechanical allodynia and thermal hyperalgesia was not observed in response to intrathecal glycyrrhizic acid, a compound similar to carbenoxolone in all respects but it does not decouple gap junctions. Thus, blockade of mechanical allodynia and thermal hyperalgesia by carbenoxolone does appear to reflect an effect on gap junctions. Examination of carbenoxolone's effects on intrathecal human immunodeficiency virus type 1 gp120 showed that blockade of pain facilitation might result, at least in part, via suppression of interleukin-1 and, in turn, interleukin-6. These data provide the first suggestion that spread of excitation via gap junctions might contribute importantly to inflammatory and traumatic neuropathic pain. The current studies provide evidence for involvement of gap junctions in spinal cord pain facilitation. Intrathecal carbenoxolone, a gap junction decoupler, reversed neuropathy-induced mirror image pain and intrathecal gp120-induced allodynia. In addition, it decreased gp120-induced proinflammatory cytokines. This suggests gap junction activation might lead to proinflammatory cytokine release by distantly activated glia.

Local administration of mangiferin prevents experimental inflammatory mechanical hyperalgesia through CINC-1/epinephrine/PKA pathway and TNF-α inhibition.

PubMed

Rocha, Lilian Wünsch; Bonet, Ivan José Magayewski; Tambeli, Claudia Herrera; de-Faria, Felipe Meira; Parada, Carlos Amilcar

2018-07-05

Steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to control inflammatory pain, but there is a risk of gastrointestinal bleeding and increased heart failure risk. The search for new drugs remains ongoing, and natural products are a source for potential new compounds. Mangiferin, a natural xanthone C-glucoside, has demonstrated biological activity, including anti-inflammatory and analgesic properties, but it's mechanisms are poorly understood. In this study, we investigated the mechanisms underlying the anti-inflammatory and analgesic effects of local administration of mangiferin. We employed an electronic von Frey apparatus to evaluate mechanical hyperalgesia induced by carrageenan in rats. Mangiferin (150-1200 µg/paw), administered locally into the hindpaw, prevented hyperalgesia in a dose-dependent - 150 µg (- 9%), 300 µg (- 27%, P < 0.01), 600 µg (- 77%, P < 0.001) and 1000 µg (- 93%, P < 0.001) - and local manner. Mangiferin showed decreased levels of TNF-α (P < 0.001) and CINC-1 (P < 0.001), but not IL-1β; it also prevented neutrophil migration (P < 0.01), but not the increased COX-2 expression in peripheral tissue challenged with carrageenan. To further explore the mechanisms of mangiferin actions, rats were injected with modulators of inflammation and nociception; mangiferin prevented hyperalgesia induced by IL-1β (P < 0.01), CINC-1 (P < 0.01), epinephrine (P < 0.01), 8-Br-cAMP (P < 0.01) or capsaicin (P < 0.01), but not that induced by PGE 2 or α,β-MeATP. Our study shows that mangiferin has anti-inflammatory and analgesic properties when locally administrated. The control of the inflammatory response and mechanical hyperalgesia by mangiferin depends on the inhibition of TNF-α production/release and the CINC1/epinephrine/PKA pathway, supporting its marked inhibition of inflammatory mechanical hyperalgesia. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of removal of dietary polyunsaturated fatty acids on plasma extravasation and mechanical allodynia in a trigeminal neuropathic pain model

PubMed Central

Martin, Yasmina B; Avendaño, Carlos

2009-01-01

Background Neuropathic pain (NP) is partially mediated by neuroinflammatory mechanisms, and also modulates local neurogenic inflammation. Dietary lipids, in particular the total amount and relative proportions of polyunsaturated fatty acids (PUFAs) of the ω-3 and ω-6 families, have been reported to modify the threshold for thermal and mechanical allodynia in the partial sciatic nerve ligation model of NP in rats. The effects of dietary lipids on other popular NP models, such as the chronic constriction injury (CCI), have not yet been examined. It is also unknown whether dietary PUFAs exert any effect on the capsaicin (CAP)-induced neurogenic inflammation under control or NP conditions. In this study we investigated these interrelated phenomena in the trigeminal territory, which has been much less explored, and for which not all data derived from limb nerves can be directly applied. Results We studied the effects of a CCI of the infraorbital nerve (IoN) on the development of mechanical allodynia and CAP-induced plasma extravasation in rats fed either a regular diet (RD), or a modified diet (MD) with much lower total content and ω-3:ω-6 ratio of PUFAs. In rats kept on MD, mechanical allodynia following CCI-IoN was more pronounced and developed earlier. Extravasation was substantially increased in naive rats fed MD, and displayed differential diet-depending changes one and four weeks after CCI-IoN. When compared with basal levels (in naive and/or sham cases), the net effect of CCI-IoN on ipsilateral extravasation was a reduction in the MD group, but an increase in the RD group, effectively neutralizing the original intergroup differences. Conclusion In summary, PUFA intake reduces CAP-induced neurogenic plasma extravasation in the trigeminal territory, and their removal significantly alters the mechanical allodynia and the plasma extravasation that result from a unilateral CCI-IoN. It is likely that this "protective" effect of dietary lipids is temporary. Also

Serotonergic mechanism of the relieving effect of bee venom acupuncture on oxaliplatin-induced neuropathic cold allodynia in rats.

PubMed

Lee, Ji-Hye; Li, Dong Xing; Yoon, Heera; Go, Donghyun; Quan, Fu Shi; Min, Byung-Il; Kim, Sun Kwang

2014-12-06

Oxaliplatin, an important chemotherapy drug for advanced colorectal cancer, often induces peripheral neuropathy, especially cold allodynia. Our previous study showed that bee venom acupuncture (BVA), which has been traditionally used in Korea to treat various pain symptoms, potently relieves oxaliplatin-induced cold allodynia in rats. However, the mechanism for this anti-allodynic effect of BVA remains poorly understood. We investigated whether and how the central serotonergic system, a well-known pathway for acupuncture analgesia, mediates the relieving effect of BVA on cold allodynia in oxaliplatin-injected rats. The behavioral signs of cold allodynia in Sprague-Dawley (SD) rats were induced by a single injection of oxaliplatin (6 mg/kg, i.p.). Before and after BVA treatment, the cold allodynia signs were evaluated by immersing the rat's tail into cold water (4°C) and measuring the withdrawal latency. For BVA treatment, a diluted BV (0.25 mg/kg) was subcutaneously administered into Yaoyangguan (GV3) acupoint, which is located between the spinous processes of the fourth and the fifth lumbar vertebra. Serotonin was depleted by a daily injection of DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for 3 days. The amount of serotonin in the spinal cord was measured by ELISA. Serotonergic receptor antagonists were administered intraperitoneally or intrathecally before BVA treatment. The serotonin levels in the spinal cord were significantly increased by BVA treatment and such increase was significantly reduced by PCPA. This PCPA pretreatment abolished the relieving effect of BVA on oxaliplatin-induced cold allodynia. Either of methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 1 mg/kg, i.p.) or MDL-72222 (5-HT3 receptor antagonist, 1 mg/kg, i.p) blocked the anti-allodynic effect of BVA. Further, an intrathecal injection of MDL-72222 (12 μg) completely blocked the BVA-induced anti-allodynic action, whereas NAN-190 (5-HT1A receptor antagonist, 15 μg, i.t.) or

Differential coding of hyperalgesia in the human brain: a functional MRI study.

PubMed

Maihöfner, Christian; Handwerker, Hermann O

2005-12-01

Neuropathic pain can be both ongoing or stimulus-induced. Stimulus-induced pain, also known as hyperalgesia, can be differentiated into primary and secondary hyperalgesia. The former results from sensitization of peripheral nociceptive structures, the latter involves sensitization processes within the central nervous system (CNS). Hypersensitivity towards heat stimuli, i.e. thermal hyperalgesia, is a key feature of primary hyperalgesia, whereas secondary hyperalgesia is characterized by hypersensitivity towards mechanical (e.g. pin-prick) stimulation. Using functional magnetic resonance imaging (fMRI), we investigated if brain activation patterns associated with primary and secondary hyperalgesia might differ. Thermal and pin-prick hyperalgesia were induced on the left forearm in 12 healthy subjects by topical capsaicin (2.5%, 30 min) application. Equal pain intensities of both hyperalgesia types were applied during fMRI experiments, based on previous quantitative sensory testing. Simultaneously, subjects had to rate the unpleasantness of stimulus-related pain. Pin-prick hyperalgesia (i.e. subtraction of brain activations during pin-prick stimulation before and after capsaicin exposure) led to activations of primary and secondary somatosensory cortices (S1 and S2), associative-somatosensory cortices, insula and superior and inferior frontal cortices (SFC, IFC). Brain areas activated during thermal hyperalgesia (i.e. subtraction of brain activations during thermal stimulation before and after capsaicin exposure) were S1 and S2, insula, associative-somatosensory cortices, cingulate cortex (GC), SFC, middle frontal cortex (MFC) and IFC. When compared to pin-prick hyperalgesia, thermal hyperalgesia led to an increased activation of bilateral anterior insular cortices, MFC, GC (Brodmann area 24' and 32') and contralateral SFC and IFC, despite equal pain intensities. Interestingly, stronger activations of GC, contralateral MFC and anterior insula significantly correlated

Advanced oxidation protein products sensitized the transient receptor potential vanilloid 1 via NADPH oxidase 1 and 4 to cause mechanical hyperalgesia.

PubMed

Ding, Ruoting; Jiang, Hui; Sun, Baihui; Wu, Xiaoliang; Li, Wei; Zhu, Siyuan; Liao, Congrui; Zhong, Zhaoming; Chen, Jianting

2016-12-01

Oxidative stress is a possible pathogenesis of hyperalgesia. Advanced oxidation protein products (AOPPs), a new family of oxidized protein compounds, have been considered as a novel marker of oxidative stress. However, the role of AOPPs in the mechanism of hyperalgesia remains unknown. Our study aims to investigate whether AOPPs have an effect on hyperalgesia and the possible underlying mechanisms. To identify the AOPPs involved, we induced hyperalgesia in rats by injecting complete Freund's adjuvant (CFA) in hindpaw. The level of plasma AOPPs in CFA-induced rats was 1.6-fold in comparison with what in normal rats (P<0.05). After intravenous injection of AOPPs-modified rat serum albumin (AOPPs-RSA) in Sprague-Dawley rats, the paw mechanical thresholds, measured by the electronic von Frey system, significantly declined. Immunofluorescence staining indicated that AOPPs increased expressions of NADPH oxidase 1 (Nox1), NADPH oxidase 4 (Nox4), transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) in the dorsal root ganglia (DRG) tissues. In-vitro studies were performed on primary DRG neurons which were obtained from both thoracic and lumbar DRG of rats. Results indicated that AOPPs triggered reactive oxygen species (ROS) production in DRG neurons, which were significantly abolished by ROS scavenger N-acetyl-l-cysteine (NAC) and small-interfering RNA (siRNA) silencing of Nox1 or Nox4. The expressions of Nox1, Nox4, TRPV1 and CGRP were significantly increased in AOPPs-induced DRG neurons. And relevant siRNA or inhibitors notably suppressed the expressions of these proteins and the calcium influxes in AOPPs-induced DRG neurons. In conclusion, AOPPs increased significantly in CFA-induced hyperalgesia rats and they activated Nox1/Nox4-ROS to sensitize TRPV1-dependent Ca2+ influx and CGRP release which led to inducing mechanical hyperalgesia. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2/3 receptors on nociceptors.

PubMed

Joseph, Elizabeth K; Green, Paul G; Bogen, Oliver; Alvarez, Pedro; Levine, Jon D

2013-02-13

Endothelin-1 (ET-1) is unique among a broad range of hyperalgesic agents in that it induces hyperalgesia in rats that is markedly enhanced by repeated mechanical stimulation at the site of administration. Antagonists to the ET-1 receptors, ET(A) and ET(B), attenuated both initial as well as stimulation-induced enhancement of hyperalgesia (SIEH) by endothelin. However, administering antisense oligodeoxynucleotide to attenuate ET(A) receptor expression on nociceptors attenuated ET-1 hyperalgesia but had no effect on SIEH, suggesting that this is mediated via a non-neuronal cell. Because vascular endothelial cells are both stretch sensitive and express ET(A) and ET(B) receptors, we tested the hypothesis that SIEH is dependent on endothelial cells by impairing vascular endothelial function with octoxynol-9 administration; this procedure eliminated SIEH without attenuating ET-1 hyperalgesia. A role for protein kinase Cε (PKCε), a second messenger implicated in the induction and maintenance of chronic pain, was explored. Intrathecal antisense for PKCε did not inhibit either ET-1 hyperalgesia or SIEH, suggesting no role for neuronal PKCε; however, administration of a PKCε inhibitor at the site of testing selectively attenuated SIEH. Compatible with endothelial cells releasing ATP in response to mechanical stimulation, P2X(2/3) receptor antagonists eliminated SIEH. The endothelium also appears to contribute to hyperalgesia in two ergonomic pain models (eccentric exercise and hindlimb vibration) and in a model of endometriosis. We propose that SIEH is produced by an effect of ET-1 on vascular endothelial cells, sensitizing its release of ATP in response to mechanical stimulation; ATP in turn acts at the nociceptor P2X(2/3) receptor.

Antinociceptive and antiallodynic effects of Momordica charantia L. in tibial and sural nerve transection-induced neuropathic pain in rats.

PubMed

Jain, Vivek; Pareek, Ashutosh; Paliwal, Nishant; Ratan, Yashumati; Jaggi, Amteshwar Singh; Singh, Nirmal

2014-02-01

This study was designed to investigate the ameliorative potential of Momordica charantia L. (MC) in tibial and sural nerve transection (TST)-induced neuropathic pain in rats. TST was performed by sectioning tibial and sural nerve portions (2 mm) of the sciatic nerve, and leaving the common peroneal nerve intact. Acetone drop, pin-prick, hot plate, paint-brush, and walking track tests were performed to assess cold allodynia, mechanical and heat hyperalgesia, and dynamic mechanical allodynia and tibial functional index, respectively. The levels of tumour necrosis factor (TNF)-alpha and thio-barbituric acid reactive substances (TBARS) were measured in the sciatic nerve as an index of inflammation and oxidative stress. MC (all doses, orally, once daily) was administered to the rats for 24 consecutive days. TST led to significant development of cold allodynia, mechanical and heat hyperalgesia, dynamic mechanical allodynia, and functional deficit in walking along with rise in the levels of TBARS and TNF-alpha. Administration of MC (200, 400, and 800 mg/kg) significantly attenuated TST-induced behavioural and biochemical changes. Furthermore, pretreatment of BADGE (120 mg/kg, intraperitoneally) abolished the protective effect of MC in TST-induced neuropathic pain. Collectively, it is speculated that PPAR-gamma agonistic activity, anti-inflammatory, and antioxidative potential is critical for antinociceptive effect of MC in neuropathic pain.

Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy.

PubMed

Singhmar, Pooja; Huo, XiaoJiao; Li, Yan; Dougherty, Patrick M; Mei, Fang; Cheng, Xiaodong; Heijnen, Cobi J; Kavelaars, Annemieke

2018-05-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer treatment that significantly compromises quality of life of cancer patients and survivors. Identification of targets for pharmacological intervention to prevent or reverse CIPN is needed. We investigated exchange protein regulated by cAMP (Epac) as a potential target. Epacs are cAMP-binding proteins known to play a pivotal role in mechanical allodynia induced by nerve injury and inflammation. We demonstrate that global Epac1-knockout (Epac1-/-) male and female mice are protected against paclitaxel-induced mechanical allodynia. In addition, spinal cord astrocyte activation and intraepidermal nerve fiber (IENF) loss are significantly reduced in Epac1-/- mice as compared to wild-type mice. Moreover, Epac1-/- mice do not develop the paclitaxel-induced deficits in mitochondrial bioenergetics in the sciatic nerve that are a hallmark of CIPN. Notably, mice with cell-specific deletion of Epac1 in Nav1.8-positive neurons (N-Epac1-/-) also show reduced paclitaxel-induced mechanical allodynia, astrocyte activation, and IENF loss, indicating that CIPN develops downstream of Epac1 activation in nociceptors. The Epac-inhibitor ESI-09 reversed established paclitaxel-induced mechanical allodynia in wild-type mice even when dosing started 10 days after completion of paclitaxel treatment. In addition, oral administration of ESI-09 suppressed spinal cord astrocyte activation in the spinal cord and protected against IENF loss. Ex vivo, ESI-09 blocked paclitaxel-induced abnormal spontaneous discharges in dorsal root ganglion neurons. Collectively, these findings implicate Epac1 in nociceptors as a novel target for treatment of CIPN. This is clinically relevant because ESI-09 has the potential to reverse a debilitating and long-lasting side effect of cancer treatment.

PHARMACOLOGIC TREATMENT OF HYPERALGESIA EXPERIMENTALLY INDUCED BY NUCLEUS PULPOSUS

PubMed Central

de Souza Grava, André Luiz; Ferrari, Luiz Fernando; Parada, Carlos Amílcar; Defino, Helton Luiz Aparecido

2015-01-01

Objective: To evaluate the effect of anti-inflammatory drugs (dexamethasone, indomethacin, atenolol and indomethacin plus atenolol) and analgesic drugs (morphine) on hyperalgesia experimentally induced by the nucleus pulposus (NP) in contact with the L5 dorsal root ganglion (DRG). Methods: Thirty male Wistar rats of weights ranging from 220 to 250 g were used in the study. Hyperalgesia was induced by means of a fragment of NP removed from the sacrococcygeal region that was placed in contact with the L5 dorsal root ganglion. The 30 animals were divided into experimental groups according to the drug used. The drugs were administered for two weeks after the surgical procedure to induce hyperalgesia. Mechanical and thermal hyperalgesia was evaluated using the paw pressure test, von Frey electronic test and Hargreaves test, over a seven-week period. Results: The greatest reduction of hyperalgesia was observed in the group of animals treated with morphine, followed by dexamethasone, indomethacin and atenolol. Reductions in hyperalgesia were observed after drug administration ceased, except for the group of animals treated with morphine, in which there was an increase in hyperalgesia after discontinuation of the treatment. Conclusion: Hyperalgesia induced by NP contact with the DRG can be reduced through administration of anti-inflammatory and analgesic drugs, but a greater reduction was observed with the administration of dexamethasone. PMID:27026966

Contribution of capsaicin-sensitive primary afferents to mechanical hyperalgesia induced by ventral root transection in rats: the possible role of BDNF.

PubMed

Li, Wei; Wang, Jian-Xiu; Zhou, Zhong-He; Lu, Yao; Li, Xiao-Qiu; Liu, Bao-Jun; Chen, Hui-Sheng

2016-01-01

A recent study showed that brain-derived neurotrophic factor (BDNF) may play a role in the development of the neuropathic pain resulting from injury to motor efferent fibres, such as that in the ventral root transection (VRT) model. Capsaicin stimulation of afferent fibres was also shown to result in the release of BDNF into the spinal cord. Here, the effects of ablation of capsaicin-sensitive primary afferents (CSPAs) by local application of capsaicin on the sciatic nerve on VRT-induced mechanical hyperalgesia were observed. The paw withdrawal mechanical threshold (PWMT) was measured before and then 1 and 3 days and 1, 2, 3, 4 and 6 weeks after VRT. The results showed that local application of capsaicin significantly inhibited the decrease in the PWMT induced by VRT, suggesting the inhibitory effect of locally delivered capsaicin. Furthermore, intrathecal administration of exogenous BDNF not only produced mechanical hyperalgesia but also significantly blocked the inhibitory effect of capsaicin. Taken together, the results of this study suggest that CSPA fibres may contribute to mechanical hyperalgesia in the VRT model.

The transient receptor potential ankyrin-1 mediates mechanical hyperalgesia induced by the activation of B1 receptor in mice.

PubMed

Meotti, Flavia Carla; Figueiredo, Cláudia Pinto; Manjavachi, Marianne; Calixto, João B

2017-02-01

The kinin receptor B 1 and the transient receptor potential ankyrin 1 (TRPA1) work as initiators and gatekeepers of nociception and inflammation. This study reports that the nociceptive transmission induced by activation of B 1 receptor is dependent on TRPA1 ion channel. The mechanical hyperalgesia was induced by intrathecal (i.t.) injection of B 1 agonist des-Arginine 9 -bradykinin (DABK) or TRPA1 agonist cinnamaldehyde and was evaluated by the withdrawal response after von Frey Hair application in the hind paw. After behavioral experiments, lumbar spinal cord and dorsal root ganglia (DRG) were harvested to assess protein expression and mRNA by immunohistochemistry and real time-PCR, respectively. The pharmacological antagonism (HC030031) or the down-regulation of TRPA1 greatly inhibited the mechanical hyperalgesia induced by DABK. Intrathecal injection of DABK up regulated the ionized calcium binding adaptor molecule (Iba-1) in lumbar spinal cord (L5-L6); TRPA1 protein and mRNA in lumbar spinal cord; and B 1 receptor mRNA in both lumbar spinal cord and DRG. The knockdown of TRPA1 prevented microglia activation induced by DABK. Furthermore, the mechanical hyperalgesia induced by either DABK or by cinnamaldehyde was significantly reduced by inhibition of cyclooxygenase (COX), protein kinase C (PKC) or phospholipase C (PLC). In summary, this study revealed that TRPA1 positively modulates the mechanical hyperalgesia induced by B 1 receptor activation in the spinal cord and that the classical GPCR downstream molecules PLC, diacylglycerol (DAG), 3,4,5-inositide phosphate (IP 3 ) and PKC are involved in the nociceptive transmission triggered by these two receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

Fast non-genomic effects of progesterone-derived neurosteroids on nociceptive thresholds and pain symptoms.

PubMed

Charlet, Alexandre; Lasbennes, François; Darbon, Pascal; Poisbeau, Pierrick

2008-10-31

Fast Inhibitory controls mediated by glycine (GlyRs) and GABAA receptors (GABAARs) play an important role to prevent the apparition of pathological pain symptoms of allodynia and hyperalgesia. The use of positive allosteric modulators of these receptors, specifically expressed in the spinal cord, may represent an interesting strategy to limit or block pain expression. In this study, we have used stereoisomers of progesterone metabolites, acting only via non-genomic effects, in order to evaluate the contribution of GlyRs and GABAARs for the reduction of mechanical and thermal heat hypernociception. We show that 3alpha neurosteroids were particularly efficient to elevate nociceptive thresholds in naive animal. It also reduced mechanical allodynia and thermal heat hyperalgesia in the carrageenan model of inflammatory pain. This effect is likely to be mediated by GABAA receptors since 3beta isomer was inefficient. More interestingly, 3alpha5beta neurosteroid was only efficient on mechanical allodynia while having no effect on thermal heat hyperalgesia. We characterized these paradoxical effects of 3alpha5beta neurosteroid using the strychnine and bicuculline models of allodynia. We clearly show that 3alpha5beta neurosteroid exerts an antinociceptive effect via a positive allosteric modulation of GABAARs but, at the same time, is pronociceptive by reducing GlyR function. This illustrates the importance of the inhibitory amino acid receptor channels and their allosteric modulators in spinal pain processing. Moreover, our results indicate that neurosteroids, which are synthesized in the dorsal horn of the spinal cord and have limited side effects, may be of significant interest in order to treat pathological pain symptoms.

One night of total sleep deprivation promotes a state of generalized hyperalgesia: a surrogate pain model to study the relationship of insomnia and pain.

PubMed

Schuh-Hofer, Sigrid; Wodarski, Rachel; Pfau, Doreen B; Caspani, Ombretta; Magerl, Walter; Kennedy, Jeffrey D; Treede, Rolf-Detlef

2013-09-01

Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5 ± 4.1 year; mean ± SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P<0.001) and resulted in higher scores of the State Anxiety Inventory (P<0.01). In addition to previously reported hyperalgesia to heat (P<0.05) and blunt pressure (P<0.05), study participants developed hyperalgesia to cold (P<0.01) and increased mechanical pain sensitivity to pinprick stimuli (P<0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Pulsed radiofrequency reduced complete Freund's adjuvant-induced mechanical hyperalgesia via the spinal c-Jun N-terminal kinase pathway.

PubMed

Chen, Kuan-Hung; Yang, Chien-Hui; Juang, Sin-Ei; Huang, Hui-Wen; Cheng, Jen-Kun; Sheen-Chen, Shyr-Ming; Cheng, Jiin-Tsuey; Lin, Chung-Ren

2014-03-01

Pulsed radiofrequency (PRF) treatment involves the pulsed application of a radiofrequency electric field to a nerve. The technology offers pain relief for patients suffering from chronic pain who do not respond well to conventional treatments. We tested whether PRF treatment attenuated complete Freund's adjuvant (CFA) induced inflammatory pain. The profile of spinal c-Jun N-terminal kinases (JNKs) phosphorylation was evaluated to elucidate the potential mechanism. Injection of CFA into the unilateral hind paw of rats induced mechanical hyperalgesia in both the ipsilateral and contralateral hind paws. We administered 500-kHz PRF treatment in 20-ms pulses, at a rate of 2 Hz (2 pulses per second) either to the sciatic nerve in the mid-thigh, or to the L4 anterior primary ramus just distal to the intervertebral foramen in both the CFA group and no-PRF group rats. Tissue samples were examined at 1, 3, 7, and 14 days following PRF treatments. Behavioral studies showed that PRF applied close to the dorsal root ganglion (DRG) significantly attenuated CFA-induced mechanical hyperalgesia compared to no-PRF group (P < .05). And western blotting revealed significant attenuation of the activation of JNK in the spinal dorsal horn compared to no-PRF group animals (P < .05). Application of PRF close to DRG provides an effective treatment for CFA-induced persistent mechanical hyperalgesia by attenuating JNK activation in the spinal dorsal horn.

Upregulation of EMMPRIN (OX47) in Rat Dorsal Root Ganglion Contributes to the Development of Mechanical Allodynia after Nerve Injury.

PubMed

Wang, Qun; Sun, Yanyuan; Ren, Yingna; Gao, Yandong; Tian, Li; Liu, Yang; Pu, Yanan; Gou, Xingchun; Chen, Yanke; Lu, Yan

2015-01-01

Matrix metalloproteinases (MMPs) are widely implicated in inflammation and tissue remodeling associated with various neurodegenerative diseases and play an important role in nociception and allodynia. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) plays a key regulatory role for MMP activities. However, the role of EMMPRIN in the development of neuropathic pain is not clear. Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunofluorescence were performed to determine the changes of messenger RNA and protein of EMMPRIN/OX47 and their cellular localization in the rat dorsal root ganglion (DRG) after nerve injury. Paw withdrawal threshold test was examined to evaluate the pain behavior in spinal nerve ligation (SNL) model. The lentivirus containing OX47 shRNA was injected into the DRG one day before SNL. The expression level of both mRNA and protein of OX47 was markedly upregulated in ipsilateral DRG after SNL. OX47 was mainly expressed in the extracellular matrix of DRG. Administration of shRNA targeted against OX47 in vivo remarkably attenuated mechanical allodynia induced by SNL. In conclusion, peripheral nerve injury induced upregulation of OX47 in the extracellular matrix of DRG. RNA interference against OX47 significantly suppressed the expression of OX47 mRNA and the development of mechanical allodynia. The altered expression of OX47 may contribute to the development of neuropathic pain after nerve injury.

Sickle cell mice exhibit mechanical allodynia and enhanced responsiveness in light touch cutaneous mechanoreceptors

PubMed Central

2012-01-01

Background Sickle cell disease (SCD) is associated with both acute vaso-occlusive painful events as well as chronic pain syndromes, including heightened sensitivity to touch. We have previously shown that mice with severe SCD (HbSS mice; express 100% human sickle hemoglobin in red blood cells; RBCs) have sensitized nociceptors, which contribute to increased mechanical sensitivity. Yet, the hypersensitivity in these neural populations alone may not fully explain the mechanical allodynia phenotype in mouse and humans. Findings Using the Light Touch Behavioral Assay, we found HbSS mice exhibited increased responses to repeated application of both innocuous punctate and dynamic force compared to control HbAA mice (100% normal human hemoglobin). HbSS mice exhibited a 2-fold increase in percent response to a 0.7mN von Frey monofilament when compared to control HbAA mice. Moreover, HbSS mice exhibited a 1.7-fold increase in percent response to the dynamic light touch “puffed” cotton swab stimulus. We further investigated the mechanisms that drive this behavioral phenotype by focusing on the cutaneous sensory neurons that primarily transduce innocuous, light touch. Low threshold cutaneous afferents from HbSS mice exhibited sensitization to mechanical stimuli that manifested as an increase in the number of evoked action potentials to suprathreshold force. Rapidly adapting (RA) Aβ and Aδ D-hair fibers showed the greatest sensitization, each with a 75% increase in suprathreshold firing compared to controls. Slowly adapting (SA) Aβ afferents had a 25% increase in suprathreshold firing compared to HbAA controls. Conclusions These novel findings demonstrate mice with severe SCD exhibit mechanical allodynia to both punctate and dynamic light touch and suggest that this behavioral phenotype may be mediated in part by the sensitization of light touch cutaneous afferent fibers to suprathreshold force. These findings indicate that Aβ fibers can be sensitized to mechanical

Supradural inflammatory soup in awake and freely moving rats induces facial allodynia that is blocked by putative immune modulators.

PubMed

Wieseler, Julie; Ellis, Amanda; McFadden, Andrew; Stone, Kendra; Brown, Kimberley; Cady, Sara; Bastos, Leandro F; Sprunger, David; Rezvani, Niloofar; Johnson, Kirk; Rice, Kenner C; Maier, Steven F; Watkins, Linda R

2017-06-01

Facial allodynia is a migraine symptom that is generally considered to represent a pivotal point in migraine progression. Treatment before development of facial allodynia tends to be more successful than treatment afterwards. As such, understanding the underlying mechanisms of facial allodynia may lead to a better understanding of the mechanisms underlying migraine. Migraine facial allodynia is modeled by applying inflammatory soup (histamine, bradykinin, serotonin, prostaglandin E2) over the dura. Whether glial and/or immune activation contributes to such pain is unknown. Here we tested if trigeminal nucleus caudalis (Sp5C) glial and/or immune cells are activated following supradural inflammatory soup, and if putative glial/immune inhibitors suppress the consequent facial allodynia. Inflammatory soup was administered via bilateral indwelling supradural catheters in freely moving rats, inducing robust and reliable facial allodynia. Gene expression for microglial/macrophage activation markers, interleukin-1β, and tumor necrosis factor-α increased following inflammatory soup along with robust expression of facial allodynia. This provided the basis for pursuing studies of the behavioral effects of 3 diverse immunomodulatory drugs on facial allodynia. Pretreatment with either of two compounds broadly used as putative glial/immune inhibitors (minocycline, ibudilast) prevented the development of facial allodynia, as did treatment after supradural inflammatory soup but prior to the expression of facial allodynia. Lastly, the toll-like receptor 4 (TLR4) antagonist (+)-naltrexone likewise blocked development of facial allodynia after supradural inflammatory soup. Taken together, these exploratory data support that activated glia and/or immune cells may drive the development of facial allodynia in response to supradural inflammatory soup in unanesthetized male rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation.

PubMed

Baron, R; Wasner, G; Borgstedt, R; Hastedt, E; Schulte, H; Binder, A; Kopper, F; Rowbotham, M; Levine, J D; Fields, H L

1999-03-23

Painful nerve and tissue injuries can be exacerbated by activity in sympathetic neurons. The mechanisms of sympathetically maintained pain (SMP) are unclear. To determine the effect of cutaneous sympathetic activity on pain induced by primary afferent C-nociceptor sensitization with capsaicin in humans. In healthy volunteers capsaicin was applied topically (n = 12) or injected into the forearm skin (n = 10) to induce spontaneous pain, dynamic and punctate mechanical hyperalgesia, and antidromic (axon reflex) vasodilatation (flare). Intensity of pain and hyperalgesia, axon reflex vasodilatation (laser Doppler), and flare size and area of hyperalgesia (planimetry) were assessed. The local skin temperature at the application and measurement sites was kept constant at 35 degrees C. In each individual the analyses were performed during the presence of high and low sympathetic skin activity induced by whole-body cooling and warming with a thermal suit. By this method sympathetic vasoconstrictor activity is modulated in the widest range that can be achieved physiologically. The degree of vasoconstrictor discharge was monitored by measuring skin blood flow (laser Doppler) and temperature (infrared thermometry) at the index finger. The intensity and spatial distribution of capsaicin-evoked spontaneous pain and dynamic and punctate mechanical hyperalgesia were identical during the presence of high and low sympathetic discharge. Antidromic vasodilatation and flare size were significantly diminished when sympathetic vasoconstrictor neurons were excited. Cutaneous sympathetic vasoconstrictor activity does not influence spontaneous pain and mechanical hyperalgesia after capsaicin-induced C-nociceptor sensitization. When using physiologic stimulation of sympathetic activity, the capsaicin model is not useful for elucidating mechanisms of SMP. In neuropathic pain states with SMP, different mechanisms may be present.

The perception threshold counterpart to dynamic and static mechanical allodynia assessed using von Frey filaments in peripheral neuropathic pain patients.

PubMed

Landerholm, Åsa H; Hansson, Per T

2017-12-29

Background and aim Pain due to a usually non-painful mechanical stimulus, mechanical allodynia, is an oppressive symptom in subgroups of patients with neuropathic pain. Dynamic mechanical allodynia (DMA) is evoked by a normally innocuous light moving mechanical stimulus on the skin and static mechanical allodynia (SMA) by a sustained, normally innocuous pressure against the skin. DMA is claimed to be mediated by myelinated fibres and SMA by C-fibres. Also A-delta fibres have been implicated in the static subtype. A low intensity vertically applied stimulus of 1 second (s) is expected to activate predominantly rapidly adapting A-beta mechanoreceptors thus recruiting the same peripheral substrate as a horizontally moving brush on top of the skin. In patients with SMA we assumed an activation of Cbut also A-delta fibres from a static 10 s von Frey filament stimulus. The aim was to investigate if DMA and SMA could be assessed at perception threshold level using short or longer lasting usually non-painful von Frey filament prodding of the neuropathic skin. Patients and methods Eighteen patients with painful unilateral partial peripheral traumatic nerve injury suffering from SMA (n = 9) and/or DMA (n = 18) in a limb were studied. A compression/ischemia-induced (differential) nerve block in conjunction with repeated quantitative sensory testing of A-delta and C-fibre function using cold and warm stimuli was used to assess which nerve fibre population that contributes to pain at perception threshold level using 1 s (vF1) and 10 s (vF10) von Frey filament stimulation of the skin. Results The main outcome was the finding that elevation of vF1 and vF10 occurred simultaneously and significantly prior to an increase in the perception level to cold or warmth during the continuous nerve block. Single patients demonstrated a slight decrease in cold perception levels at the time of elevation of vF1 or vF10 and a possible contribution to mechanical allodynia from A-delta-fibres can

TRPA1, NMDA receptors and nitric oxide mediate mechanical hyperalgesia induced by local injection of magnesium sulfate into the rat hind paw.

PubMed

Srebro, Dragana P; Vučković, Sonja M; Savić Vujović, Katarina R; Prostran, Milica Š

2015-02-01

Previous studies have shown that while magnesium, an antagonist of the glutamate subtype of N-methyl-D-aspartate receptors, possesses analgesic properties, it can induce writhing in rodents. The aim of this study was to determine the effect and mechanism of action of local (intraplantar) administration of magnesium sulfate (MS) on the paw withdrawal threshold (PWT) to mechanical stimuli. The PWT was evaluated by the electronic von Frey test in male Wistar rats. Tested drugs were either co-administered intraplantarly (i.pl.) with MS or given into the contralateral paw to exclude systemic effects. MS at doses of 0.5, 1.5, 3 and 6.2 mg/paw (i.pl.) induced a statistically significant (as compared to 0.9% NaCl) and dose-dependent mechanical hyperalgesia. Only isotonic MS (250 mmol/l or 6.2% or 6.2 mg/paw) induced mechanical hyperalgesia that lasted at least six hours. Isotonic MS-induced mechanical hyperalgesia was reduced in a dose-dependent manner by co-injection of camphor, a non-selective TRPA1 antagonist (0.3, 1 and 2.5 μg/paw), MK-801, a NMDA receptor antagonist (0.001, 0.025 and 0.1 μg/paw), L-NAME, a non-selective nitric oxide (NO) synthase inhibitor (20, 50 and 100 μg/paw), ARL 17477, a selective neuronal NOS inhibitor (5.7 and 17 μg/paw), SMT, a selective inducible NOS inhibitor (1 and 2.78 μg/paw), and methylene blue, a guanylate cyclase inhibitor (5, 20 and 125 μg/paw). Drugs injected into the contralateral hind paw did not produce significant effects. These results suggest that an i.pl. injection of MS produces local peripheral mechanical hyperalgesia via activation of peripheral TRPA1 and NMDA receptors and peripheral production of NO. Copyright © 2014 Elsevier Inc. All rights reserved.

Nicotine Prevents and Reverses Paclitaxel-Induced Mechanical Allodynia in a Mouse Model of CIPN.

PubMed

Kyte, S Lauren; Toma, Wisam; Bagdas, Deniz; Meade, Julie A; Schurman, Lesley D; Lichtman, Aron H; Chen, Zhi-Jian; Del Fabbro, Egidio; Fang, Xianjun; Bigbee, John W; Damaj, M Imad; Gewirtz, David A

2018-01-01

Chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration, continues to be a dose-limiting and debilitating side effect during and/or after cancer chemotherapy. Paclitaxel, a taxane commonly used to treat breast, lung, and ovarian cancers, causes CIPN in 59-78% of cancer patients. Novel interventions are needed due to the current lack of effective CIPN treatments. Our studies were designed to investigate whether nicotine can prevent and/or reverse paclitaxel-induced peripheral neuropathy in a mouse model of CIPN, while ensuring that nicotine will not stimulate lung tumor cell proliferation or interfere with the antitumor properties of paclitaxel. Male C57BL/6J mice received paclitaxel every other day for a total of four injections (8 mg/kg, i.p.). Acute (0.3-0.9 mg/kg, i.p.) and chronic (24 mg/kg per day, s.c.) administration of nicotine respectively reversed and prevented paclitaxel-induced mechanical allodynia. Blockade of the antinociceptive effect of nicotine with mecamylamine and methyllycaconitine suggests that the reversal of paclitaxel-induced mechanical allodynia is primarily mediated by the α 7 nicotinic acetylcholine receptor subtype. Chronic nicotine treatment also prevented paclitaxel-induced intraepidermal nerve fiber loss. Notably, nicotine neither promoted proliferation of A549 and H460 non-small cell lung cancer cells nor interfered with paclitaxel-induced antitumor effects, including apoptosis. Most importantly, chronic nicotine administration did not enhance Lewis lung carcinoma tumor growth in C57BL/6J mice. These data suggest that the nicotinic acetylcholine receptor-mediated pathways may be promising drug targets for the prevention and treatment of CIPN. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Immediate and lasting effects of a thoracic spine manipulation in a patient with signs of cervical radiculopathy and upper extremity hyperalgesia: A case report.

PubMed

Deschenes, Beth K; Zafereo, Jason

2017-01-01

Patients with cervical radiculopathy (CR) may present with accompanying symptoms of hyperalgesia, allodynia, heaviness in the arm, and non-segmental pain that do not appear to be related to a peripheral spinal nerve. These findings may suggest the presence of central or autonomic nervous system involvement, requiring a modified management approach. The purpose of this case report is to describe the treatment of a patient with signs of CR and upper extremity (UE) hyperalgesia who had a significant decrease in her UE pain and hypersensitivity after a single thoracic spine manipulation (TSM). A 48-year-old female presented to physical therapy with acute neck pain radiating into her left UE that significantly limited her ability to sleep and work. After a single TSM, the patient demonstrated immediate and lasting reduction in hyperalgesia, hypersensitivity to touch, elimination of perceived heaviness and coldness in her left UE, and improved strength in the C6-8 myotome, allowing for improved functional activity capacity and tolerance to a multi-modal PT program. Based on these results, clinicians should consider the early application of TSM in patients with CR who have atypical, widespread, or severe neurological symptoms that limit early mobilization and tolerance to treatment at the painful region.

Nerve growth factor and associated nerve sprouting contribute to local mechanical hyperalgesia in a rat model of bone injury.

PubMed

Yasui, M; Shiraishi, Y; Ozaki, N; Hayashi, K; Hori, K; Ichiyanagi, M; Sugiura, Y

2012-08-01

To clarify the mechanism of tenderness after bone injury, we investigated changes in the withdrawal threshold to mechanical stimuli, nerve distribution and nerve growth factor (NGF)-expression in a rat model of bone injury without immobilization for bone injury healing. Rats were divided into three groups as follows: (1) rats incised in the skin and periosteum, followed by drilling a hole in the tibia [bone lesion group (BLG)]; (2) those incised in the skin and periosteum without bone drilling [periosteum lesion group (PLG)]; and (3) those incised in the skin [skin lesion group (SLG)]. Mechanical hyperalgesia continued for 28 days at a lesion in the BLG, 21 days in PLG and 5 days in SLG after treatments, respectively. Endochondral ossification was observed on days 5-28 in BLG and on days 5-21 in PLG. Nerve growth appeared in deep connective tissue (DCT) at day 28 in BLG. Nerve fibres increased in both cutaneous tissue and DCT at day 7 in PLG, but they were not found at day 28. Mechanical hyperalgesia accompanied with endochondral ossification and nerve fibres increasing at the lesion in both BLG and PLG. NGF was expressed in bone-regenerating cells during the bone injury healing. Anti-NGF and trk inhibitor K252a inhibited hyperalgesia in the different time course. This study shows that localized tenderness coincides with the bone healing and involves NGF expression and nerve sprouting after bone injury. The findings present underlying mechanisms and provide pathophysiological relevance of local tenderness to determination of bone fracture and its healing. © 2011 European Federation of International Association for the Study of Pain Chapters.

Analgesic Effects of Duloxetine on Formalin-Induced Hyperalgesia and Its Underlying Mechanisms in the CeA

PubMed Central

Zhang, Lie; Yin, Jun-Bin; Hu, Wei; Zhao, Wen-Jun; Fan, Qing-Rong; Qiu, Zhi-Chun; He, Ming-Jie; Ding, Tan; Sun, Yan; Kaye, Alan D.; Wang, En-Ren

2018-01-01

In rodents, the amygdala has been proposed to serve as a key center for the nociceptive perception. Previous studies have shown that extracellular signal-regulated kinase (ERK) signaling cascade in the central nucleus of amygdala (CeA) played a functional role in inflammation-induced peripheral hypersensitivity. Duloxetine (DUL), a serotonin and noradrenaline reuptake inhibitor, produced analgesia on formalin-induced spontaneous pain behaviors. However, it is still unclear whether single DUL pretreatment influences formalin-induced hypersensitivity and what is the underlying mechanism. In the current study, we revealed that systemic pretreatment with DUL not only dose-dependently suppressed the spontaneous pain behaviors, but also relieved mechanical and thermal hypersensitivity induced by formalin hindpaw injection. Consistent with the analgesic effects of DUL on the pain behaviors, the expressions of Fos and pERK that were used to check the neuronal activities in the spinal cord and CeA were also dose-dependently reduced following DUL pretreatment. Meanwhile, no emotional aversive behaviors were observed at 24 h after formalin injection. The concentration of 5-HT in the CeA was correlated with the dose of DUL in a positive manner at 24 h after formalin injection. Direct injecting 5-HT into the CeA suppressed both the spontaneous pain behaviors and hyperalgesia induced by formalin injection. However, DUL did not have protective effects on the formalin-induced edema of hindpaw. In sum, the activation of CeA neurons may account for the transition from acute pain to long-term hyperalgesia after formalin injection. DUL may produce potent analgesic effects on the hyperalgesia and decrease the expressions of p-ERK through increasing the concentration of serotonin in the CeA. PMID:29692727

Analgesic Effects of Duloxetine on Formalin-Induced Hyperalgesia and Its Underlying Mechanisms in the CeA.

PubMed

Zhang, Lie; Yin, Jun-Bin; Hu, Wei; Zhao, Wen-Jun; Fan, Qing-Rong; Qiu, Zhi-Chun; He, Ming-Jie; Ding, Tan; Sun, Yan; Kaye, Alan D; Wang, En-Ren

2018-01-01

In rodents, the amygdala has been proposed to serve as a key center for the nociceptive perception. Previous studies have shown that extracellular signal-regulated kinase (ERK) signaling cascade in the central nucleus of amygdala (CeA) played a functional role in inflammation-induced peripheral hypersensitivity. Duloxetine (DUL), a serotonin and noradrenaline reuptake inhibitor, produced analgesia on formalin-induced spontaneous pain behaviors. However, it is still unclear whether single DUL pretreatment influences formalin-induced hypersensitivity and what is the underlying mechanism. In the current study, we revealed that systemic pretreatment with DUL not only dose-dependently suppressed the spontaneous pain behaviors, but also relieved mechanical and thermal hypersensitivity induced by formalin hindpaw injection. Consistent with the analgesic effects of DUL on the pain behaviors, the expressions of Fos and pERK that were used to check the neuronal activities in the spinal cord and CeA were also dose-dependently reduced following DUL pretreatment. Meanwhile, no emotional aversive behaviors were observed at 24 h after formalin injection. The concentration of 5-HT in the CeA was correlated with the dose of DUL in a positive manner at 24 h after formalin injection. Direct injecting 5-HT into the CeA suppressed both the spontaneous pain behaviors and hyperalgesia induced by formalin injection. However, DUL did not have protective effects on the formalin-induced edema of hindpaw. In sum, the activation of CeA neurons may account for the transition from acute pain to long-term hyperalgesia after formalin injection. DUL may produce potent analgesic effects on the hyperalgesia and decrease the expressions of p-ERK through increasing the concentration of serotonin in the CeA.

Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain.

PubMed

Hewitt, Ellen; Pitcher, Thomas; Rizoska, Biljana; Tunblad, Karin; Henderson, Ian; Sahlberg, Britt-Louise; Grabowska, Urszula; Classon, Björn; Edenius, Charlotte; Malcangio, Marzia; Lindström, Erik

2016-09-01

Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µmol/kg) and pregabalin (63-377 µmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µmol/kg) in combination with the minimum effective dose of pregabalin (75 µmol/kg) or gabapentin (146 µmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Anterior Cingulate Cortex Contributes to Alcohol Withdrawal- Induced and Socially Transferred Hyperalgesia.

PubMed

Smith, Monique L; Walcott, Andre T; Heinricher, Mary M; Ryabinin, Andrey E

2017-01-01

Pain is often described as a "biopsychosocial" process, yet social influences on pain and underlying neural mechanisms are only now receiving significant experimental attention. Expression of pain by one individual can be communicated to nearby individuals by auditory, visual, and olfactory cues. Conversely, the perception of another's pain can lead to physiological and behavioral changes in the observer, which can include induction of hyperalgesia in "bystanders" exposed to "primary" conspecifics in which hyperalgesia has been induced directly. The current studies were designed to investigate the neural mechanisms responsible for the social transfer of hyperalgesia in bystander mice housed and tested with primary mice in which hyperalgesia was induced using withdrawal (WD) from voluntary alcohol consumption. Male C57BL/6J mice undergoing WD from a two-bottle choice voluntary alcohol-drinking procedure served as the primary mice. Mice housed in the same room served as bystanders. Naïve, water-drinking controls were housed in a separate room. Immunohistochemical mapping identified significantly enhanced Fos immunoreactivity (Fos-ir) in the anterior cingulate cortex (ACC) and insula (INS) of bystander mice compared to naïve controls, and in the dorsal medial hypothalamus (DMH) of primary mice. Chemogenetic inactivation of the ACC but not primary somatosensory cortex reversed the expression of hyperalgesia in both primary and bystander mice. These studies point to an overlapping neural substrate for expression of socially transferred hyperalgesia and that expressed during alcohol WD.

Central or Peripheral Delivery of an Adenosine A1 Receptor Agonist Improves Mechanical Allodynia in a Mouse Model of Painful Diabetic Neuropathy

PubMed Central

Katz, N. K.; Ryals, J. M.; Wright, D. E.

2014-01-01

Diabetic peripheral neuropathy is a common complication of diabetes mellitus, and a significant proportion of individuals suffer debilitating pain that significantly affects their quality of life. Unfortunately, symptomatic treatment options have limited efficacy, and often carry significant risk of systemic adverse effects. Activation of the adenosine A1 receptor (A1R) by the analgesic small molecule adenosine has been shown to have antinociceptive benefits in models of inflammatory and neuropathic pain. The current study used a mouse model of painful diabetic neuropathy to determine the effect of diabetes on endogenous adenosine production, and if central or peripheral delivery of adenosine receptor agonists could alleviate signs of mechanical allodynia in diabetic mice. Diabetes was induced using streptozocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Hydrolysis of AMP into adenosine by ectonucleotidases was determined in the dorsal root ganglia (DRG) and spinal cord at 8-weeks post-induction of diabetes. AMP, adenosine and the specific A1R agonist, N6-cyclopentyladenosine (CPA), were administered both centrally (intrathecal) and peripherally (intraplantar) to determine the effect of activation of adenosine receptors on mechanical allodynia in diabetic mice. Eight weeks post-induction, diabetic mice displayed significantly decreased hydrolysis of extracellular AMP in the DRG; at this same time, diabetic mice displayed significantly decreased mechanical withdrawal thresholds compared to nondiabetic controls. Central delivery AMP, adenosine and CPA significantly improved mechanical withdrawal thresholds in diabetic mice. Surprisingly, peripheral delivery of CPA also improved mechanical allodynia in diabetic mice. This study provides new evidence that diabetes significantly affects endogenous AMP hydrolysis, suggesting that altered adenosine production could contribute to the development of painful

[Herpes simplex virus-mediated RNA interference targeting vesicular glutamate transporter 3 attenuates tactile allodynia in mice].

PubMed

Liu, Jie-Qiong; Li, Chen-Hong; Luo, Qiong; Yin, Ping-Ping; Lei, Tao; Luo, Fang

2016-11-20

To construct a replication-deficient herpes simplex virus (HSV-1) for delivering a short hairpin RNA (shRNA) targeting vesicular glutamate transporter 3 (VGLUT3) and observe its effect in alleviating allodynia in mice. The recombinant HSV-1 vector carrying the shRNA targeting Vglut3 (HSV-1-shvglut3) was constructed and inoculated in the sciatic nerve in a mouse model of mechanical allodynia to test its analgesia effect. Mechanical allodynia and heat hypersensitivity of the mice were tested by von Frey filaments and Hargreaves' test, respectively. VGLUT3 expression in the dorsal root ganglion (DRG) was evaluated by immunohistochemistry and Western blotting. Following inoculation in the sciatic nerve, the HSV vector HSV-1-shvglut3 was retrogradely transported to the DRG. Mechanical withdraw thresholds of the mouse models receiving HSV-1-shvglut3 inoculation were reversed to nearly the baseline level, and VGLUT3 expression in the DRG was down-regulated 2 weeks after vector inoculation. The analgesic effect lasted for over 2 weeks in these mice without obvious systematic side effects or changes in heat hypersensitivity threshold. Vglut3 in the DRG is a promising therapeutic target for alleviating mechanical allodynia, and HSV-1 vector-mediated RNA interference is safe and efficient for inducing long-lasting analgesia after peripheral inoculation of the vector.

A comprehensive review of opioid-induced hyperalgesia.

PubMed

Lee, Marion; Silverman, Sanford M; Hansen, Hans; Patel, Vikram B; Manchikanti, Laxmaiah

2011-01-01

Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilizing former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, and healthy human volunteers after acute opioid exposure using human experimental pain testing. The precise molecular mechanism of OIH, while not yet understood, varies substantially in the basic science literature, as well as clinical medicine. It is generally thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways. While there are many proposed mechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms. Of these, the central glutaminergic system is considered the most common possibility. Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH include activation, inhibition of the glutamate transporter system, facilitation of calcium regulated intracellular protein kinase C, and cross

α5GABAA Receptors Mediate Tonic Inhibition in the Spinal Cord Dorsal Horn and Contribute to the Resolution Of Hyperalgesia.

PubMed

Perez-Sanchez, Jimena; Lorenzo, Louis-Etienne; Lecker, Irene; Zurek, Agnieszka A; Labrakakis, Charalampos; Bridgwater, Erica M; Orser, Beverley A; De Koninck, Yves; Bonin, Robert P

2017-06-01

Neuronal inhibition mediated by GABA A receptors constrains nociceptive processing in the spinal cord, and loss of GABAergic inhibition can produce allodynia and hyperalgesia. Extrasynaptic α5 subunit-containing GABA A receptors (α5GABA A Rs) generate a tonic conductance that inhibits neuronal activity and constrains learning and memory; however, it is unclear whether α5GABA A Rs similarly generate a tonic conductance in the spinal cord dorsal horn to constrain nociception. We assessed the distribution of α5GABA A Rs in the spinal cord dorsal horn by immunohistochemical analysis, and the activity and function of α5GABA A Rs in neurons of the superficial dorsal horn using electrophysiological and behavioral approaches in male, null-mutant mice lacking the GABA A R α5 subunit (Gabra5-/-) and wild-type mice (WT). The expression of α5GABA A Rs in the superficial dorsal horn followed a laminar pattern of distribution, with a higher expression in lamina II than lamina I. Similarly, the tonic GABA A current in lamina II neurons had a larger contribution from α5GABA A Rs than in lamina I, with no significant contribution of these receptors to synaptic GABA A current. In behavioural tests, WT and Gabra5-/- mice exhibited similar acute thermal and mechanical nociception, and similar mechanical sensitization immediately following intraplantar capsaicin or Complete Freund's Adjuvant (CFA). However, Gabra5-/- mice showed prolonged recovery from sensitization in these models, and increased responses in the late phase of the formalin test. Overall, our data suggest that tonically-active α5GABA A Rs in the spinal cord dorsal horn accelerate the resolution of hyperalgesia and may therefore serve as a novel therapeutic target to promote recovery from pathological pain. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Activation of the cAMP-PKA signaling pathway in rat dorsal root ganglion and spinal cord contributes toward induction and maintenance of bone cancer pain.

PubMed

Zhu, Gui-Qin; Liu, Su; He, Duan-Duan; Liu, Yue-Peng; Song, Xue-Jun

2014-08-01

The objective of this study was to explore the role of cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling in the development of bone cancer pain in rats. Female Sprague-Dawley rats (N=48) were divided randomly into four groups: sham (n=8), tumor cell implantation (TCI) (n=16), TCI+saline (n=8), and TCI+PKA inhibitor (n=16). Bone cancer-induced pain behaviors - thermal hyperalgesia and mechanical allodynia - were tested at postoperative days -3, -1, 1, 3, 5, 7, 10, and 14. A PKA inhibitor, Rp-cAMPS (1 mmol/l/20 μl), was injected intrathecally on postoperative days 3, 4, and 5 (early phase) or 7, 8, and 9 postoperative days (late phase). The expression of PKA mRNA in dorsal root ganglia (DRG) was detected by reverse transcription-PCR. The concentration of cAMP and activity of PKA in DRG and spinal cord were measured by enzyme-linked immunosorbent assay. TCI treatment induced significant pain behaviors, manifested as thermal hyperalgesia and mechanical allodynia. Spinal administration of the PKA inhibitor Rp-cAMPS during the early phase and late phase significantly delayed or reversed, respectively, TCI-induced thermal hyperalgesia and mechanical allodynia. TCI treatment also led to obvious tumor growth and bone destruction. The level of PKA mRNA in the DRG, as well as the concentration of cAMP and the activity of PKA, in both the DRG and spinal cord were significantly increased after TCI treatment (P<0.01). We conclude that the inhibition of the cAMP-PKA signaling pathway may reduce bone cancer pain.

Sensory Symptom Profiles and Co-Morbidities in Painful Radiculopathy

PubMed Central

Gockel, Ulrich; Brosz, Mathias; Freynhagen, Rainer; Tölle, Thomas R.; Baron, Ralf

2011-01-01

Painful radiculopathies (RAD) and classical neuropathic pain syndromes (painful diabetic polyneuropathy, postherpetic neuralgia) show differences how the patients express their sensory perceptions. Furthermore, several clinical trials with neuropathic pain medications failed in painful radiculopathy. Epidemiological and clinical data of 2094 patients with painful radiculopathy were collected within a cross sectional survey (painDETECT) to describe demographic data and co-morbidities and to detect characteristic sensory abnormalities in patients with RAD and compare them with other neuropathic pain syndromes. Common co-morbidities in neuropathic pain (depression, sleep disturbance, anxiety) do not differ considerably between the three conditions. Compared to other neuropathic pain syndromes touch-evoked allodynia and thermal hyperalgesia are relatively uncommon in RAD. One distinct sensory symptom pattern (sensory profile), i.e., severe painful attacks and pressure induced pain in combination with mild spontaneous pain, mild mechanical allodynia and thermal hyperalgesia, was found to be characteristic for RAD. Despite similarities in sensory symptoms there are two important differences between RAD and other neuropathic pain disorders: (1) The paucity of mechanical allodynia and thermal hyperalgesia might be explained by the fact that the site of the nerve lesion in RAD is often located proximal to the dorsal root ganglion. (2) The distinct sensory profile found in RAD might be explained by compression-induced ectopic discharges from a dorsal root and not necessarily by nerve damage. These differences in pathogenesis might explain why medications effective in DPN and PHN failed to demonstrate efficacy in RAD. PMID:21573064

Allodynia mediated by C-tactile afferents in human hairy skin.

PubMed

Nagi, Saad S; Rubin, Troy K; Chelvanayagam, David K; Macefield, Vaughan G; Mahns, David A

2011-08-15

We recently showed a contribution of low-threshold cutaneous mechanoreceptors to vibration-evoked changes in the perception of muscle pain. Neutral-touch stimulation (vibration) of the hairy skin during underlying muscle pain evoked an overall increase in pain intensity, i.e. allodynia. This effect appeared to be dependent upon cutaneous afferents, as allodynia was abolished by intradermal anaesthesia. However, it remains unclear whether allodynia results from activation of a single class of cutaneous afferents or the convergence of inputs from multiple classes. Intriguingly, no existing human study has examined the contribution of C-tactile (CT) afferents to allodynia. Detailed psychophysical observations were made in 29 healthy subjects (18 males and 11 females). Sustained muscle pain was induced by infusing hypertonic saline (HS: 5%) into tibialis anterior muscle (TA). Sinusoidal vibration (200 Hz–200 μm) was applied to the hairy skin overlying TA. Pain ratings were recorded using a visual analogue scale (VAS). In order to evaluate the role of myelinated and unmyelinated cutaneous afferents in the expression of vibration-evoked allodynia, compression block of the sciatic nerve, and low-dose intradermal anaesthesia (Xylocaine 0.25%) were used, respectively. In addition, the modulation of muscle pain by gentle brushing (1.0 and 3.0 cm s(−1))--known to excite CT fibres--was examined. Brushing stimuli were applied to the hairy skin with all fibres intact and following the blockade of myelinated afferents. During tonic muscle pain (VAS 4–6), vibration evoked a significant and reproducible increase in muscle pain (allodynia) that persisted following compression of myelinated afferents. During compression block, the sense of vibration was abolished, but the vibration-evoked allodynia persisted. In contrast, selective anaesthesia of unmyelinated cutaneous afferents abolished the allodynia, whereas the percept of vibration remained unaffected. Furthermore

Transplantation of Reprogrammed Autologous Stem Cells for Chronic Pain and Drug Abuse

DTIC Science & Technology

2012-10-01

Hyperalgesia and Mechanical Allodynia by Curcumin in a Rat Model of Partial Thickness Thermal Injury Clifford, John Evaluation Of A Non-Invasive System Of...Thermal Injury Garza, Thomas Biochemical Correlates for the Analgesic Action Of Curcumin : A Naturally occurring Anti-inflammatory Agent Greer, Angie

Antinociceptive action of hemopressin in experimental hyperalgesia.

PubMed

Dale, Camila Squarzoni; Pagano, Rosana de Lima; Rioli, Vanessa; Hyslop, Stephen; Giorgi, Renata; Ferro, Emer Suavinho

2005-03-01

Endogenous hemorphins, derived from degradation of the beta-chain of hemoglobin, lower arterial blood pressure and exert an antinociceptive action in experimental models of nociception. Hemopressin, derived from the alpha-chain of hemoglobin, also decreases blood pressure, but its effects on pain have not been studied. In this work, we examined the influence of hemopressin on inflammatory pain. Hemopressin reverted the hyperalgesia induced by either carrageenin or bradykinin when injected concomitantly or 2.5 h after the phlogistic agents. Hemopressin administered systemically also reverted the hyperalgesia induced by carrageenin. Naloxone did not prevent the antinociceptive action of this peptide. These data suggest that hemopressin inhibits peripheral hyperalgesic responses by mechanisms independent of opioid receptor activation.

Nociceptive Neuropeptide Increases and Periorbital Allodynia in a Model of Traumatic Brain Injury

PubMed Central

Elliott, Melanie B.; Oshinsky, Michael L.; Amenta, Peter S.; Awe, Olatilewa O.; Jallo, Jack I.

2014-01-01

Objective This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury. Methods Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1–labeled macrophages/microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were evaluated using immunohistochemistry because of their potential involvement in nociceptor sensitization. Results Incision-only control mice showed no changes from baseline periorbital von Frey mechanical thresholds. CCI significantly reduced mean periorbital von Frey thresholds (periorbital allodynia) compared with baseline and craniotomy-only at each endpoint, analysis of variance P < .0001. Craniotomy significantly reduced periorbital threshold at 14 days but not 7, 21, or 28 days compared with baseline threshold, P < .01. CCI significantly increased SP immunoreactivity in the brainstem at 7 and 14 days but not 28 days compared with craniotomy-only and controls, P < .001. CGRP levels in brainstem tissues were significantly increased in CCI groups compared with controls (incision-only and naïve mice) or craniotomy-only mice at each endpoint examined, P < .0001. There was a significant correlation between CGRP and periorbital allodynia (P < .0001, r = −0.65) but not for SP (r = 0.20). CCI significantly increased the number of macrophage/microglia in the injured cortex at each endpoint up to 28 days, although cell numbers declined over weeks

Minocycline Prevents Muscular Pain Hypersensitivity and Cutaneous Allodynia Produced by Repeated Intramuscular Injections of Hypertonic Saline in Healthy Human Participants.

PubMed

Samour, Mohamad Samir; Nagi, Saad Saulat; Shortland, Peter John; Mahns, David Anthony

2017-08-01

-treated participants showed cold allodynia. This study showed that repeated injections of HS can induce a hypersensitivity that outlasts the acute response, and the development of this hypersensitivity can be reliably attenuated with minocycline pretreatment. Four repeated injections of HS at 48-hour intervals induce a state of persistent hypersensitivity in healthy human participants. This hypersensitivity was characterized by bilateral muscular hyperalgesia and cutaneous cold allodynia, symptoms commonly reported in many chronic pain conditions. Minocycline pretreatment abolished the development of this state. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Antinociceptive effects of hydroalcoholic extract from Euterpe oleracea Mart. (Açaí) in a rodent model of acute and neuropathic pain.

PubMed

Sudo, Roberto T; Neto, Miguel L; Monteiro, Carlos E S; Amaral, Rachel V; Resende, Ângela C; Souza, Pergentino J C; Zapata-Sudo, Gisele; Moura, Roberto S

2015-07-02

Plants rich in flavonoids, such as açaí (Euterpe oleraceae Mart.), can induce antinociception in experimental animals. Here, we tested an extract obtained from the stones of açaí fruits (açaí stone extract, ASE), a native plant from the Amazon region of Brazil, in models of acute/inflammatory and chronic pain. Antinociceptive effects of ASE were evaluated in the hot plate, formalin, acetic acid writhing, carrageenan, and neuropathic pain models, as well as in thermal hyperalgesia and mechanical allodynia models induced by spinal nerve ligation. Antinociceptive activities were modulated by the administration of cholinergic, adrenergic, opioid, and L-arginine-NO antagonists. Oral administration of ASE (30, 100, or 300 mg.kg(-1)) dose-dependently reduced nociceptive responses to acute/inflammatory pain in mice, including thermal hyperalgesia, acetic acid-induced writhing, and carrageenan-induced thermal hyperalgesia. Moreover, ASE reduced the neurogenic and inflammatory phases after intraplantar injection of formalin in mice. The antinociceptive effect of ASE (100 mg · kg(-1)) in a hot plate protocol, was inhibited by pre-treatment with naloxone (1 mg · kg(-1)), atropine (2 mg · kg(-1)), yohimbine (5 mg · kg(-1)), or L-NAME (30 mg · kg(-1)). Furthermore, ASE prevented chronic pain in a rat spinal nerve ligation model, including thermal hyperalgesia and mechanical allodynia. ASE showed significant antinociceptive effect via a multifactorial mechanism of action, indicating that the extract may be useful in the development of new analgesic drugs.

Effects of binge-like ethanol exposure during adolescence on the hyperalgesia observed during sickness syndrome in rats.

PubMed

de Oliveira, Bruna M T; Telles, Tatiane M B B; Lomba, Luiz A; Correia, Diego; Zampronio, Aleksander R

2017-09-01

Acute and chronic ethanol exposure increases the risk of infection by altering the innate host's defense system. Adolescence is a critical period for brain development. Insults during this period may have long-lasting consequences. The present study investigated the effects of binge-like ethanol exposure in adolescent rats on mechanical hyperalgesia during sickness syndrome that was induced by a systemic injection of lipopolysaccharide (LPS) or an intracerebroventricular (i.c.v.) injection of interleukin-1β (IL-1β) after the cessation of ethanol exposure. Male Wistar rats were exposed to ethanol from postnatal day (PND) 25 to PND 38 in a binge-like pattern. Hyperalgesia was assessed on the right hindpaw after an intraperitoneal injection of LPS (5 and 50μg/kg, intraperitoneally) on PND 51 and PND 63 or an i.c.v. or intraplantar (i.pl.) injection of IL-β (3 and 1ng, respectively) on PND 51. Ethanol exposure during adolescence did not alter mechanical thresholds which increased normally with age. The systemic injection of LPS (0.5-50μg/kg) in adult rats induced dose-related mechanical hyperalgesia. Binge-like ethanol exposure significantly increased mechanical hyperalgesia that was induced by 50μg/kg LPS on PND 51 and 63, which lasted until 24h after the injection. This change was not observed at a lower dose of LPS (5μg/kg). Acute oral treatment with ethanol 24h prior to LPS administration did not alter mechanical hyperalgesia. The i.c.v. injection of IL-1β (1-10ng) also induced dose-related mechanical hyperalgesia in the right hindpaw in non-exposed animals. In animals that were exposed to binge-like ethanol, the i.c.v. or i.pl. injection of IL-1β also increased hyperalgesia on PND 51. These results suggest that binge-like ethanol exposure during adolescence causes alterations in the central nervous system that can increase mechanical hyperalgesia that is observed during sickness syndrome, and this effect can be observed until adulthood after the cessation

Secondary hyperalgesia phenotypes exhibit differences in brain activation during noxious stimulation.

PubMed

Asghar, Mohammad Sohail; Pereira, Manuel Pedro; Werner, Mads Utke; Mårtensson, Johan; Larsson, Henrik B W; Dahl, Jørgen Berg

2015-01-01

Noxious stimulation of the skin with either chemical, electrical or heat stimuli leads to the development of primary hyperalgesia at the site of injury, and to secondary hyperalgesia in normal skin surrounding the injury. Secondary hyperalgesia is inducible in most individuals and is attributed to central neuronal sensitization. Some individuals develop large areas of secondary hyperalgesia (high-sensitization responders), while others develop small areas (low-sensitization responders). The magnitude of each area is reproducible within individuals, and can be regarded as a phenotypic characteristic. To study differences in the propensity to develop central sensitization we examined differences in brain activity and anatomy according to individual phenotypical expression of secondary hyperalgesia by magnetic resonance imaging. Forty healthy volunteers received a first-degree burn-injury (47 °C, 7 min, 9 cm(2)) on the non-dominant lower-leg. Areas of secondary hyperalgesia were assessed 100 min after the injury. We measured neuronal activation by recording blood-oxygen-level-dependent-signals (BOLD-signals) during mechanical noxious stimulation before burn injury and in both primary and secondary hyperalgesia areas after burn-injury. In addition, T1-weighted images were used to measure differences in gray-matter density in cortical and subcortical regions of the brain. We found significant differences in neuronal activity between high- and low-sensitization responders at baseline (before application of the burn-injury) (p < 0.05). After the burn-injury, we found significant differences between responders during noxious stimulation of both primary (p < 0.01) and secondary hyperalgesia (p ≤ 0.04) skin areas. A decreased volume of the right (p = 0.001) and left caudate nucleus (p = 0.01) was detected in high-sensitization responders in comparison to low-sensitization responders. These findings suggest that brain-structure and neuronal activation to noxious

Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system

PubMed Central

Zhao, Xin; Wang, Chuang; Cui, Wu-Geng; Ma, Qing; Zhou, Wen-Hua

2015-01-01

Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain. PMID:25761874

A rat model of unilateral hindpaw burn injury: slowly developing rightwards shift of the morphine dose-response curve.

PubMed

Wang, Shuxing; Lim, Grewo; Yang, Liling; Zeng, Qing; Sung, Backil; Jeevendra Martyn, J A; Mao, Jianren

2005-07-01

Management of pain after burn injury is an unresolved clinical issue. In a rat model of hindpaw burn injury, we examined the effects of systemic morphine on nociceptive behaviors following injury. Injury was induced by immersing the dorsal part of one hindpaw into a hot water bath (85 degrees C) for 4, 7, or 12 s under pentobarbital anesthesia. Mechanical allodynia to von Frey filament stimulation and thermal hyperalgesia to radiant heat were assessed. Burn injury induced by the 12-s (but not 4-, or 7-s) hot water immersion resulted in reliable and lasting mechanical allodynia and thermal hyperalgesia evident by day 1. In addition, there was an upregulation of protein kinase Cgamma and a progressive downregulation of mu-opioid receptors within the spinal cord dorsal horn ipsilateral to injury as revealed by immunohistochemistry and Western blot. In both injured and sham rats, the anti-nociceptive effects of subcutaneous morphine were examined on post-injury days 7 and 14. While the morphine AD50 dose was comparable on day 7 between burn (1.61 mg/kg) and control (1.7 mg/kg) rats, the morphine dose-response curve was shifted to the right in burn-injured rats (4.6 mg/kg) on post-injury day 14 as compared with both the injured rats on post-injury day 7 and sham rats on day 14 (1.72 mg/kg). These data indicate that hindpaw burn injury reliably produces persistent mechanical allodynia and thermal hyperalgesia and that the reduced efficacy of morphine anti-nociception in chronic burn injury may be in part due to a downregulation of spinal mu-opioid receptors.

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.

Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.

PubMed

White, Stephanie; Marquez de Prado, Blanca; Russo, Andrew F; Hammond, Donna L

2014-01-01

This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/- mice (B6.129S6 Nf1/J) and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/- mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/- and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/- and wild type mice. Female Nf1+/- mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/- mice of both genders compared to wild type mice. Male Nf1+/- mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/- mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients.

Low-threshold mechanoreceptors play a frequency-dependent dual role in subjective ratings of mechanical allodynia.

PubMed

Löken, Line S; Duff, Eugene P; Tracey, Irene

2017-12-01

In the setting of injury, myelinated primary afferent fibers that normally signal light touch are thought to switch modality and instead signal pain. In the absence of injury, touch is perceived as more intense when firing rates of Aβ afferents increase. However, it is not known if varying the firing rates of Aβ afferents have any consequence to the perception of dynamic mechanical allodynia (DMA). We hypothesized that, in the setting of injury, the unpleasantness of DMA would be intensified as the firing rates of Aβ afferents increase. Using a stimulus-response protocol established in normal skin, where an increase in brush velocity results in an increase of Aβ afferent firing rates, we tested if brush velocity modulated the unpleasantness of capsaicin-induced DMA. We analyzed how changes in estimated low-threshold mechanoreceptor firing activity influenced perception and brain activity (functional MRI) of DMA. Brushing on normal skin was perceived as pleasant, but brushing on sensitized skin produced both painful and pleasant sensations. Surprisingly, there was an inverse relationship between Aβ firing rates and unpleasantness such that brush stimuli that produced low firing rates were most painful and those that elicited high firing rates were rated as pleasant. Concurrently to this, we found increased cortical activity in response to low Aβ firing rates in regions previously implicated in pain processing during brushing of sensitized skin, but not normal skin. We suggest that Aβ signals do not merely switch modality to signal pain during injury. Instead, they exert a high- and low-frequency-dependent dual role in the injured state, with respectively both pleasant and unpleasant consequences. NEW & NOTEWORTHY We suggest that Aβ signals do not simply switch modality to signal pain during injury but play a frequency-dependent and dual role in the injured state with both pleasant and unpleasant consequences. These results provide a framework to resolve the

GABAergic mechanisms are involved in the antihyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory hyperalgesia.

PubMed

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

2008-01-01

The purpose of this study was to investigate the involvement of GABAergic mechanisms in the antihyperalgesic effect of carbamazepine and oxcarbazepine by examining the effect of bicuculline (GABA(A) receptor antagonist) on these effects of antiepileptic drugs. Rats were intraplantarly (i.pl.) injected with the proinflammatory compound concanavalin A (Con A). A paw-pressure test was used to determine: (1) the development of hyperalgesia induced by Con A; (2) the effects of carbamazepine/oxcarbazepine on Con A-induced hyperalgesia, and (3) the effects of bicuculline on the carbamazepine/oxcarbazepine antihyperalgesia. Intraperitoneally injected bicuculline (0.5-1 mg/kg, i.p.) exhibited significant suppression of the systemic antihyperalgesic effects of carbamazepine (27 mg/kg, i.p.) and oxcarbazepine (80 mg/kg, i.p.). When applied intraplantarly, bicuculline (0.14 mg/paw, i.pl.) did not produce any change in the peripheral antihyperalgesic effects of carbamazepine (0.14 mg/paw, i.pl.) and oxcarbazepine (0.5 mg/paw, i.pl.). Bicuculline alone did not produce an intrinsic effect in the paw-pressure test. These results indicate that the antihyperalgesic effects of carbamazepine and oxcarbazepine against inflammatory hyperalgesia involve in part the GABAergic inhibitory modulation of pain transmission at central, but not at peripheral sites, which is mediated via GABA(A) receptor activation. Copyright 2008 S. Karger AG, Basel.

Intradermal administration of magnesium sulphate and magnesium chloride produces hypesthesia to mechanical but hyperalgesia to heat stimuli in humans

PubMed Central

Ushida, Takahiro; Iwatsu, Osamu; Shimo, Kazuhiro; Tetsunaga, Tomoko; Ikeuchi, Masahiko; Ikemoto, Tatsunori; Arai, Young-Chang P; Suetomi, Katsutoshi; Nishihara, Makoto

2009-01-01

Background Although magnesium ions (Mg2+) are known to display many similar features to other 2+ charged cations, they seem to have quite an important and unique role in biological settings, such as NMDA blocking effect. However, the role of Mg2+ in the neural transmission system has not been studied as sufficiently as calcium ions (Ca2+). To clarify the sensory effects of Mg2+ in peripheral nervous systems, sensory changes after intradermal injection of Mg2+ were studied in humans. Methods Magnesium sulphate, magnesium chloride and saline were injected into the skin of the anterior region of forearms in healthy volunteers and injection-induced irritating pain ("irritating pain", for short), tactile sensation, tactile pressure thresholds, pinch-pain changes and intolerable heat pain thresholds of the lesion were monitored. Results Flare formation was observed immediately after magnesium sulphate or magnesium chloride injection. We found that intradermal injections of magnesium sulphate and magnesium chloride transiently caused irritating pain, hypesthesia to noxious and innocuous mechanical stimulations, whereas secondary hyperalgesia due to mechanical stimuli was not observed. In contrast to mechanical stimuli, intolerable heat pain-evoking temperature was significantly decreased at the injection site. In addition to these results, spontaneous pain was immediately attenuated by local cooling. Conclusion Membrane-stabilizing effect and peripheral NMDA-blocking effect possibly produced magnesium-induced mechanical hypesthesia, and extracellular cation-induced sensitization of TRPV1 channels was thought to be the primary mechanism of magnesium-induced heat hyperalgesia. PMID:19715604

Opioid receptor-mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery.

PubMed

Gardell, Luis R; King, Tamara; Ossipov, Michael H; Rice, Kenner C; Lai, Josephine; Vanderah, Todd W; Porreca, Frank

2006-03-20

Opiates are commonly used to treat moderate to severe pain and can be used over prolonged periods in states of chronic pain such as those associated with cancer. In addition, to analgesic actions, studies show that opiate administration can paradoxically induce hyperalgesia. At the pre-clinical level, such hyperalgesia is associated with numerous pronociceptive neuroplastic changes within the primary afferent fibers and the spinal cord. In rodents, sustained opiate administration also induces antinociceptive tolerance. The mechanisms by which prolonged opiate exposure induces hyperalgesia and the relationship of this state to antinociceptive tolerance remain unclear. The present study was aimed at determining whether sustained opiate-induced hyperalgesia, associated neuroplasticity and antinociceptive tolerance are the result of specific opiate interaction at opiate receptors. Enantiomers of oxymorphone, a mu opioid receptor agonist, were administered to rats by spinal infusion across 7 days. Sustained spinal administration of (-)-oxymorphone, but not its inactive enantiomer (+)-oxymorphone or vehicle, upregulated spinal dynorphin content, produced thermal and tactile hypersensitivity, and produced antinociceptive tolerance. These results indicate that these pronociceptive actions of sustained opiate administration require specific interaction with opiate receptors and are unlikely to be the result of accumulation of potentially excitatory metabolic products. While the precise mechanisms, which may account for these pronociceptive changes remain to be unraveled, the present data point to plasticity initiated by opiate receptor interaction.

Passiflora incarnata attenuation of neuropathic allodynia and vulvodynia apropos GABA-ergic and opioidergic antinociceptive and behavioural mechanisms.

PubMed

Aman, Urooj; Subhan, Fazal; Shahid, Muhammad; Akbar, Shehla; Ahmad, Nisar; Ali, Gowhar; Fawad, Khwaja; Sewell, Robert D E

2016-02-24

Passiflora incarnata is widely used as an anxiolytic and sedative due to its putative GABAergic properties. Passiflora incarnata L. methanolic extract (PI-ME) was evaluated in an animal model of streptozotocin-induced diabetic neuropathic allodynia and vulvodynia in rats along with antinociceptive, anxiolytic and sedative activities in mice in order to examine possible underlying mechanisms. PI-ME was tested preliminary for qualitative phytochemical analysis and then quantitatively by proximate and GC-MS analysis. The antinociceptive property was evaluated using the abdominal constriction assay and hot plate test. The anxiolytic activity was performed in a stair case model and sedative activity in an open field test. The antagonistic activities were evaluated using naloxone and/or pentylenetetrazole (PTZ). PI-ME was evaluated for prospective anti-allodynic and anti-vulvodynic properties in a rat model of streptozotocin induced neuropathic pain using the static and dynamic testing paradigms of mechanical allodynia and vulvodynia. GC-MS analysis revealed that PI-ME contained predominant quantities of oleamide (9-octadecenamide), palmitic acid (hexadecanoic acid) and 3-hydroxy-dodecanoic acid, among other active constituents. In the abdominal constriction assay and hot plate test, PI-ME produced dose dependant, naloxone and pentylenetetrazole reversible antinociception suggesting an involvement of opioidergic and GABAergic mechanisms. In the stair case test, PI-ME at 200 mg/kg increased the number of steps climbed while at 600 mg/kg a significant decrease was observed. The rearing incidence was diminished by PI-ME at all tested doses and in the open field test, PI-ME decreased locomotor activity to an extent that was analagous to diazepam. The effects of PI-ME were antagonized by PTZ in both the staircase and open field tests implicating GABAergic mechanisms in its anxiolytic and sedative activities. In the streptozotocin-induced neuropathic nociceptive model, PI

Enhanced Area of Secondary Hyperalgesia in Women with Multiple Stressful Life Events: A Pilot Study.

PubMed

You, Dokyoung S; Creech, Suzannah K; Meagher, Mary W

2016-10-01

Stressful life events are associated with increased pain severity and chronicity. However, the mechanism underlying this association remains disputed. Recent animal studies suggest that chronic stress increases pain sensitivity and persistence by enhancing peripheral and central sensitization mechanisms. To test this hypothesis in humans, the authors examined whether sensitization is enhanced in healthy women reporting more stressful life events using the topical capsaicin test. Thirty-two healthy young women reporting varying levels of stressful life events were invited for laboratory pain testing. Capsaicin was applied topically to the volar forearm. Measurements included capsaicin-induced spontaneous pain and area of secondary hyperalgesia in the region surrounding capsaicin application. Physiological (heart rate and skin conductance) and self-reported affective (emotional valence and arousal) states were also measured. The results indicate that more stressful life events predicted a linear increase in the area of secondary hyperalgesia (β = 0.40, p = 0.023, R 2 = 0.16), but not the intensity of secondary hyperalgesia nor capsaicin-induced spontaneous pain. These findings suggest that life stressors may be associated with heightened central sensitization manifested by an increased area of secondary hyperalgesia. Additionally, life stressors were related to greater sympathetic cardiac, but not to affective responses to capsaicin-induced pain. This study shows that women reporting more stressful life events show a larger area of secondary mechanical hyperalgesia. These preliminary findings suggest that life stressors may facilitate pain processing by enhancing central sensitization. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Do Australian Football players have sensitive groins? Players with current groin pain exhibit mechanical hyperalgesia of the adductor tendon.

PubMed

Drew, Michael K; Lovell, Gregory; Palsson, Thorvaldur S; Chiarelli, Pauline E; Osmotherly, Peter G

2016-10-01

This is the first study to evaluate the mechanical sensitivity, clinical classifications and prevalence of groin pain in Australian football players. Case-control. Professional (n=66) and semi-professional (n=9) Australian football players with and without current or previous groin injuries were recruited. Diagnoses were mapped to the Doha Agreement taxonomy. Point and career prevalence of groin pain was calculated. Pressure pain thresholds (PPTs) were assessed at regional and distant sites using handheld pressure algometry across four sites bilaterally (adductor longus tendon, pubic bone, rectus femoris, tibialis anterior muscle). To assess the relationship between current groin pain and fixed effects of hyperalgesia of each site and a history of groin pain, a mixed-effect logistic regression model was utilised. Receiver Operator Characteristic (ROC) curve were determined for the model. Point prevalence of groin pain in the preseason was 21.9% with a career prevalence of 44.8%. Adductor-related groin pain was the most prevalent classification in the pre-season period. Hyperalgesia was observed in the adductor longus tendon site in athletes with current groin pain (OR=16.27, 95% CI 1.86 to 142.02). The ROC area under the curve of the regression model was fair (AUC=0.76, 95% CI 0.54 to 0.83). Prevalence data indicates that groin pain is a larger issue than published incidence rates imply. Adductor-related groin pain is the most common diagnosis in pre-season in this population. This study has shown that hyperalgesia exists in Australian football players experiencing groin pain indicating the value of assessing mechanical pain sensitivity as a component of the clinical assessment. Copyright © 2016 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis.

PubMed

Wang, Shusheng; Zhu, Hong-Yan; Jin, Yi; Zhou, Youlang; Hu, Shufen; Liu, Tong; Jiang, Xinghong; Xu, Guang-Yin

2015-04-15

The mechanism of pain in chronic pancreatitis (CP) is poorly understood. The aim of this study was designed to investigate roles of norepinephrine (NE) and P2X receptor (P2XR) signaling pathway in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Mechanical hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. P2XR-mediated responses of pancreatic dorsal root ganglion (DRG) neurons were measured utilizing calcium imaging and whole cell patch-clamp-recording techniques. Western blot analysis and immunofluorescence were performed to examine protein expression. TNBS injection produced a significant upregulation of P2X3R expression and an increase in ATP-evoked responses of pancreatic DRG neurons. The sensitization of P2X3Rs was reversed by administration of β-adrenergic receptor antagonist propranolol. Incubation of DRG neurons with NE significantly enhanced ATP-induced intracellular calcium signals, which were abolished by propranolol, and partially blocked by protein kinase A inhibitor H-89. Interestingly, TNBS injection led to a significant elevation of NE concentration in DRGs and the pancreas, an upregulation of β2-adrenergic receptor expression in DRGs, and amplification of the NE-induced potentiation of ATP responses. Importantly, pancreatic hyperalgesia was markedly attenuated by administration of purinergic receptor antagonist suramin or A317491 or β2-adrenergic receptor antagonist butoxamine. Sensitization of P2X3Rs, which was likely mediated by adrenergic signaling in primary sensory neurons, contributes to pancreatic pain, thus identifying a potential target for treating pancreatic pain caused by inflammation. Copyright © 2015 the American Physiological Society.

Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-α expression in a mouse model.

PubMed

Gu, Xiaoping; Zheng, Yaguo; Ren, Bingxu; Zhang, Rui; Mei, Fengmei; Zhang, Juan; Ma, Zhengliang

2010-10-05

Tumor necrosis factor α (TNF-α) may have a pivotal role in the genesis of mechanical allodynia and thermal hyperalgesia during inflammatory and neuropathic pain. Thalidomide has been shown to selectively inhibit TNF-α production. Previous studies have suggested that thalidomide exerts anti-nociceptive effects in various pain models, but its effects on bone cancer pain have not previously been studied. Therefore, in the present study, we investigated the effect of thalidomide on bone cancer-induced hyperalgesia and up-regulated expression of spinal TNF-α in a mouse model. Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer related pain behaviors. At day 5, 7, 10 and 14 after operation, the expression of TNF-α in the spinal cord was higher in tumor-bearing mice compared to the sham mice. Intraperitoneal injection of thalidomide (50 mg/kg), started at day 1 after surgery and once daily thereafter until day 7, attenuated bone cancer-evoked mechanical allodynia and thermal hyperalgesia as well as the up-regulation of TNF-α in the spinal cord. These results suggest that thalidomide can efficiently alleviate bone cancer pain and it may be a useful alternative or adjunct therapy for bone cancer pain. Our data also suggest a role of spinal TNF-α in the development of bone cancer pain.

A novel method for modeling facial allodynia associated with migraine in awake and freely moving rats

PubMed Central

Wieseler, Julie; Ellis, Amanda; Sprunger, David; Brown, Kim; McFadden, Andrew; Mahoney, John; Rezvani, Niloofar; Maier, Steven F.; Watkins, Linda R.

2009-01-01

Migraine is a neurovascular disorder that induces debilitating headaches associated with multiple symptoms including facial allodynia, characterized by heightened responsivity to normally innocuous mechanical stimuli. It is now well accepted that immune activation and immune-derived inflammatory mediators enhance pain responsivity, including in the trigeminal system. Nociceptive (“pain” responsive) trigeminal nerves densely innervate the cranial meninges. We have recently proposed that the meninges may serve as a previously unidentified, key interface between the peripheral immune system and the CNS with potential implications for understanding underlying migraine mechanisms. Our focus here is the development of a model for facial allodynia associated with migraine. We developed a model wherein an indwelling catheter is placed between the skull and dura, allowing immunogenic stimuli to be administered over the dura in awake and freely moving rats. Since the catheter does not contact the brain itself, any proinflammatory cytokines induced following manipulation derive from resident or recruited meningeal immune cells. While surgery alone does not alter immune activation markers, TNF or IL6 mRNA and/or protein, it does decrease gene expression and increase protein expression of IL-1 at 4 days after surgery. Using this model we show the induction of facial allodynia in response to supradural administration of either the HIV glycoprotein gp120 or inflammatory soup (bradykinin, histamine, serotonin, and prostaglandin E2), and the induction of hindpaw allodynia in our model after inflammatory soup. This model allows time and dose dependent assessment of the relationship between changes in meningeal inflammation and corresponding exaggerated pain behaviors. PMID:19837113

Spinal Changes of a Newly Isolated Neuropeptide Endomorphin-2 Concomitant with Vincristine-Induced Allodynia

PubMed Central

Huang, Ben-Qing; Liu, Ji-Dong; Liu, Hui; Zhang, Nan; Li, Li; Chen, Jian-Hua

2014-01-01

Chemotherapy-induced neuropathic pain (CNP) is the major dose-limiting factor in cancer chemotherapy. However, the neural mechanisms underlying CNP remain unclear. There is increasing evidence implicating the involvement of spinal endomorphin-2 (EM2) in neuropathic pain. In this study, we used a vincristine-evoked rat CNP model displaying mechanical allodynia and central sensitization, and observed a significant decrease in the expression of spinal EM2 in CNP. Also, while intrathecal administration of exogenous EM2 attenuated allodynia and central sensitization, the mu-opioid receptor antagonist β-funaltrexamine facilitated these events. We found that the reduction in spinal EM2 was mediated by increased activity of dipeptidylpeptidase IV, possibly as a consequence of chemotherapy-induced oxidative stress. Taken together, our findings suggest that a decrease in spinal EM2 expression causes the loss of endogenous analgesia and leads to enhanced pain sensation in CNP. PMID:24586889

Impact of suggestion on the human experimental model of cold hyperalgesia after topical application of high-concentration menthol [40%].

PubMed

Helfert, S; Reimer, M; Barnscheid, L; Hüllemann, P; Rengelshausen, J; Keller, T; Baron, R; Binder, A

2018-05-14

Human experimental pain models in healthy subjects offer unique possibilities to study mechanisms of pain within a defined setting of expected pain symptoms, signs and mechanisms. Previous trials in healthy subjects demonstrated that topical application of 40% menthol is suitable to induce cold hyperalgesia. The objective of this study was to evaluate the impact of suggestion on this experimental human pain model. The study was performed within a single-centre, randomized, placebo-controlled, double-blind, two-period crossover trial in a cohort of 16 healthy subjects. Subjects were tested twice after topical menthol application (40% dissolved in ethanol) and twice after ethanol (as placebo) application. In the style of a balanced placebo trial design, the subjects received during half of the testing the correct information about the applied substance (topical menthol or ethanol) and during half of the testing the incorrect information, leading to four tested conditions (treatment conditions: menthol-told-menthol and menthol-told-ethanol; placebo conditions: ethanol-told-menthol and ethanol-told-ethanol). Cold but not mechanical hyperalgesia was reliably induced by the model. The cold pain threshold decreased in both treatment conditions regardless whether true or false information was given. Minor suggestion effects were found in subjects with prior ethanol application. The menthol model is a reliable, nonsuggestible model to induce cold hyperalgesia. Mechanical hyperalgesia is not as reliable to induce. Cold hyperalgesia may be investigated under unbiased and suggestion-free conditions using the menthol model of pain. © 2018 European Pain Federation - EFIC®.

Quantitative validation of sensory mapping in persistent postherniorrhaphy inguinal pain patients undergoing triple neurectomy.

PubMed

Bjurström, M F; Álvarez, R; Nicol, A L; Olmstead, R; Amid, P K; Chen, D C

2017-04-01

Neurectomy of the inguinal nerves may be considered for selected refractory cases of chronic postherniorrhaphy inguinal pain (CPIP). There is to date a paucity of easily applicable clinical tools to identify neuropathic pain and examine the neurosensory effects of remedial surgery. The present quantitative sensory testing (QST) pilot study evaluates a sensory mapping technique. Longitudinal (preoperative, immediate postoperative, and late postoperative) dermatomal sensory mapping and a comprehensive QST protocol were conducted in CPIP patients with unilateral, predominantly neuropathic inguinodynia presenting for triple neurectomy (n = 13). QST was conducted in four areas on the affected, painful side and in one contralateral comparison site. QST variables were compared according to sensory mapping outcomes: (o)/normal sensation, (+)/pain, and (-)/numbness. Diagnostic ability of the sensory mapping outcomes to detect QST-assessed allodynia or hypoesthesia was estimated through calculation of specificity and sensitivity values. Preoperatively, patients exhibited mechanical hypoesthesia and allodynia and pressure allodynia and hyperalgesia in painful areas mapped (+) (p < .05); sensory mapping outcome (+) demonstrated high ability to detect mechanical allodynia [sensitivity 0.74 (95% CI 0.61-0.86), specificity 0.94 (0.84-1.00)] and pressure allodynia [sensitivity 0.96 (0.89-1.00), specificity 1.00 (1.00-1.00)], but not thermal allodynia. Postoperatively, mapped areas of numbness (-) were associated with mechanical and thermal hypoesthesia (p < .05); (-) showed high sensitivity and specificity to detect mechanical and cold hypoesthesia. Sensory mapping provides an accurate clinical neuropathic assessment with strong correlation to QST findings of preoperative mechanical and pressure allodynia, and postoperative mechanical and thermal hypoesthesia in CPIP patients undergoing neurectomy.

The inhibition of spinal synaptic plasticity mediated by activation of AMP-activated protein kinase signaling alleviates the acute pain induced by oxaliplatin.

PubMed

Ling, Yun-Zhi; Li, Zhen-Yu; Ou-Yang, Han-Dong; Ma, Chao; Wu, Shao-Ling; Wei, Jia-You; Ding, Huan-Huan; Zhang, Xiao-Long; Liu, Meng; Liu, Cui-Cui; Huang, Zhen-Zhen; Xin, Wen-Jun

2017-02-01

Our recent findings demonstrated that oxaliplatin entering CNS may directly induce spinal central sensitization, and contribute to the rapid development of CNS-related side effects including acute pain during chemotherapy. However, the mechanism is largely unclear. In the current study, we found that the amplitude of C-fiber-evoked field potentials was significantly increased and the expression of phosphorylated mammalian AMP-activated protein kinase α (AMPKα) was markedly decreased following high frequency stimulation (HFS) or single intraperitoneal injection of oxaliplatin (4mg/kg). Spinal local application of AMPK agonist metformin (25μg) prevented the long term potentiation (LTP) induction and the activation of mTOR/p70S6K signal pathway, and significantly attenuated the acute thermal hyperalgesia and mechanical allodynia following single oxaliplatin treatment. Importantly, we found that incubation of low concentration oxaliplatin at dose of 6.6nM (the detected concentration in CSF following a single intraperitoneal injection of oxaliplatin) also significantly inhibited the AMPKα activation and increased the amplitude of sEPSCs, the number of action potential, and the expression of p-mTOR and p-p70S6K in spinal cord slices. Metformin (25μg) or rapamycin (2μg) inhibited the increased excitability of dorsal horn neurons and the decrease of p-AMPKα expression induced by low concentration oxaliplatin incubation. Furthermore, spinal application of AMPK inhibitor compound C (5μg) induced the spinal LTP, thermal hyperalgesia and mechanical allodynia, and rapamycin attenuated the spinal LTP, the thermal hyperalgesia and mechanical allodynia following oxaliplatin treatment (i.p.). Local application of metformin significantly decreased the mTOR and p70S6K activation induced by tetanus stimulation or oxaliplatin (i.p.). These results suggested that the decreased AMPKα activity via negatively regulating mTOR/p70S6K signal pathway enhanced the synaptic plasticity

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.

Spinal sigma-1 receptor activation increases the production of D-serine in astrocytes which contributes to the development of mechanical allodynia in a mouse model of neuropathic pain.

PubMed

Moon, Ji-Young; Choi, Sheu-Ran; Roh, Dae-Hyun; Yoon, Seo-Yeon; Kwon, Soon-Gu; Choi, Hoon-Seong; Kang, Suk-Yun; Han, Ho-Jae; Kim, Hyun-Woo; Beitz, Alvin J; Oh, Seog-Bae; Lee, Jang-Hern

2015-10-01

We have previously demonstrated that activation of the spinal sigma-1 receptor (Sig-1R) plays an important role in the development of mechanical allodynia (MA) via secondary activation of the N-methyl-d-aspartate (NMDA) receptor. Sig-1Rs have been shown to localize to astrocytes, and blockade of Sig-1Rs inhibits the pathologic activation of astrocytes in neuropathic mice. However, the mechanism by which Sig-1R activation in astrocytes modulates NMDA receptors in neurons is currently unknown. d-serine, synthesized from l-serine by serine racemase (Srr) in astrocytes, is an endogenous co-agonist for the NMDA receptor glycine site and can control NMDA receptor activity. Here, we investigated the role of d-serine in the development of MA induced by spinal Sig-1R activation in chronic constriction injury (CCI) mice. The production of d-serine and Srr expression were both significantly increased in the spinal cord dorsal horn post-CCI surgery. Srr and d-serine were only localized to astrocytes in the superficial dorsal horn, while d-serine was also localized to neurons in the deep dorsal horn. Moreover, we found that Srr exists in astrocytes that express Sig-1Rs. The CCI-induced increase in the levels of d-serine and Srr was attenuated by sustained intrathecal treatment with the Sig-1R antagonist, BD-1047 during the induction phase of neuropathic pain. In behavioral experiments, degradation of endogenous d-serine with DAAO, or selective blockade of Srr by LSOS, effectively reduced the development of MA, but not thermal hyperalgesia in CCI mice. Finally, BD-1047 administration inhibited the development of MA and this inhibition was reversed by intrathecal treatment with exogenous d-serine. These findings demonstrate for the first time that the activation of Sig-1Rs increases the expression of Srr and d-serine in astrocytes. The increased production of d-serine induced by CCI ultimately affects dorsal horn neurons that are involved in the development of MA in neuropathic

PLGA-Curcumin Attenuates Opioid-Induced Hyperalgesia and Inhibits Spinal CaMKIIα

PubMed Central

Hu, Xiaoyu; Huang, Fang; Szymusiak, Magdalena; Tian, Xuebi; Liu, Ying; Wang, Zaijie Jim

2016-01-01

Opioid-induced hyperalgesia (OIH) is one of the major problems associated with prolonged use of opioids for the treatment of chronic pain. Effective treatment for OIH is lacking. In this study, we examined the efficacy and preliminary mechanism of curcumin in attenuating OIH. We employed a newly developed PLGA-curcumin nanoformulation (PLGA-curcumin) in order to improve the solubility of curcumin, which has been a major obstacle in properly characterizing curcumin’s mechanism of action and efficacy. We found that curcumin administered intrathecally or orally significantly attenuated hyperalgesia in mice with morphine-induced OIH. Furthermore, we demonstrated that the effects of curcumin on OIH correlated with the suppression of chronic morphine-induced CaMKIIα activation in the superficial laminae of the spinal dorsal horn. These data suggest that PLGA-curcumin may reverse OIH possibly by inhibiting CaMKIIα and its downstream signaling. PMID:26744842

Assessing the role of metabotropic glutamate receptor 5 in multiple nociceptive modalities.

PubMed

Zhu, Chang Z; Wilson, Sonya G; Mikusa, Joseph P; Wismer, Carol T; Gauvin, Donna M; Lynch, James J; Wade, Carrie L; Decker, Michael W; Honore, Prisca

2004-12-15

Preclinical data, performed in a limited number of pain models, suggest that functional blockade of metabotropic glutamate (mGlu) receptors may be beneficial for pain management. In the present study, effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective mGlu5 receptor antagonist, were examined in a wide variety of rodent nociceptive and hypersensitivity models in order to fully characterize the potential analgesic profile of mGlu5 receptor blockade. Effects of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), as potent and selective as MPEP at mGlu5/mGlu1 receptors but more selective than MPEP at N-methyl-aspartate (NMDA) receptors, were also evaluated in selected nociceptive and side effect models. MPEP (3-30 mg/kg, i.p.) produced a dose-dependent reversal of thermal and mechanical hyperalgesia following complete Freund's adjuvant (CFA)-induced inflammatory hypersensitivity. Additionally, MPEP (3-30 mg/kg, i.p.) decreased thermal hyperalgesia observed in carrageenan-induced inflammatory hypersensitivity without affecting paw edema, abolished acetic acid-induced writhing activity in mice, and was shown to reduce mechanical allodynia and thermal hyperalgesia observed in a model of post-operative hypersensitivity and formalin-induced spontaneous pain. Furthermore, at 30 mg/kg, i.p., MPEP significantly attenuated mechanical allodynia observed in three neuropathic pain models, i.e. spinal nerve ligation, sciatic nerve constriction and vincristine-induced neuropathic pain. MTEP (3-30 mg/kg, i.p.) also potently reduced CFA-induced thermal hyperalgesia. However, at 100 mg/kg, i.p., MPEP and MTEP produced central nerve system (CNS) side effects as measured by rotarod performance and exploratory locomotor activity. These results suggest a role for mGlu5 receptors in multiple nociceptive modalities, though CNS side effects may be a limiting factor in developing mGlu5 receptor analgesic compounds.

Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression

PubMed Central

Song, Zhi-Jing; Miao, Shuai; Zhao, Ye; Wang, Xiu-Li; Liu, Yue-Peng

2018-01-01

Purpose Preventing opioid-induced hyperalgesia and tolerance continues to be a major clinical challenge, and the underlying mechanisms of hyperalgesia and tolerance remain elusive. Here, we investigated the role of sonic hedgehog (Shh) signaling in opioid-induced hyperalgesia and tolerance. Methods Shh signaling expression, behavioral changes, and neurochemical alterations induced by morphine were analyzed in male adult CD-1 mice with repeated administration of morphine. To investigate the contribution of Shh to morphine-induced hyperalgesia (MIH) and tolerance, Shh signaling inhibitor cyclopamine and Shh small interfering RNA (siRNA) were used. To explore the mechanisms of Shh signaling in MIH and tolerance, brain-derived neurotrophic factor (BDNF) inhibitor K252 and anti-BDNF antibody were used. Results Repeated administration of morphine produced obvious hyperalgesia and tolerance. The behavioral changes were correlated with the upregulation and activation of morphine treatment-induced Shh signaling. Pharmacologic and genetic inhibition of Shh signaling significantly delayed the generation of MIH and tolerance and associated neurochemical changes. Chronic morphine administration also induced upregulation of BDNF. Inhibiting BDNF effectively delayed the generation of MIH and tolerance. The upregulation of BDNF induced by morphine was significantly suppressed by inhibiting Shh signaling. In naïve mice, exogenous activation of Shh signaling caused a rapid increase of BDNF expression, as well as thermal hyperalgesia. Inhibiting BDNF significantly suppressed smoothened agonist-induced hyperalgesia. Conclusion These findings suggest that Shh signaling may be a critical mediator for MIH and tolerance by regulating BDNF expression. Inhibiting Shh signaling, especially during the early phase, may effectively delay or suppress MIH and tolerance. PMID:29662325

Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-α expression in a mouse model

PubMed Central

2010-01-01

Background Tumor necrosis factor α (TNF-α) may have a pivotal role in the genesis of mechanical allodynia and thermal hyperalgesia during inflammatory and neuropathic pain. Thalidomide has been shown to selectively inhibit TNF-α production. Previous studies have suggested that thalidomide exerts anti-nociceptive effects in various pain models, but its effects on bone cancer pain have not previously been studied. Therefore, in the present study, we investigated the effect of thalidomide on bone cancer-induced hyperalgesia and up-regulated expression of spinal TNF-α in a mouse model. Results Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer related pain behaviors. At day 5, 7, 10 and 14 after operation, the expression of TNF-α in the spinal cord was higher in tumor-bearing mice compared to the sham mice. Intraperitoneal injection of thalidomide (50 mg/kg), started at day 1 after surgery and once daily thereafter until day 7, attenuated bone cancer-evoked mechanical allodynia and thermal hyperalgesia as well as the up-regulation of TNF-α in the spinal cord. Conclusions These results suggest that thalidomide can efficiently alleviate bone cancer pain and it may be a useful alternative or adjunct therapy for bone cancer pain. Our data also suggest a role of spinal TNF-α in the development of bone cancer pain. PMID:20923560

NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain

PubMed Central

Kim, Donghoon; You, Byunghyun; Jo, Eun-Kyeong; Han, Sang-Kyou; Simon, Melvin I.; Lee, Sung Joong

2010-01-01

Increasing evidence supports the notion that spinal cord microglia activation plays a causal role in the development of neuropathic pain after peripheral nerve injury; yet the mechanisms for microglia activation remain elusive. Here, we provide evidence that NADPH oxidase 2 (Nox2)-derived ROS production plays a critical role in nerve injury-induced spinal cord microglia activation and subsequent pain hypersensitivity. Nox2 expression was induced in dorsal horn microglia immediately after L5 spinal nerve transection (SNT). Studies using Nox2-deficient mice show that Nox2 is required for SNT-induced ROS generation, microglia activation, and proinflammatory cytokine expression in the spinal cord. SNT-induced mechanical allodynia and thermal hyperalgesia were similarly attenuated in Nox2-deficient mice. In addition, reducing microglial ROS level via intrathecal sulforaphane administration attenuated mechanical allodynia and thermal hyperalgesia in SNT-injured mice. Sulforaphane also inhibited SNT-induced proinflammatory gene expression in microglia, and studies using primary microglia indicate that ROS generation is required for proinflammatory gene expression in microglia. These studies delineate a pathway involving nerve damage leading to microglial Nox2-generated ROS, resulting in the expression of proinflammatory cytokines that are involved in the initiation of neuropathic pain. PMID:20679217

Anoctamin 1 contributes to inflammatory and nerve-injury induced hypersensitivity.

PubMed

Lee, Byeongjun; Cho, Hawon; Jung, Jooyoung; Yang, Young Duk; Yang, Dong-Jin; Oh, Uhtaek

2014-01-23

Various pathological conditions such as inflammation or injury can evoke pain hypersensitivity. That represents the response to innocuous stimuli or exaggerated response to noxious stimuli. The molecular mechanism based on the pain hypersensitivity is associated with changes in many of ion channels in dorsal-root ganglion (DRG) neurons. Anoctamin 1 (ANO1/TMEM16A), a Ca2+ activated chloride channel is highly visible in small DRG neurons and responds to heat. Mice with an abolished function of ANO1 in DRG neurons demonstrated attenuated pain-like behaviors when exposed to noxious heat, suggesting a role in acute thermal nociception. In this study, we further examined the function of ANO1 in mediating inflammation- or injury-induced hyperalgesia or allodynia. Using Advillin/Ano1fl/fl (Adv/Ano1fl/fl) mice that have a functional ablation of Ano1 mainly in DRG neurons, we were able to determine its role in mediating thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury. The thermal hyperalgesia and mechanical allodynia induced by carrageenan injection and spared-nerve injury were significantly reduced in Adv/Ano1fl/fl mice. In addition, flinching or licking behavior after bradykinin or formalin injection was also significantly reduced in Adv/Ano1fl/fl mice. Since pathological conditions augment nociceptive behaviors, we expected ANO1's contribution to the excitability of DRG neurons. Indeed, the application of inflammatory mediators reduced the threshold for action potential (rheobase) or time for induction of the first action potential in DRG neurons isolated from control (Ano1fl/fl) mice. These parameters for neuronal excitability induced by inflammatory mediators were not changed in Adv/Ano1fl/fl mice, suggesting an active contribution of ANO1 in augmenting the neuronal excitability. In addition to ANO1's role in mediating acute thermal pain as a heat sensor, ANO1 is also capable of augmenting the excitability of DRG neurons under

Pain increases during sympathetic arousal in patients with complex regional pain syndrome.

PubMed

Drummond, P D; Finch, P M; Skipworth, S; Blockey, P

2001-10-09

To investigate the effect of sympathetic arousal on pain and vasomotor responses in healthy control subjects and patients with complex regional pain syndrome (CRPS), and to determine whether pain increases in patients with particular symptoms. In experiments 1 and 2, capsaicin was applied to the forearm of 24 healthy subjects to induce thermal hyperalgesia. Vascular responses were monitored and subjects rated thermal hyperalgesia before and after being startled (experiment 1), and before, during, and after mental arithmetic, breath holding, forehead cooling, the Valsalva maneuver, and a cold pressor test in experiment 2. In a third experiment, sensitivity to heat, cold, and mechanical stimulation was investigated in 61 patients with CRPS. Pain ratings and vascular and electrodermal responses were recorded after patients were startled and during forehead cooling. In experiment 1, thermal hyperalgesia decreased in healthy control subjects after they were startled, and digital blood vessels constricted symmetrically. In experiment 2, thermal hyperalgesia decreased during and after other forms of sympathetic arousal. However, in experiment 3, ratings of clinical pain increased during forehead cooling or after being startled in over 70% of patients with CRPS. Pain increased most consistently during forehead cooling in patients with cold allodynia or punctate allodynia. Digital blood vessels constricted more intensely on the symptomatic than the nonsymptomatic side in patients with CRPS during sympathetic arousal. Normal inhibitory influences on pain during sympathetic arousal are compromised in the majority of patients with CRPS. The augmented vasoconstrictor response in the symptomatic limb during sympathetic arousal is consistent with adrenergic supersensitivity. An adrenergic sensitivity in nociceptive afferents might contribute to pain and hyperalgesia during sympathetic arousal in certain patients with CRPS.

Identification of Allodynic Migraine Patients with the Turkish Version of the Allodynia Symptom Checklist: Reliability and Consistency Study

PubMed Central

YALIN, Osman Özgür; ULUDÜZ, Derya; SUNGUR, Mehmet Ali; SART, Hande; ÖZGE, Aynur

2017-01-01

Introduction Cutaneous allodynia is regarded as an expression of central sensitization in migraine. Although the gold standard is quantitative sensory testing, several practical assessment questionnaires have been developed to assess allodynia in migraine. We aimed to establish the first valid Turkish allodynia assessment questionnaire based on a 12-item allodynia symptom checklist and to evaluate the associated factors. Methods The first part of the study included the translation and cultural adaptation of a Turkish version of the checklist. The Turkish version of the questionnaire was administered to 344 episodic and chronic migraine patients, who were chosen according to the International Classification of Headache Disorders -III beta criteria. Results The total checklist score showed excellent test–retest reliability (r=0.821). The internal consistency of the checklist was assessed using Cronbach alpha values and was found to be acceptable (Cronbach alpha for the checklist=0.767). Data analysis revealed that 10 items of the questionnaire adequately identified allodynic subjects. Cutaneous allodynia was present in 218 (63.4%) migraine patients. Allodynia was more prominent in patients experiencing migraine with aura (p=0.008) and in females (p<0.001). Multiple logistic regression analysis found that female gender, aura existence, longer headache duration, and higher attack frequency were the major determinants of cutaneous allodynia. Conclusion Allodynia is common and has clinical significance in migraine; therefore, establishing a validated Turkish questionnaire for the assessment of allodynia was necessary. In this study, a Turkish version of the allodynia symptom checklist was validated and found to be convenient for the identification of allodynia in migraine patients. PMID:29033640

Identification of Allodynic Migraine Patients with the Turkish Version of the Allodynia Symptom Checklist: Reliability and Consistency Study.

PubMed

Yalin, Osman Özgür; Uludüz, Derya; Sungur, Mehmet Ali; Sart, Hande; Özge, Aynur

2017-09-01

Cutaneous allodynia is regarded as an expression of central sensitization in migraine. Although the gold standard is quantitative sensory testing, several practical assessment questionnaires have been developed to assess allodynia in migraine. We aimed to establish the first valid Turkish allodynia assessment questionnaire based on a 12-item allodynia symptom checklist and to evaluate the associated factors. The first part of the study included the translation and cultural adaptation of a Turkish version of the checklist. The Turkish version of the questionnaire was administered to 344 episodic and chronic migraine patients, who were chosen according to the International Classification of Headache Disorders -III beta criteria. The total checklist score showed excellent test-retest reliability (r=0.821). The internal consistency of the checklist was assessed using Cronbach alpha values and was found to be acceptable (Cronbach alpha for the checklist=0.767). Data analysis revealed that 10 items of the questionnaire adequately identified allodynic subjects. Cutaneous allodynia was present in 218 (63.4%) migraine patients. Allodynia was more prominent in patients experiencing migraine with aura (p=0.008) and in females (p<0.001). Multiple logistic regression analysis found that female gender, aura existence, longer headache duration, and higher attack frequency were the major determinants of cutaneous allodynia. Allodynia is common and has clinical significance in migraine; therefore, establishing a validated Turkish questionnaire for the assessment of allodynia was necessary. In this study, a Turkish version of the allodynia symptom checklist was validated and found to be convenient for the identification of allodynia in migraine patients.

Hedgehog signaling regulates nociceptive sensitization.

PubMed

Babcock, Daniel T; Shi, Shanping; Jo, Juyeon; Shaw, Michael; Gutstein, Howard B; Galko, Michael J

2011-09-27

Nociceptive sensitization is a tissue damage response whereby sensory neurons near damaged tissue enhance their responsiveness to external stimuli. This sensitization manifests as allodynia (aversive withdrawal to previously nonnoxious stimuli) and/or hyperalgesia (exaggerated responsiveness to noxious stimuli). Although some factors mediating nociceptive sensitization are known, inadequacies of current analgesic drugs have prompted a search for additional targets. Here we use a Drosophila model of thermal nociceptive sensitization to show that Hedgehog (Hh) signaling is required for both thermal allodynia and hyperalgesia following ultraviolet irradiation (UV)-induced tissue damage. Sensitization does not appear to result from developmental changes in the differentiation or arborization of nociceptive sensory neurons. Genetic analysis shows that Hh signaling acts in parallel to tumor necrosis factor (TNF) signaling to mediate allodynia and that distinct transient receptor potential (TRP) channels mediate allodynia and hyperalgesia downstream of these pathways. We also demonstrate a role for Hh in analgesic signaling in mammals. Intrathecal or peripheral administration of cyclopamine (CP), a specific inhibitor of Sonic Hedgehog signaling, blocked the development of analgesic tolerance to morphine (MS) or morphine antinociception in standard assays of inflammatory pain in rats and synergistically augmented and sustained morphine analgesia in assays of neuropathic pain. We demonstrate a novel physiological role for Hh signaling, which has not previously been implicated in nociception. Our results also identify new potential therapeutic targets for pain treatment. Copyright © 2011 Elsevier Ltd. All rights reserved.

Dose-response study of topical allyl isothiocyanate (mustard oil) as a human surrogate model of pain, hyperalgesia, and neurogenic inflammation.

PubMed

Andersen, Hjalte H; Lo Vecchio, Silvia; Gazerani, Parisa; Arendt-Nielsen, Lars

2017-09-01

Despite being a ubiquitous animal pain model, the natural TRPA1-agonist allyl isothiocyanate (AITC, also known as "mustard oil") has only been sparsely investigated as a potential human surrogate model of pain, sensitization, and neurogenic inflammation. Its dose-response as an algogenic, sensitizing irritant remains to be elucidated in human skin. Three concentrations of AITC (10%, 50%, and 90%) and vehicle (paraffin) were applied for 5 minutes to 3 × 3 cm areas on the volar forearms in 14 healthy volunteers, and evoked pain intensity (visual analog scale 0-100 mm) and pain quality were assessed. In addition, a comprehensive battery of quantitative sensory tests was conducted, including assessment of mechanical and thermal sensitivity. Neurogenic inflammation was quantified using full-field laser perfusion imaging. Erythema and hyperpigmentation were assessed before, immediately after, and ≈64 hours after AITC exposure. AITC induced significant dose-dependent, moderate-to-severe spontaneous burning pain, mechanical and heat hyperalgesia, and dynamic mechanical allodynia (P < 0.05). No significant differences in induced pain hypersensitivity were observed between the 50% and 90% AITC concentrations. Acute and prolonged inflammation was evoked by all concentrations, and assessments by full-field laser perfusion imaging demonstrated a significant dose-dependent increase with a ceiling effect from 50% to 90%. Topical AITC application produces pain and somatosensory sensitization in a dose-dependent manner with optimal concentrations recommended to be >10% and ≤50%. The model is translatable to humans and could be useful in pharmacological proof-of-concept studies of TRPA1-antagonists, analgesics, and anti-inflammatory compounds or for exploratory clinical purposes, eg, loss- or gain-of-function in peripheral neuropathies.

Osthole, a herbal compound, alleviates nucleus pulposus-evoked nociceptive responses through the suppression of overexpression of acid-sensing ion channel 3 (ASIC3) in rat dorsal root ganglion

PubMed Central

He, Qiu-Lan; Chen, Yuling; Qin, Jian; Mo, Sui-Lin; Wei, Ming; Zhang, Jin-Jun; Li, Mei-Na; Zou, Xue-Nong; Zhou, Shu-Feng; Chen, Xiao-Wu; Sun, Lai-Bao

2012-01-01

Summary Background Osthole (Ost), a natural coumarin derivative, has been shown to inhibit many pro-inflammatory mediators and block voltage-gated Na+ channels. During inflammation, acidosis is an important pain inducer which activates nociceptors by gating depolarizing cationic channels, such as acid-sensing ion channel 3 (ASIC3). The aim of this study was to examine the effects of Ost on nucleus pulposus-evoked nociceptive responses and ASIC3 over-expression in the rat dorsal root ganglion, and to investigate the possible mechanism. Material/Methods Radicular pain was generated with application of nucleus pulposus (NP) to nerve root. Mechanical allodynia was evaluated using von Frey filaments with logarithmically incremental rigidity to calculate the 50% probability thresholds for mechanical paw withdrawal. ASIC3 protein expression in dorsal root ganglions (DRGs) was assessed with Western blot and immunohistochemistry. Membrane potential (MP) shift of DRG neurons induced by ASIC3-sensitive acid (pH6.5) was determined by DiBAC4 (3) fluorescence intensity (F.I.). Results The NP-evoked mechanical hyperalgesia model showed allodynia for 3 weeks, and ASIC3 expression was up-regulated in DRG neurons, reaching peak on Day 7. Epidural administration of Ost induced a remarkable and prolonged antinociceptive effect, accompanied by an inhibition of over-expressed ASIC3 protein and of abnormal shift of MP. Amiloride (Ami), an antagonist of ASIC3, strengthened the antinociceptive effect of Ost. Conclusions Up-regulation of ASIC3 expression may be associated with NP-evoked mechanical hyperalgesia. A single epidural injection of Ost decreased ASIC3 expression in DGR neurons and the pain in the NP-evoked mechanical hyperalgesia model. Osthole may be of great benefit for preventing chronic pain status often seen in lumbar disc herniation (LDH). PMID:22648244

Increased Hyperalgesia and Proinflammatory Cytokines in the Spinal Cord and Dorsal Root Ganglion After Surgery and/or Fentanyl Administration in Rats

PubMed Central

Chang, Lu; Ye, Fang; Luo, Quehua; Tao, Yuanxiang

2018-01-01

BACKGROUND: Perioperative fentanyl has been reported to induce hyperalgesia and increase postoperative pain. In this study, we tried to investigate behavioral hyperalgesia, the expression of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and the activation of microglia in the spinal cord and dorsal root ganglion (DRG) in a rat model of surgical plantar incision with or without perioperative fentanyl. METHODS: Four groups of rats (n = 32 for each group) were subcutaneously injected with fentanyl at 60 μg/kg or normal saline for 4 times with 15-minute intervals. Plantar incisions were made to rats in 2 groups after the second drug injection. Mechanical and thermal nociceptive thresholds were assessed by the tail pressure test and paw withdrawal test on the day before, at 1, 2, 3, 4 hours, and on the days 1–7 after drug injection. The lumbar spinal cord, bilateral DRG, and cerebrospinal fluid of 4 rats in each group were collected to measure IL-1β, IL-6, and TNF-α on the day before, at the fourth hour, and on the days 1, 3, 5, and 7 after drug injection. The lumbar spinal cord and bilateral DRG were removed to detect the ionized calcium-binding adapter molecule 1 on the day before and on the days 1 and 7 after drug injection. RESULTS: Rats injected with normal saline only demonstrated no significant mechanical or thermal hyperalgesia or any increases of IL-1β, IL-6, and TNF-α in the spinal cord or DRG. However, injection of fentanyl induced analgesia within as early as 4 hours and a significant delayed tail mechanical and bilateral plantar thermal hyperalgesia after injections lasting for 2 days, while surgical plantar incision induced a significant mechanical and thermal hyperalgesia lasting for 1–4 days. The combination of fentanyl and incision further aggravated the hyperalgesia and prolonged the duration of hyperalgesia. The fentanyl or surgical incision upregulated the expression

Increased Hyperalgesia and Proinflammatory Cytokines in the Spinal Cord and Dorsal Root Ganglion After Surgery and/or Fentanyl Administration in Rats.

PubMed

Chang, Lu; Ye, Fang; Luo, Quehua; Tao, Yuanxiang; Shu, Haihua

2018-01-01

Perioperative fentanyl has been reported to induce hyperalgesia and increase postoperative pain. In this study, we tried to investigate behavioral hyperalgesia, the expression of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and the activation of microglia in the spinal cord and dorsal root ganglion (DRG) in a rat model of surgical plantar incision with or without perioperative fentanyl. Four groups of rats (n = 32 for each group) were subcutaneously injected with fentanyl at 60 μg/kg or normal saline for 4 times with 15-minute intervals. Plantar incisions were made to rats in 2 groups after the second drug injection. Mechanical and thermal nociceptive thresholds were assessed by the tail pressure test and paw withdrawal test on the day before, at 1, 2, 3, 4 hours, and on the days 1-7 after drug injection. The lumbar spinal cord, bilateral DRG, and cerebrospinal fluid of 4 rats in each group were collected to measure IL-1β, IL-6, and TNF-α on the day before, at the fourth hour, and on the days 1, 3, 5, and 7 after drug injection. The lumbar spinal cord and bilateral DRG were removed to detect the ionized calcium-binding adapter molecule 1 on the day before and on the days 1 and 7 after drug injection. Rats injected with normal saline only demonstrated no significant mechanical or thermal hyperalgesia or any increases of IL-1β, IL-6, and TNF-α in the spinal cord or DRG. However, injection of fentanyl induced analgesia within as early as 4 hours and a significant delayed tail mechanical and bilateral plantar thermal hyperalgesia after injections lasting for 2 days, while surgical plantar incision induced a significant mechanical and thermal hyperalgesia lasting for 1-4 days. The combination of fentanyl and incision further aggravated the hyperalgesia and prolonged the duration of hyperalgesia. The fentanyl or surgical incision upregulated the expression of IL-1β, IL-6, and TNF-α in the

Tumor-evoked hyperalgesia and sensitization of nociceptive dorsal horn neurons in a murine model of cancer pain

PubMed Central

Khasabov, Sergey G.; Hamamoto, Darryl T.; Harding-Rose, Catherine; Simone, Donald A.

2009-01-01

Pain associated with cancer, particularly when tumors metastasize to bone, is often severe and debilitating. Better understanding of the neurobiological mechanisms underlying cancer pain will likely lead to the development of more effective treatments. The aim of this study was to characterize changes in response properties of nociceptive dorsal horn neurons following implantation of fibrosarcoma cells into and around the calcaneus bone, an established model of cancer pain. Extracellular electrophysiological recordings were made from wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons in mice with tumor-evoked hyperalgesia and control mice. WDR and HT neurons were examined for ongoing activity and responses to mechanical, heat, and cold stimuli applied to the plantar surface of the hind paw. Behavioral experiments showed that mice exhibited hyperalgesia to mechanical and heat stimuli applied to their tumor-bearing hind paw. WDR, but not HT, nociceptive dorsal horn neurons in tumor-bearing mice exhibited sensitization to mechanical, heat, and cold stimuli and may contribute to tumor-evoked hyperalgesia. Specifically, the proportion of WDR neurons that exhibited ongoing activity and their evoked discharge rates were greater in tumor-bearing than in control mice. In addition, WDR neurons exhibited lower response thresholds for mechanical and heat stimuli, and increased responses to suprathreshold mechanical, heat, and cold stimuli. Our findings show that sensitization of WDR neurons contribute to cancer pain and support the notion that the mechanisms underlying cancer pain differ from those that contribute to inflammatory and neuropathic pain. PMID:17935703

Osthole, a Coumadin Analog from Cnidium monnieri (L.) Cusson, Ameliorates Nucleus Pulposus-Induced Radicular Inflammatory Pain by Inhibiting the Activation of Extracellular Signal-Regulated Kinase in Rats.

PubMed

Wu, Hai-Xuan; Wang, Yi-Min; Xu, Hui; Wei, Ming; He, Qiu-Lan; Li, Mei-Na; Sun, Lai-Bao; Cao, Ming-Hui

2017-01-01

This study was aimed at assessing the role of extracellular signal regulated kinase (ERK) in mechanical allodynia resulting from lumbar disc herniation (LDH) and exploring the osthole's anti-nociceptive effect on ERK activation. Radicular pain was generated by applying nucleus pulposus (NP) to the L5 dorsal root ganglion (DRG). Allodynia was measured using Von Frey filaments to calculate the mechanical pain threshold. Phosphorylated ERK and total ERK protein in the lumbar spinal dorsal horn was detected by using the Western blot technique. Cyclooxygenase 2 (COX-2) mRNA was assessed by real-time reverse-transcription polymerase chain reaction. The application of NP to L5 DRG induced mechanical hypersensitivity which lasted for at least 28 days, and a significant increase of ERK phosphorylation in the ipsilateral spinal dorsal horn from postoperative day (POD) 1 to POD 21. ERK inhibitor attenuated NP-induced hyperalgesia compared to the dimethyl sulfoxide-(vehicle control) administered group (p < 0.05). Epidural treatment with osthole could ameliorate NP-evoked hyperalgesia by suppressing the activation of ERK rather than decreasing the expression of ERK protein. Osthole could also inhibit the increased expression of COX-2 mRNA in spinal dorsal horn, which was a known downstream effect of ERK signaling pathway. Our results suggest that ERK activation in the spinal dorsal horn plays a vital role in NP-evoked hyperalgesia. Osthole exerts analgesic effect on radicular inflammatory pain in LDH rat model, by down-regulating the mRNA expression of the target gene of COX-2 via inhibiting ERK activation in the spinal dorsal horn. © 2017 S. Karger AG, Basel.

Depression-like behavior and mechanical allodynia are reduced by bis selenide treatment in mice with chronic constriction injury: a comparison with fluoxetine, amitriptyline, and bupropion.

PubMed

Jesse, Cristiano R; Wilhelm, Ethel A; Nogueira, Cristina W

2010-12-01

Neuropathic pain is associated with significant co-morbidities, including depression, which impact considerably on the overall patient experience. Pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. Neuropathic pain is characterized by hyperexcitability within nociceptive pathways and remains difficult to treat with standard analgesics. The present study determined the effect of bis selenide and conventional antidepressants (fluoxetine, amitriptyline, and bupropion) on neuropathic pain using mechanical allodynic and on depressive-like behavior. Male mice were subjected to chronic constriction injury (CCI) or sham surgery and were assessed on day 14 after operation. Mice received oral treatment with bis selenide (1-5 mg/kg), fluoxetine, amitriptyline, or bupropion (10-30 mg/kg). The response frequency to mechanical allodynia in mice was measured with von Frey hairs. Mice were evaluated in the forced swimming test (FST) test for depression-like behavior. The CCI procedure produced mechanical allodynia and increased depressive-like behavior in the FST. All of the drugs produced antiallodynic effects in CCI mice and produced antidepressant effects in control mice without altering locomotor activity. In CCI animals, however, only the amitriptyline and bis selenide treatments significantly reduced immobility in the FST. These data demonstrate an important dissociation between the antiallodynic and antidepressant effects in mice when tested in a model of neuropathic pain. Depressive behavior in CCI mice was reversed by bis selenide and amitriptyline but not by the conventional antidepressants fluoxetine and buproprion. Bis selenide was more potent than the other drugs tested for antidepressant-like and antiallodynic effects in mice.

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

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.

Persistent visceral allodynia in rats exposed to colorectal irradiation is reversed by mesenchymal stromal cell treatment.

PubMed

Durand, Christelle; Pezet, Sophie; Eutamène, Hélène; Demarquay, Christelle; Mathieu, Noëlle; Moussa, Lara; Daudin, Rachel; Holler, Valérie; Sabourin, Jean-Christophe; Milliat, Fabien; François, Agnès; Theodorou, Vassilia; Tamarat, Radia; Benderitter, Marc; Sémont, Alexandra

2015-08-01

Each year, millions of people worldwide are treated for primary or recurrent pelvic malignancies, involving radiotherapy in almost 50% of cases. Delayed development of visceral complications after radiotherapy is recognized in cancer survivors. Therapeutic doses of radiation may lead to the damage of healthy tissue around the tumor and abdominal pain. Because of the lack of experimental models, the underlying mechanisms of radiation-induced long-lasting visceral pain are still unknown. This makes managing radiation-induced pain difficult, and the therapeutic strategies proposed are mostly inefficient. The aim of our study was to develop an animal model of radiation-induced visceral hypersensitivity to (1) analyze some cellular and molecular mechanisms involved and (2) to test a therapeutic strategy using mesenchymal stromal cells (MSCs). Using a single 27-Grays colorectal irradiation in rats, we showed that such exposure induces a persistent visceral allodynia that is associated with an increased spinal sensitization (enhanced p-ERK neurons), colonic neuroplasticity (as increased density of substance P nerve fibers), and colonic mast cell hyperplasia and hypertrophy. Mast cell stabilization by ketotifen provided evidence of their functional involvement in radiation-induced allodynia. Finally, intravenous injection of 1.5 million MSCs, 4 weeks after irradiation, induced a time-dependent reversion of the visceral allodynia and a reduction of the number of anatomical interactions between mast cells and PGP9.5+ nerve fibers. Moreover, unlike ketotifen, MSC treatment has the key advantage to limit radiation-induced colonic ulceration. This work provides new insights into the potential use of MSCs as cellular therapy in the treatment of pelvic radiation disease.

Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats.

PubMed

Xu, Dabo; Gao, Jun; Gillilland, Merritt; Wu, Xiaoyin; Song, Il; Kao, John Y; Owyang, Chung

2014-02-01

Rifaximin is used to treat patients with functional gastrointestinal disorders, but little is known about its therapeutic mechanism. We propose that rifaximin modulates the ileal bacterial community, reduces subclinical inflammation of the intestinal mucosa, and improves gut barrier function to reduce visceral hypersensitivity. We induced visceral hyperalgesia in rats, via chronic water avoidance or repeat restraint stressors, and investigated whether rifaximin altered the gut microbiota, prevented intestinal inflammation, and improved gut barrier function. Quantitative polymerase chain reaction (PCR) and 454 pyrosequencing were used to analyze bacterial 16S ribosomal RNA in ileal contents from the rats. Reverse transcription, immunoblot, and histologic analyses were used to evaluate levels of cytokines, the tight junction protein occludin, and mucosal inflammation, respectively. Intestinal permeability and rectal sensitivity were measured. Water avoidance and repeat restraint stress each led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function. Oral rifaximin altered the composition of bacterial communities in the ileum (Lactobacillus species became the most abundant) and prevented mucosal inflammation, impairment to intestinal barrier function, and visceral hyperalgesia in response to chronic stress. Neomycin also changed the composition of the ileal bacterial community (Proteobacteria became the most abundant species). Neomycin did not prevent intestinal inflammation or induction of visceral hyperalgesia induced by water avoidance stress. Rifaximin alters the bacterial population in the ileum of rats, leading to a relative abundance of Lactobacillus. These changes prevent intestinal abnormalities and visceral hyperalgesia in response to chronic psychological stress. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Rifaximin Alters Intestinal Bacteria and Prevents Stress-Induced Gut Inflammation and Visceral Hyperalgesia in Rats

PubMed Central

Xu, Dabo; Gao, Jun; Gillilland, Merritt; Wu, Xiaoyin; Song, Il; Kao, John Y.; Owyang, Chung

2014-01-01

Background & Aims Rifaximin is used to treat patients with functional gastrointestinal disorders, but little is known about its therapeutic mechanism. We propose that rifaximin modulates the ileal bacterial community, reduces subclinical inflammation of the intestinal mucosa, and improves gut barrier function to reduce visceral hypersensitivity. Methods We induced visceral hyperalgesia in rats, via chronic water avoidance or repeat restraint stressors, and investigated whether rifaximin altered the gut microbiota, prevented intestinal inflammation, and improved gut barrier function. Quantitative polymerase chain reaction and 454 pyrosequencing were used to analyze bacterial 16S rRNA in ileal contents from the rats. Reverse transcription, immunoblot, and histologic analyses were used to evaluate levels of cytokines, the tight junction protein occludin, and mucosal inflammation, respectively. Intestinal permeability and rectal sensitivity were measured. Results Water avoidance and repeat restraint stress each led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function. Oral rifaximin altered the composition of bacterial communities in the ileum (Lactobacillus species became the most abundant) and prevented mucosal inflammation, impairment to intestinal barrier function, and visceral hyperalgesia in response to chronic stress. Neomycin also changed the composition of the ileal bacterial community (Proteobacteria became the most abundant species). Neomycin did not prevent intestinal inflammation or induction of visceral hyperalgesia induced by water avoidance stress. Conclusions Rifaximin alters the bacterial population in the ileum of rats, leading to a relative abundance of Lactobacillus. These changes prevent intestinal abnormalities and visceral hyperalgesia in response to chronic psychological stress. PMID:24161699

Resveratrol-decreased hyperalgesia mediated by the P2X7 receptor in gp120-treated rats.

PubMed

Wu, Bing; Ma, Yucheng; Yi, Zhihua; Liu, Shuangmei; Rao, Shenqiang; Zou, Lifang; Wang, Shouyu; Xue, Yun; Jia, Tianyu; Zhao, Shanhong; Shi, Liran; Li, Lin; Yuan, Huilong; Liang, Shangdong

2017-01-01

Background Chronic pain is a common symptom in human immunodeficiency virus (HIV)-1 infection/acquired immunodeficiency syndrome patients. The literature shows that the HIV envelope glycoprotein 120 (gp120) can directly cause hyperalgesia by stimulating primary sensory afferent nerves. The P2X 7 receptor in the dorsal root ganglia (DRG) is closely related to neuropathic and inflammatory pain. In this study, we aimed to explore the effect of resveratrol (RES) on gp120-induced neuropathic pain that is mediated by the P2X 7 receptor in the rat DRG. Results Mechanical hyperalgesia in rats treated with gp120 was increased compared with that in the sham group. The P2X 7 expression levels in rats treated with gp120 were higher than those in the sham group. Co-localization of the P2X 7 receptor and glial fibrillary acidic protein (GFAP, a marker of satellite glial cells [SGCs]) in the DRG SGCs of the gp120 group exhibited more intense staining than that of the sham group. RES decreased the mechanical hyperalgesia and P2X 7 expression levels in gp120 treatment rats. Co-localization of the P2X 7 receptor and GFAP in the gp120+ RES group was significantly decreased compared to the gp120 group. RES decreased the IL-1β and TNF-α receptor (R) expression levels and ERK1/2 phosphorylation levels as well as increased IL-10 expression in the DRG of gp120-treated rats. Whole cell clamping demonstrated that RES significantly inhibited adenosine triphosphate-activated currents in HEK293 cells that were transfected with the P2X 7 plasmid. Conclusions RES relieved mechanical hyperalgesia in gp120-treated rats by inhibiting the P2X 7 receptor.

LASSBio-1135: a dual TRPV1 antagonist and anti-TNF-alpha compound orally effective in models of inflammatory and neuropathic pain.

PubMed

Lima, Cleverton K F; Silva, Rafael M; Lacerda, Renata B; Santos, Bruna L R; Silva, Rafaela V; Amaral, Luciana S; Quintas, Luís E M; Fraga, Carlos A M; Barreiro, Eliezer J; Guimaraes, Marília Z P; Miranda, Ana L P

2014-01-01

LASSBio-1135 is an imidazo[1,2-a]pyridine derivative with high efficacy in screening models of nociception and inflammation, presumed as a weak COX-2 inhibitor. In order to tease out its mechanism of action, we investigated others possible target for LASSBio-1135, such as TNF-α and TRPV1, to better characterize it as a multitarget compound useful in the treatment of chronic pain. TRPV1 modulation was assessed in TRPV1-expressing Xenopus oocytes against capsaicin and low pH-induced current. Modulation of TNF-α production was evaluated in culture of macrophages stimulated with LPS. In vivo efficacy of LASSBio-1135 was investigated in carrageenan and partial sciatic ligation-induced thermal hyperalgesia and mechanical allodynia. Corroborating its previous demonstration of efficacy in a model of capsaicin-induced hyperalgesia, LASSBio-1135 blocks capsaicin-elicited currents in a non-competitive way with an IC50 of 580 nM as well as low pH-induced current at 50 µM. As an additional action, LASSBio-1135 inhibited TNF-α release in these cells stimulated by LPS with an IC50 of 546 nM by reducing p38 MAPK phosphorilation. Oral administration of 100 µmol x Kg(-1) LASSBio-1135 markedly reduced thermal hyperalgesia induced by carrageenan, however at 10 µmol x Kg(-1) only a partial reduction was observed at the 4th h. Neutrophil recruitment and TNF-α production after carrageenan stimulus was also inhibited by the treatment with LASSBio-1135. Modulating TRPV1 and TNF-α production, two key therapeutic targets of neuropathic pain, 100 µmol x Kg(-1) LASSBio-1135 was orally efficacious in reversing thermal hyperalgesia and mechanical allodynia produced by partial sciatic ligation 7-11 days after surgery without provoking hyperthermia, a common side effect of TRPV1 antagonists. In conclusion LASSBio-1135, besides being a weak COX-2 inhibitor, is a non-competitive TRPV1 antagonist and a TNF-α inhibitor. As a multitarget compound, LASSBio-1135 is orally efficacious in a model

Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model.

PubMed

Larsen, Malte Selch; Keizer, Ron; Munro, Gordon; Mørk, Arne; Holm, René; Savic, Rada; Kreilgaard, Mads

2016-05-01

Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia. A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous). The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate (K m  = 44.1 mg/kg, V max  = 41.9 mg/h∙kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E max function describing reversal of hyperalgesia (EC 50, plasma  = 16.7 μg/mL, EC 50, brain  = 3.3 μg/mL). The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin.

Pathological mechanism of musculoskeletal manifestations associated with CRPS type II: an animal study.

PubMed

Ota, Hideyuki; Arai, Tetsuya; Iwatsuki, Katsuyuki; Urano, Hideki; Kurahashi, Toshikazu; Kato, Shuichi; Yamamoto, Michiro; Hirata, Hitoshi

2014-10-01

Patients with complex regional pain syndrome (CRPS) often complain of abnormal sensations beyond the affected body part, but causes of this spread of musculoskeletal manifestations into contiguous areas remain unclear. In addition, immobilization can predispose to the development of CRPS. We examined functional, biochemical, and histological alterations in affected parts, including contiguous zones, using an animal model. Ten-week-old male Wistar rats were assigned to 5 groups: a normal group receiving no treatment, a sham operation group with surgical exploration, an immobilization group with surgical exploration plus internal knee joint immobilization, a surgical neuropathy group prepared by spinal nerve ligation (SNL) of the left L5 nerve root, and a surgical neuropathy+immobilization group with simultaneous SNL and knee joint immobilization. Mechanical allodynia and knee contracture were compared between groups, and tissues were harvested for histological assessments and gene and protein expression analyses. Neither surgical procedures nor immobilization induced detectable mechanical sensitivity. However, the addition of nerve injury resulted in detectable mechanical allodynia, and immobilization not only accelerated hyperalgesia, but also resulted in muscle fibrosis. Nerve growth factor (NGF) and other mediators of neurogenic inflammation were highly expressed not only in denervated muscles, but also in innervated muscles in contiguous areas, suggesting the spread of NGF production beyond the myotome of the injured nerve. Transforming growth factor β was involved in the development of contracture in CRPS. These findings imply that neuroinflammatory components play major roles in the progression and dispersion of both sensory pathologies and pathologies that are exacerbated by immobilization. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

The BDNF/TrkB signaling pathway is involved in heat hyperalgesia mediated by Cdk5 in rats.

PubMed

Zhang, Hong-Hai; Zhang, Xiao-Qin; Xue, Qing-Sheng; Yan-Luo; Huang, Jin-Lu; Zhang, Su; Shao, Hai-Jun; Lu, Han; Wang, Wen-Yuan; Yu, Bu-Wei

2014-01-01

Cyclin-dependent kinase 5 (Cdk5) has been shown to play an important role in mediating inflammation-induced heat hyperalgesia. However, the underlying mechanism remains unclear. The aim of this study was to determine whether roscovitine, an inhibitor of Cdk5, could reverse the heat hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA) via the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway in the dorsal horn of the spinal cord in rats. Heat hyperalgesia induced by peripheral injection of CFA was significantly reversed by roscovitine, TrkB-IgG, and the TrkB inhibitor K252a, respectively. Furthermore, BDNF was significantly increased from 0.5 h to 24 h after CFA injection in the spinal cord dorsal horn. Intrathecal adminstration of the Cdk5 inhibitor roscovitine had no obvious effects on BDNF levels. Increased TrkB protein level was significantly reversed by roscovitine between 0.5 h and 6 h after CFA injection. Cdk5 and TrkB co-immunoprecipitation results suggested Cdk5 mediates the heat hyperalgesia induced by CFA injection by binding with TrkB, and the binding between Cdk5 and TrkB was markedly blocked by intrathecal adminstration of roscovitine. Our data suggested that the BDNF-TrkB signaling pathway was involved in CFA-induced heat hyperalgesia mediated by Cdk5. Roscovitine reversed the heat hyperalgesia induced by peripheral injection of CFA by blocking BDNF/TrkB signaling pathway, suggesting that severing the close crosstalk between Cdk5 and the BDNF/TrkB signaling cascade may present a potential target for anti-inflammatory pain.

Psychophysics, flare, and neurosecretory function in human pain models: capsaicin versus electrically evoked pain.

PubMed

Geber, Christian; Fondel, Ricarda; Krämer, Heidrun H; Rolke, Roman; Treede, Rolfe-Detlef; Sommer, Claudia; Birklein, Frank

2007-06-01

Intradermal capsaicin injection (CAP) and electrical current stimulation (ES) are analyzed in respect to patterns and test-retest reliability of pain as well as sensory and neurosecretory changes. In 10 healthy subjects, 2x CAP (50 microg) and 2x ES (5 to 30 mA) were applied to the volar forearm. The time period between 2 identical stimulations was about 4 months. Pain ratings, areas of mechanical hyperalgesia, and allodynia were assessed. The intensity of sensory changes was quantified by using quantitative sensory testing. Neurogenic flare was assessed by using laser Doppler imaging. Calcitonin gene-related peptide (CGRP) release was quantified by dermal microdialysis in combination with an enzyme immunoassay. Time course and peak pain ratings were different between CAP and ES. Test-retest correlation was high (r > or = 0.73). Both models induced primary heat hyperalgesia and primary plus secondary pin-prick hyperalgesia. Allodynia occurred in about half of the subjects. Maximum flare sizes did not differ between CAP and ES, but flare intensities were higher for ES. Test-retest correlation was higher for flare sizes than for flare intensity. A significant CGRP release could only be measured after CAP. The different time courses of pain stimulation (CAP: rapidly decaying pain versus ES: pain plateau) led to different peripheral neurosecretory effects but induced similar central plasticity and hyperalgesia. The present study gives a detailed overview of psychophysical and neurosecretory characteristics induced by noxious stimulation with capsaicin and electrical current. We describe differences, similarities, and reproducibility of these human pain models. These data might help to interpret past and future results of human pain studies using experimental pain.

Cutaneous Allodynia and Its Risk Factors in Korean Patients with Migraine: A Survey of Two Tertiary Care Hospitals.

PubMed

Kim, Sun-Young; Park, Sung-Pa

2016-01-01

To measure the prevalence of cutaneous allodynia in Korean patients with migraine and to characterize the differential risks of migraine-associated factors and psychiatric disorders in its development. The study included consecutive patients with migraine who visited headache clinics at two tertiary care hospitals. Questionnaires including the 12-item Allodynia Symptom Checklist (ASC-12) and the Migraine Disability Assessment (MIDAS) were administered to the patients. The Mini International Neuropsychiatric Interview-Plus, Version 5.0.0 (MINI), was performed to diagnose current major depressive disorder (MDD) and current generalized anxiety disorder (GAD). To determine the predictive factors of cutaneous allodynia, a two-step logistic regression model was used. A total of 332 patients were eligible for the study. Chronic migraine (CM) was present in 140 patients (42.2%). Current MDD and current GAD were identified in 73 (21.9%) and 59 patients (17.7%), respectively. Cutaneous allodynia was present in 48 patients (14.5%). Univariate analyses indicated that cutaneous allodynia was associated with female gender, CM, medication overuse headache, headache intensity, photophobia, phonophobia, MIDAS grade, current MDD, and current GAD. Multivariate analyses revealed that current MDD was the strongest risk factor for cutaneous allodynia (adjusted odds ratio [AOR] = 4.552; 95% confidence intervals [CI] = 2.300-9.007; P = .000), followed by CM (AOR = 3.666; 95% CI = 1.787-7.521; P = .000) and photophobia (AOR = 2.707; 95% CI = 1.340-5.469; P = .005). Korean patients with migraine have a low prevalence of cutaneous allodynia. Both depression and migraine-associated features are important factors in the occurrence of cutaneous allodynia.

An adenosine kinase inhibitor attenuates tactile allodynia in a rat model of diabetic neuropathic pain.

PubMed

Lynch, J J; Jarvis, M F; Kowaluk, E A

1999-01-08

The present study was conducted to characterize the development of tactile allodynia in the streptozotocin-induced rat model of diabetes, and to evaluate the antinociceptive effects of systemically administered morphine and the adenosine kinase inhibitor, 5'-deoxy-5-iodotubercidin (5'd-5IT) in this model. Rats were injected with 75 mg/kg streptozotocin (i.p.), and blood glucose levels were determined 3-4 weeks later. Diabetic (blood glucose levels > or = 250 mg/dl) and vehicle-injected rats were examined weekly for the development of tactile allodynia by measuring the threshold for hind paw withdrawal using von Frey hairs. Withdrawal thresholds were reduced to 6.8+/-0.6 g (mean+/-S.E.M.) in approximately one-third of streptozotocin-treated rats 7 weeks after streptozotocin treatment as compared to control thresholds (13.2+/-0.1 g), and this allodynia persisted for at least an additional 7 weeks. In additional experiments, morphine sulfate (5-21 micromol/kg, i.p.) produced dose-dependent antinociceptive effects on tactile allodynia for up to 2 h post-dosing. The adenosine kinase inhibitor, 5'd-5IT (2.5 and 5 micromol/kg, i.p.) also dose-dependently attenuated tactile allodynia. Pretreatment with the opioid receptor antagonist, naloxone (27 micromol/kg, i.p.) or the non-selective adenosine receptor antagonist, theophylline (111 micromol/kg, i.p.) significantly diminished the anti-allodynic effects of morphine and 5'd-5IT, respectively. The present study demonstrates that the potent and selective adenosine kinase inhibitor, 5'd-5IT, is equally effective as morphine in blocking tactile allodynia in this model.

Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors

PubMed Central

Wang, Yunfei; Cao, Shu-e; Tian, Jianmin; Liu, Guozhe; Zhang, Xiaoran; Li, Pingfa

2013-01-01

Common chemotherapeutic agents such as vincristine often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is refractory to common analgesics and represents a challenging clinical issue. Angelicae dahuricae radix is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the active component(s) that attribute to the analgesic action have not been identified. This work described the anti-hyperalgesic effect of one coumarin component, auraptenol, in a mouse model of chemotherapeutic agent vincristine-induced neuropathic pain. We reported that auraptenol dose-dependently reverted the mechanical hyperalgesia in mice within the dose range of 0.05–0.8 mg/kg. In addition, the anti-hyperalgesic effect of auraptenol was significantly blocked by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). Within the dose range studied, auraptenol did not significantly alter the general locomotor activity in mice. Taken together, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust analgesic efficacy in mice. These data support further studies to assess the potential of auraptenol as a novel analgesic for the management of neuropathic pain. PMID:24287473

Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation

PubMed Central

2011-01-01

Background Intrathecal lidocaine reverses tactile allodynia after nerve injury, but whether neuropathic pain is attenuated by intrathecal lidocaine pretreatment is uncertain. Methods Sixty six adult male Sprague-Dawley rats were divided into three treatment groups: (1) sham (Group S), which underwent removal of the L6 transverse process; (2) ligated (Group L), which underwent left L5 spinal nerve ligation (SNL); and (3) pretreated (Group P), which underwent L5 SNL and was pretreated with intrathecal 2% lidocaine (50 μl). Neuropathic pain was assessed based on behavioral responses to thermal and mechanical stimuli. Expression of sodium channels (Nav1.3 and Nav1.8) in injured dorsal root ganglia and microglial proliferation/activation in the spinal cord were measured on post-operative days 3 (POD3) and 7 (POD7). Results Group L presented abnormal behavioral responses indicative of mechanical allodynia and thermal hyperalgesia, exhibited up-regulation of Nav1.3 and down-regulation of Nav1.8, and showed increased microglial activation. Compared with ligation only, pretreatment with intrathecal lidocaine before nerve injury (Group P), as measured on POD3, palliated both mechanical allodynia (p < 0.01) and thermal hyperalgesia (p < 0.001), attenuated Nav1.3 up-regulation (p = 0.003), and mitigated spinal microglial activation (p = 0.026) by inhibiting phosphorylation (activation) of p38 MAP kinase (p = 0.034). p38 activation was also suppressed on POD7 (p = 0.002). Conclusions Intrathecal lidocaine prior to SNL blunts the response to noxious stimuli by attenuating Nav1.3 up-regulation and suppressing activation of spinal microglia. Although its effects are limited to 3 days, intrathecal lidocaine pretreatment can alleviate acute SNL-induced neuropathic pain. PMID:21676267

The Role of an Aggrecan 32mer Fragment in Post-Traumatic Osteoarthritis

DTIC Science & Technology

2017-10-01

Award Number: W81XWH-16-1-0706 TITLE: The Role of an Aggrecan 32mer Fragment in Post -Traumatic Osteoarthritis PRINCIPAL INVESTIGATOR: Professor...TITLE AND SUBTITLE The Role of an Aggrecan 32mer Fragment in Post - Traumatic Osteoarthritis 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0706 5c...reduction in knee hyperalgesia, but not mechanical allodynia, in mice at 8 weeks post -surgery. This trend was not statistically significant, however, we are

Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin.

PubMed

Stoicea, Nicoleta; Russell, Daric; Weidner, Greg; Durda, Michael; Joseph, Nicholas C; Yu, Jeffrey; Bergese, Sergio D

2015-01-01

Chronic pain patients receiving opioid drugs are at risk for opioid-induced hyperalgesia (OIH), wherein opioid pain medication leads to a paradoxical pain state. OIH involves central sensitization of primary and secondary afferent neurons in the dorsal horn and dorsal root ganglion, similar to neuropathic pain. Gabapentin, a gamma-aminobutyric acid (GABA) analog anticonvulsant used to treat neuropathic pain, has been shown in animal models to reduce fentanyl hyperalgesia without compromising analgesic effect. Chronic pain patients have also exhibited lower opioid consumption and improved pain response when given gabapentin. However, few human studies investigating gabapentin use in OIH have been performed in recent years. In this review, we discuss the potential mechanisms that underlie OIH and provide a critical overview of interventional therapeutic strategies, especially the clinically-successful drug gabapentin, which may reduce OIH.

Social transfer of alcohol withdrawal-induced hyperalgesia in female prairie voles.

PubMed

Walcott, Andre T; Smith, Monique L; Loftis, Jennifer M; Ryabinin, Andrey E

2018-03-27

The expression of pain serves as a way for animals to communicate potential dangers to nearby conspecifics. Recent research demonstrated that mice undergoing alcohol or morphine withdrawal, or inflammation, could socially communicate their hyperalgesia to nearby mice. However, it is unknown whether such social transfer of hyperalgesia can be observed in other species of rodents. Therefore, the present study investigated if the social transfer of hyperalgesia occurs in the highly social prairie vole (Microtus ochrogaster). We observe that adult female prairie voles undergoing withdrawal from voluntary two-bottle choice alcohol drinking display an increase in nociception. This alcohol withdrawal-induced hypersensitiity is socially transferred to female siblings within the same cage and female strangers housed in separate cages within the same room. These experiments reveal that the social transfer of pain phenomenon is not specific to inbred mouse strains and that prairie voles display alcohol withdrawal and social transfer-induced hyperalgesia.

Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on inflammatory and neuropathic pain in mice.

PubMed

Marabese, I; de Novellis, V; Palazzo, E; Scafuro, M A; Vita, D; Rossi, F; Maione, S

2007-02-01

In this study, the effect of (S)-3,4-dicarboxyphenylglycine (DCPG), a selective mGlu8 receptor agonist, has been investigated in inflammatory and neuropathic pain models in order to elucidate the role of mGlu8 receptor in modulating pain perception. Inflammatory pain was induced by the peripheral injection of formalin or carrageenan in awake mice. Systemic administration of (S)-3,4-DCPG, performed 15 min before formalin, decreased both early and delayed nociceptive responses of the formalin test. When this treatment was carried out 15 min after the peripheral injection of formalin it still reduced the late hyperalgesic phase. Similarly, systemic (S)-3,4-DCPG reduced carrageenan-induced thermal hyperalgesia and mechanical allodynia when administered 15 min before carrageenan, but no effect on pain behaviour was observed when (S)-3,4-DCPG was given after the development of carrageenan-induced inflammatory pain. When microinjected into the lateral PAG (RS)-alpha-methylserine-O-phoshate (MSOP), a group III receptor antagonist, antagonised the analgesic effect induced by systemic administration of (S)-3,4-DCPG in both of the inflammatory pain models. Intra-lateral PAG (S)-3,4-DCPG reduced pain behaviour when administered 10 min before formalin or carrageenan; both the effects were blocked by intra-lateral PAG MSOP. (S)-3,4-DCPG was ineffective in alleviating thermal hyperalgesia and mechanical allodynia 7 days after the chronic constriction injury of the sciatic nerve, whereas it proved effective 3 days after surgery. Taken together these results suggest that stimulation of mGlu8 receptors relieve formalin and carrageenan-induced hyperalgesia in inflammatory pain, whereas it would seem less effective in established inflammatory or neuropathic pain.

Knee joint mobilization reduces secondary mechanical hyperalgesia induced by capsaicin injection into the ankle joint.

PubMed

Sluka, K A; Wright, A

2001-01-01

Joint mobilization is a treatment approach commonly used by physical therapists for the management of a variety of painful conditions. However, the clinical effectiveness when compared to placebo and the neurophysiological mechanism of action are not known. The purpose of this study was to establish that application of a manual therapy technique will produce antihyperalgesia in an animal model of joint inflammation and that the antihyperalgesia produced by joint mobilization depends on the time of treatment application. Capsaicin (0.2%, 50 microl) was injected into the lateral aspect of the left ankle joint and mechanical withdrawal threshold assessed before and after capsaicin injection in Sprague-Dawley rats. Joint mobilization of the ipsilateral knee joint was performed 2 h after capsaicin injection for a total of 3 min, 9 min or 15 min under halothane anaesthesia. Control groups included animals that received halothane for the same time as the group that received joint mobilization and those whose limbs were held for the same duration as the mobilization (no halothane). Capsaicin resulted in a decreased mechanical withdrawal threshold by 2 h after injection that was maintained through 4 h. Both 9 and 15 min of mobilization, but not 3 min of mobilization, increased the withdrawal threshold to mechanical stimuli to baseline values when compared with control groups. The antihyperalgesic effect of joint mobilization lasted 30 min. Thus, joint mobilization (9 or 15 min duration) produces a significant reversal of secondary mechanical hyperalgesia induced by intra-articular injection of capsaicin. Copyright 2001 European Federation of Chapters of the International Association for the Study of Pain.

Role of the Excitability Brake Potassium Current IKD in Cold Allodynia Induced by Chronic Peripheral Nerve Injury.

PubMed

González, Alejandro; Ugarte, Gonzalo; Restrepo, Carlos; Herrera, Gaspar; Piña, Ricardo; Gómez-Sánchez, José Antonio; Pertusa, María; Orio, Patricio; Madrid, Rodolfo

2017-03-22

Cold allodynia is a common symptom of neuropathic and inflammatory pain following peripheral nerve injury. The mechanisms underlying this disabling sensory alteration are not entirely understood. In primary somatosensory neurons, cold sensitivity is mainly determined by a functional counterbalance between cold-activated TRPM8 channels and Shaker-like Kv1.1-1.2 channels underlying the excitability brake current I KD Here we studied the role of I KD in damage-triggered painful hypersensitivity to innocuous cold. We found that cold allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in mice, was related to both an increase in the proportion of cold-sensitive neurons (CSNs) in DRGs contributing to the sciatic nerve, and a decrease in their cold temperature threshold. I KD density was reduced in high-threshold CSNs from CCI mice compared with sham animals, with no differences in cold-induced TRPM8-dependent current density. The electrophysiological properties and neurochemical profile of CSNs revealed an increase of nociceptive-like phenotype among neurons from CCI animals compared with sham mice. These results were validated using a mathematical model of CSNs, including I KD and TRPM8, showing that a reduction in I KD current density shifts the thermal threshold to higher temperatures and that the reduction of this current induces cold sensitivity in former cold-insensitive neurons expressing low levels of TRPM8-like current. Together, our results suggest that cold allodynia is largely due to a functional downregulation of I KD in both high-threshold CSNs and in a subpopulation of polymodal nociceptors expressing TRPM8, providing a general molecular and neural mechanism for this sensory alteration. SIGNIFICANCE STATEMENT This paper unveils the critical role of the brake potassium current I KD in damage-triggered cold allodynia. Using a well-known form of nerve injury and combining behavioral analysis, calcium imaging, patch clamping, and

Mu-opioid receptors in nociceptive afferents produce a sustained suppression of hyperalgesia in chronic pain.

PubMed

Severino, Amie; Chen, Wenling; Hakimian, Joshua K; Kieffer, Brigitte L; Gaveriaux-Ruff, Claire; Walwyn, Wendy; Marvizon, Juan Carlos

2018-04-17

The latent sensitization model of chronic pain reveals that recovery from some types of long-term hyperalgesia is an altered state in which nociceptive sensitization persists but is suppressed by the ongoing activity of analgesic receptors such as µ-opioid receptors (MORs). To determine whether these MORs are the ones present in nociceptive afferents, we bred mice expressing Cre-recombinase under the Nav1.8 channel promoter (Nav1.8cre) with MOR-floxed mice (flMOR). These Nav1.8cre/flMOR mice had reduced MOR expression in primary afferents, as revealed by quantitative PCR, in situ hybridization and immunofluorescence colocalization with the neuropeptide CGRP. We then studied the recovery from chronic pain of these mice and their flMOR littermates. When Nav1.8cre/flMOR mice were injected in the paw with complete Freund's adjuvant they developed mechanical hyperalgesia that persisted for over two months, whereas the responses of flMOR mice returned to baseline after three weeks. We then used the inverse agonist naltrexone to assess ongoing MOR activity. Naltrexone produced a robust reinstatement of hyperalgesia in control flMOR mice, but produced no effect in the Nav1.8/flMOR males and a weak reinstatement of hyperalgesia in Nav1.8/flMOR females. Naltrexone also reinstated swelling of the hind paw in flMOR mice and female Nav1.8cre/flMOR mice, but not male Nav1.8cre/flMOR mice. The MOR agonist DAMGO inhibited substance P release in flMOR mice but not Nav1.8cre/flMOR mice, demonstrating a loss of MOR function at the central terminals of primary afferents. We conclude that MORs in nociceptive afferents mediate an ongoing suppression of hyperalgesia to produce remission from chronic pain.

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.

Laser therapy reduces gelatinolytic activity in the rat trigeminal ganglion during temporomandibular joint inflammation.

PubMed

Desiderá, A C; Nascimento, G C; Gerlach, R F; Leite-Panissi, C R A

2015-07-01

To investigate whether low-level laser therapy (LLLT) alters the expression and activity of MMP-2 and MMP-9 in the trigeminal ganglion (TG) during different stages of temporomandibular joint (TMJ) inflammation in rats. It also evaluated whether LLLT modifies mechanical allodynia and orofacial hyperalgesia. Wistar rats (±250 g) were divided into groups that received saline (SAL) or complete Freund's adjuvant (CFA, 50 μl) in the TMJ, and that later underwent LLLT (20 J cm(-2) ) at their TMJ or not (groups SAL, SAL + LLLT, CFA, and CFA + LLLT). LLLT was applied on days 3, 5, 7, and 9 after SAL or CFA. Mechanical allodynia was evaluated on days 1, 3, 5, 7, and 10; orofacial hyperalgesia was assessed on day 10. Gelatin zymography and in situ zymography aided quantification of MMPs in the TG. Low-level laser therapy abolished the reduction in the mechanical orofacial threshold and the increase in orofacial rubbing during the orofacial formalin test induced by CFA. LLLT also decreased the CFA-induced rise in the levels of MMP-9 and MMP-2 as well as the gelatinolytic activity in the TG. Low-level laser therapy could constitute an adjuvant therapy to treat temporomandibular disorders and prevent inflammation-induced alterations in the levels of MMP-2 and MMP-9 and in the gelatinolytic activity in TGs. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Objective sensory evaluation of the spread of complex regional pain syndrome.

PubMed

Edinger, Lara; Schwartzman, Robert J; Ahmad, Ayesha; Erwin, Kirsten; Alexander, Guillermo M

2013-01-01

The spread of complex regional pain syndrome (CRPS) has been well documented. Many severe refractory long-standing patients have total body pain (TBP) that evolved from a single extremity injury. The purpose of this study was to document by objective sensory threshold testing the extent of body area involvement in 20 long-standing patients with CRPS who have TBP. A comparison of sensory threshold testing parameters between 20 long-standing refractory patients with CRPS who have TBP versus 10 healthy participants. Twenty patients with CRPS who stated that they suffered from total body pain were chosen from the Drexel University College of Medicine CRPS database. They were compared to 10 healthy participants that were age and gender matched to the patients with CRPS. The sensory parameters tested were: skin temperature; static and mechanical allodynia; thermal allodynia; mechanical hyperalgesia; after sensations following all sensory tests. The sites chosen for testing in the patients with CRPS were the most painful area in each of 8 body regions that comprised the total body area. Five patients with CRPS had signs of CRPS over 100% of their body (20%). One patient had pain over 87% and another had pain over 90% of their body area. The average percentage of body involvement was 62% (range 37% - 100%). All patients with CRPS had at least one sensory parameter abnormality in all body regions. All patients with CRPS had lower pain thresholds for static allodynia in all body areas, while 50% demonstrated a lower threshold for dynamic allodynia in all body regions compared to the healthy participants. Cold allodynia had a higher median pain rating on the Likert pain scale in all body areas versus healthy participants except for the chest, abdomen, and back. Eighty-five percent of the patients with CRPS had a significantly lower pain threshold for mechanical hyperalgesia in all body areas compared to the healthy participants. After sensations occurred after all sensory

Clinical evidence of parietal cortex dysfunction and correlation with extent of allodynia in CRPS type 1.

PubMed

Cohen, H; McCabe, C; Harris, N; Hall, J; Lewis, J; Blake, D R

2013-04-01

Unusual symptoms such as digit misidentification and neglect-like phenomena have been reported in complex regional pain syndrome (CRPS), which we hypothesized could be explained by parietal lobe dysfunction. Twenty-two patients with chronic CRPS attending an in-patient rehabilitation programme underwent standard neurological examination followed by clinical assessment of parietal lobe function and detailed sensory testing. Fifteen (68%) patients had evidence of parietal lobe dysfunction. Six (27%) subjects failed six or more test categories and demonstrated new clinical signs consistent with their parietal testing impairments, which were impacting significantly on activities of daily living. A higher incidence was noted in subjects with >1 limb involvement, CRPS affecting the dominant side and in left-handed subjects. Eighteen patients (82%) had mechanical allodynia covering 3-57.5% of the body surface area. Allochiria (unilateral tactile stimulation perceived only in the analogous location on the opposite limb), sensory extinction (concurrent bilateral tactile stimulation perceived only in one limb), referred sensations (unilateral tactile stimulation perceived concurrently in another discrete body area) and dysynchiria (unilateral non-noxious tactile stimulation perceived bilaterally as noxious) were present in some patients. Greater extent of body surface allodynia was correlated with worse parietal function (Spearman's rho = -0.674, p = 0.001). In patients with chronic CRPS, detailed clinical examination may reveal parietal dysfunction, with severity relating to the extent of allodynia. © 2012 European Federation of International Association for the Study of Pain Chapters.

Nicotinic Acetylcholine Receptors Mediate the Suppressive Effect of an Injection of Diluted Bee Venom into the GV3 Acupoint on Oxaliplatin-Induced Neuropathic Cold Allodynia in Rats.

PubMed

Yoon, Heera; Kim, Min Joon; Yoon, Insoo; Li, Dong Xing; Bae, Hyunsu; Kim, Sun Kwang

2015-01-01

Oxaliplatin, a platinum-based chemotherapy drug, often induces acute neuropathic pain, especially cold allodynia, even after a single administration. Subcutaneous injection of diluted bee venom (BV) into acupoints has been used to treat various pain symptoms in traditional oriental medicine. Although we previously demonstrated the suppressive effect of BV injection on oxaliplatin-induced cold allodynia in rats, its neurochemical mechanism remained unclear. This study investigates whether and how the cholinergic system mediates the relieving effect of BV injection on cold allodynia in oxaliplatin-administered rats. The behavioral signs of cold allodynia induced by an oxaliplatin administration (6 mg/kg, intraperitoneally (i.p.)) were evaluated by a tail immersion test in cold water (4°C). BV (0.25 mg/kg, subcutaneously (s.c.)) injection into the Yaoyangguan acupoint, located between the spinous processes of the fourth and fifth lumbar vertebrae, significantly alleviated the cold allodynia. This relieving effect of BV injection on oxaliplatin-induced cold allodynia was blocked by a pretreatment with mecamylamine (a non-selective nicotinic receptor antagonist, 2 mg/kg, i.p.), but not by atropine (a non-selective muscarinic receptor antagonist, 1 mg/kg, i.p.). Further, dihydro-β-erythroidinehydrobromide (DHβE, an α4β2 nicotinic antagonist, 5 mg/kg, i.p.) prevented the anti-allodynic effect of BV, whereas methyllycaconitine (an α7 nicotinic antagonist, 6 mg/kg, i.p.) did not. Finally, intrathecal administration of DHβE (10 nM) blocked the BV-induced anti-allodynic effect. These results suggest that nicotinic acetylcholine receptors, especially spinal α4β2 receptors, but not muscarinic receptors, mediate the suppressive effect of BV injection on oxaliplatin-induced acute cold allodynia in rats.

δ-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice

PubMed Central

Pradhan, Amynah A; Smith, Monique L; Zyuzin, Jekaterina; Charles, Andrew

2014-01-01

Background and Purpose Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the δ-opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of δ-opioid receptor agonists for migraine by characterizing their effects in mouse migraine models. Experimental Approach Mechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine-associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation. Key Results NTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different δ-opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG-evoked hyperalgesia. SNC80 also abolished NTG-induced conditioned place aversion, suggesting that δ-opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies. Conclusions and Implications These data show that δ-opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that δ-opioid receptors are a promising therapeutic target for this disorder. PMID:24467301

Inhibition by local bupivacaine-releasing microspheres of acute postoperative pain from hairy skin incision.

PubMed

Ohri, Rachit; Wang, Jeffrey Chi-Fei; Blaskovich, Phillip D; Pham, Lan N; Costa, Daniel S; Nichols, Gary A; Hildebrand, William P; Scarborough, Nelson L; Herman, Clifford J; Strichartz, Gary R

2013-09-01

Acute postoperative pain causes physiological deficits and slows recovery. Reduction of such pain by local anesthetics that are delivered for several days postoperatively is a desirable clinical objective, which is approached by a new formulation and applied in animal studies reported here. We subcutaneously injected a new formulation of poly-lactic-co-glycolic acid polymer microspheres, which provides steady drug release for 96+ hours into rats at the dorsal region 2 hours before surgery. A single 1.2-cm-long skin incision was followed by blunt dissection of skin away from the underlying fascia, and closed by 2 sutures, followed by 14 days of testing. Microspheres containing 5, 10, 20, and 40 mg bupivacaine were injected locally 2 hours before surgery; bupivacaine-free microspheres were the vehicle control, and bupivacaine HCl solution (0.5%), the positive control. Mechanical sensitivity was determined by the frequency of local muscle contractions to repeated pokes with nylon monofilaments (von Frey hairs) exerting 4 and 15 g forces, testing, respectively, allodynia and hyperalgesia, and by pinprick. Injection of bupivacaine microspheres (40 mg drug) into intact skin reduced responses to 15 g von Frey hairs for 6 hours and to pinprick for 36 hours. Respective reductions from bupivacaine HCl lasted for 3 and 2 hours. Skin incision and dissection alone caused mechanical allodynia and hyperalgesia for 14 days. Microspheres containing 20 or 40 mg bupivacaine suppressed postoperative hypersensitivity for up to 3 days, reduced integrated allodynia (area under curve of response versus time) over postoperative days 1 to 5 by 51% ± 20% (mean ± SE) and 78% ± 12%, and reduced integrated hyperalgesia by 55% ± 13% and 64% ± 11%, for the respective doses. Five and ten milligrams bupivacaine in microspheres and the 0.5% bupivacaine solution were ineffective in reducing postoperative hypersensitivity, as were 40 mg bupivacaine microspheres injected contralateral to the

Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.

PubMed

Matsuo, Hideaki; Uchida, Kenzo; Nakajima, Hideaki; Guerrero, Alexander Rodriguez; Watanabe, Shuji; Takeura, Naoto; Sugita, Daisuke; Shimada, Seiichiro; Nakatsuka, Terumasa; Baba, Hisatoshi

2014-09-01

Although transcutaneous electrical nerve stimulation (TENS) is widely used for the treatment of neuropathic pain, its effectiveness and mechanism of action in reducing neuropathic pain remain uncertain. We investigated the effects of early TENS (starting from the day after surgery) in mice with neuropathic pain, on hyperalgesia, glial cell activation, pain transmission neuron sensitization, expression of proinflammatory cytokines, and opioid receptors in the spinal dorsal horn. Following nerve injury, TENS and behavioral tests were performed every day. Immunohistochemical, immunoblot, and flow cytometric analysis of the lumbar spinal cord were performed after 8 days. Early TENS reduced mechanical and thermal hyperalgesia and decreased the activation of microglia and astrocytes (P<0.05). In contrast, the application of TENS at 1 week (TENS-1w) or 2 weeks (TENS-2w) after injury was ineffective in reducing hyperalgesia (mechanical and thermal) or activation of microglia and astrocytes. Early TENS decreased p-p38 within microglia (P<0.05), the expression levels of protein kinase C (PKC-γ), and phosphorylated anti-phospho-cyclic AMP response element-binding protein (p-CREB) in the superficial spinal dorsal horn neurons (P<0.05), mitogen-activated protein (MAP) kinases, and proinflammatory cytokines, and increased the expression levels of opioid receptors (P<0.05). The results suggested that the application of early TENS relieved hyperalgesia in our mouse model of neuropathic pain by inhibiting glial activation, MAP kinase activation, PKC-γ, and p-CREB expression, and proinflammatory cytokines expression, as well as maintenance of spinal opioid receptors. The findings indicate that TENS treatment is more effective when applied as early after nerve injury as possible. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

[Analgesic effect of ferulic acid on CCI mice: behavior and neurobiological analysis].

PubMed

Lv, Wei-Hong; Zhang, Lu; Wu, Shu-Juan; Chen, Sai-Zhen; Zhu, Xin-Bo; Pan, Jian-Chun

2013-11-01

To study the analgesic effect of chronic administration with ferulic acid, and preliminarily discuss its mechanism. Thermal hyperalgesia and mechanical allodynia tests were conducted to observe the analgesic effect of chronic administration with ferulic acid on CCI mice. The neurochemical detection method was applied to observe the effect chronic administration with ferulic acid on monoamine neurotransmitter and monoamine oxidase activity. Compared with the normal group, CCI mice showed notable reduction in heat sensation and nociceptive threshold in and mechanical allodynia. Ferulic acid (10, 20, 40 and 80 mg x kg(-1), po) could significantly reverse the situations. In an in-depth study, we found that the reason for these results was that ferulic acid was dose-dependent in increasing 5-HT and NE levels in hippocampus, frontal cortex and amygdale and could inhibit MAO-A activity in mouse brains. These results showed that ferulic acid has the analgesic effect. Its mechanism may be related to the inhibition of monoamine oxidase activity and the increase in monoamine neurotransmitter in mouse brains.

Inflammation enhances Y1 receptor signaling, neuropeptide Y-mediated inhibition of hyperalgesia, and substance P release from primary afferent neurons

PubMed Central

Taylor, Bradley K.; Fu, Weisi; Kuphal, Karen E.; Stiller, Carl-Olav; Winter, Michelle K.; Chen, Wenling; Corder, Gregory F.; Urban, Janice H.; McCarson, Kenneth E.; Marvizon, Juan Carlos

2014-01-01

Neuropeptide Y (NPY) is present in the superficial laminae of the dorsal horn and inhibits spinal nociceptive processing, but the mechanisms underlying its anti-hyperalgesic actions are unclear. We hypothesized that NPY acts at neuropeptide Y1 receptors in dorsal horn to decrease nociception by inhibiting substance P (SP) release, and that these effects are enhanced by inflammation. To evaluate SP release, we used microdialysis and neurokinin 1 receptor (NK1R) internalization in rat. NPY decreased capsaicin-evoked SP-like immunoreactivity in microdialysate of the dorsal horn. NPY also decreased non-noxious stimulus (paw brush)-evoked NK1R internalization (as well as mechanical hyperalgesia and mechanical and cold allodynia) after intraplantar injection of carrageenan. Similarly, in rat spinal cord slices with dorsal root attached, [Leu31, Pro34]-NPY inhibited dorsal root stimulus-evoked NK1R internalization. In rat dorsal root ganglion neurons, Y1 receptors colocalized extensively with calcitonin gene-related peptide (CGRP). In dorsal horn neurons, Y1 receptors were extensively expressed and this may have masked detection of terminal co-localization with CGRP or SP. To determine whether the pain inhibitory actions of Y1 receptors are enhanced by inflammation, we administered [Leu31, Pro34]-NPY after intraplantar injection of complete Freund's adjuvant (CFA) in rat. We found that [Leu31, Pro34]-NPY reduced paw clamp-induced NK1R internalization in CFA rats but not uninjured controls. To determine the contribution of increased Y1 receptor-G protein coupling, we measured [35S]GTPγS binding simulated by [Leu31, Pro34]-NPY in mouse dorsal horn. CFA inflammation increased the affinity of Y1 receptor G-protein coupling. We conclude that Y1 receptors contribute to the anti-hyperalgesic effects of NPY by mediating inhibition of SP release, and that Y1 receptor signaling in the dorsal horn is enhanced during inflammatory nociception. PMID:24184981

Pain referral and regional deep tissue hyperalgesia in experimental human hip pain models.

PubMed

Izumi, Masashi; Petersen, Kristian Kjær; Arendt-Nielsen, Lars; Graven-Nielsen, Thomas

2014-04-01

Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (P<.05). Referred pain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (P<.05). PPTs at the injection site were decreased after hypertonic saline injections into GMT and GMM compared with baseline, ALT injections, and isotonic saline. Cuff PPTs from the thigh were decreased after hypertonic saline injections into the ALT compared with baseline, GMT injections, and isotonic saline (P<.05). More subjects had positive joint pain provocation tests after hypertonic compared with isotonic saline injections (P<.05), indicating that this provocation test also assessed hyperalgesia in extra-articular soft tissues. The experimental models may open for better understanding of pain mechanisms associated with painful hip disorders. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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.

Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury.

PubMed

Fairbanks, C A; Schreiber, K L; Brewer, K L; Yu, C G; Stone, L S; Kitto, K F; Nguyen, H O; Grocholski, B M; Shoeman, D W; Kehl, L J; Regunathan, S; Reis, D J; Yezierski, R P; Wilcox, G L

2000-09-12

Antagonists of glutamate receptors of the N-methyl-d-aspartate subclass (NMDAR) or inhibitors of nitric oxide synthase (NOS) prevent nervous system plasticity. Inflammatory and neuropathic pain rely on plasticity, presenting a clinical opportunity for the use of NMDAR antagonists and NOS inhibitors in chronic pain. Agmatine (AG), an endogenous neuromodulator present in brain and spinal cord, has both NMDAR antagonist and NOS inhibitor activities. We report here that AG, exogenously administered to rodents, decreased hyperalgesia accompanying inflammation, normalized the mechanical hypersensitivity (allodynia/hyperalgesia) produced by chemical or mechanical nerve injury, and reduced autotomy-like behavior and lesion size after excitotoxic spinal cord injury. AG produced these effects in the absence of antinociceptive effects in acute pain tests. Endogenous AG also was detected in rodent lumbosacral spinal cord in concentrations similar to those previously detected in brain. The evidence suggests a unique antiplasticity and neuroprotective role for AG in processes underlying persistent pain and neuronal injury.

Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury

PubMed Central

Fairbanks, Carolyn A.; Schreiber, Kristin L.; Brewer, Kori L.; Yu, Chen-Guang; Stone, Laura S.; Kitto, Kelley F.; Nguyen, H. Oanh; Grocholski, Brent M.; Shoeman, Don W.; Kehl, Lois J.; Regunathan, Soundararajan; Reis, Donald J.; Yezierski, Robert P.; Wilcox, George L.

2000-01-01

Antagonists of glutamate receptors of the N-methyl-d-aspartate subclass (NMDAR) or inhibitors of nitric oxide synthase (NOS) prevent nervous system plasticity. Inflammatory and neuropathic pain rely on plasticity, presenting a clinical opportunity for the use of NMDAR antagonists and NOS inhibitors in chronic pain. Agmatine (AG), an endogenous neuromodulator present in brain and spinal cord, has both NMDAR antagonist and NOS inhibitor activities. We report here that AG, exogenously administered to rodents, decreased hyperalgesia accompanying inflammation, normalized the mechanical hypersensitivity (allodynia/hyperalgesia) produced by chemical or mechanical nerve injury, and reduced autotomy-like behavior and lesion size after excitotoxic spinal cord injury. AG produced these effects in the absence of antinociceptive effects in acute pain tests. Endogenous AG also was detected in rodent lumbosacral spinal cord in concentrations similar to those previously detected in brain. The evidence suggests a unique antiplasticity and neuroprotective role for AG in processes underlying persistent pain and neuronal injury. PMID:10984543

Social environment alters opioid-induced hyperalgesia and antinociceptive tolerance in adolescent mice.

PubMed

Bates, M L S; Emery, M A; Wellman, P J; Eitan, S

2016-07-01

Chronic opioid treatment is complicated by the development of tolerance and hyperalgesia. Social environment alters both opioid-induced behaviours and nociceptive mechanisms. Our previous studies demonstrated that, in adolescent rodents, the susceptibility to acquire opioid dependence and reward is dependent on the nature of social housing conditions. Specifically, our previous studies demonstrate that housing morphine-treated mice with drug-naïve animals mitigates the abuse liability of opioids. Thus, this study tested the effect of social housing conditions on the development of adaptive processes to morphine antinociception. Adolescent males were group-housed in different conditions. In the mixed treatment condition, mice treated with 20 mg/kg morphine (i.e. 'morphine cage-mates') and saline (i.e. 'saline cage-mates') were housed together. In the separated treatment conditions, all mice in the cage received morphine (i.e. 'morphine only') or saline (i.e. 'saline only'). All animals were tested for baseline pain sensitivity and for the response to morphine in the tail withdrawal, hot plate, acetone and von Frey filament tests, during and after discontinuation of opioid treatment. Both morphine cage-mate and morphine only animals developed antinociceptive tolerance. However, this effect was more robust and persistent in the morphine only group. Notably, morphine only animals, but not morphine cage-mates, developed opioid-induced hyperalgesia. This study demonstrates that housing morphine-treated mice with drug-naïve animals mitigates the development of opioid-induced hyperalgesia and antinociceptive tolerance. Thus, this study indicates that social environment influences the effectiveness of opioid pain management. © 2016 European Pain Federation - EFIC®

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

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

Antinociceptive effect of cyclic phosphatidic acid and its derivative on animal models of acute and chronic pain.

PubMed

Kakiuchi, Yasutaka; Nagai, Jun; Gotoh, Mari; Hotta, Harumi; Murofushi, Hiromu; Ogawa, Tomoyo; Ueda, Hiroshi; Murakami-Murofushi, Kimiko

2011-05-14

Cyclic phosphatidic acid (cPA) is a structural analog of lysophosphatidic acid (LPA), but possesses different biological functions, such as the inhibition of autotaxin (ATX), an LPA-synthesizing enzyme. As LPA is a signaling molecule involved in nociception in the peripheral and central systems, cPA is expected to possess analgesic activity. We characterized the effects of cPA and 2-carba-cPA (2ccPA), a chemically stable cPA analog, on acute and chronic pain. (1) The systemic injection of 2ccPA significantly inhibited somato-cardiac and somato-somatic C-reflexes but not the corresponding A-reflexes in anesthetized rats. (2) 2ccPA reduced sensitivity measured as the paw withdrawal response to electrical stimulation applied to the hind paws of mice through the C-fiber, but not Aδ or Aβ. (3) In mice, pretreatment with 2ccPA dose-dependently inhibited the second phase of formalin-induced licking and biting responses. (4) In mice, pretreatment and repeated post-treatments with 2ccPA significantly attenuated thermal hyperalgesia and mechanical allodynia following partial ligation of the sciatic nerve. (5) In rats, repeated post-treatments with 2ccPA also significantly attenuated thermal hyperalgesia and mechanical allodynia following chronic sciatic nerve constriction. Our results suggest that cPA and its stable analog 2ccPA inhibit chronic and acute inflammation-induced C-fiber stimulation, and that the central effects of 2ccPA following repeated treatments attenuate neuropathic pain.

Perturbing NR2B-PSD-95 interaction relieves neuropathic pain by inactivating CaMKII-CREB signaling.

PubMed

Xu, Fangxia; Zhao, Xin; Liu, Lin; Song, Jia; Zhu, Yingjun; Chu, Shuaishuai; Shao, Xueming; Li, Xiuxiu; Ma, Zhengliang; Gu, Xiaoping

2017-09-06

Neuropathic pain is characterized by central sensitization. The interaction between N-methyl-D-aspartate receptors (NMDARs) and postsynaptic density protein-95 (PSD-95) plays a major role in central sensitization. Here, we aimed to investigate the analgesic effect of disruption of the interaction between NMDAR and PSD-95. Chronic dorsal root ganglia compression model rats were used to mimic sciatica. Thermal hyperalgesia and mechanical allodynia were evaluated. The expression of spinal phospho-NR2B, PSD-95, calcium/calmodulin-dependent protein kinase II (CaMKII), and cAMP response element binding protein (CREB) was measured using western blotting. A mimetic peptide Myr-NR2B9c was injected intrathecally to disrupt the interaction between PSD-95 and NR2B and detected by coimmunoprecipitation. Chronic dorsal root ganglia compression surgery induced thermal hyperalgesia and mechanical allodynia, and upregulated pain-related proteins such as phospho-NR2B, PSD-95, CaMKII, and CREB expressions in the spinal cord. Myr-NR2B9c disrupted the interaction between NR2B-containing NMDARs and PSD-95 in the spinal cord. Intrathecal administration of Myr-NR2B9c attenuated neuropathic pain behaviors and downregulated the expressions of phospho-NR2B, PSD-95, CaMKII, and CREB in the spinal cord. The present study indicates that dissociation of NR2B-containing NMDARs from PSD-95 inactivates CaMKII and CREB signaling and relieves pain.

Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury

PubMed Central

Ellis, Amanda; Grace, Peter M.; Wieseler, Julie; Favret, Jacob; Springer, Kendra; Skarda, Bryce; Hutchinson, Mark R.; Falci, Scott; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

2016-01-01

Central neuropathic pain (CNP) is a pervasive, debilitating problem that impacts thousands of people living with central nervous system disorders, including spinal cord injury (SCI). Current therapies for treating this type of pain are ineffective and often have dose-limiting side effects. Although opioids are one of the most commonly used CNP treatments, recent animal literature has indicated that administering opioids shortly after a traumatic injury can actually have deleterious effects on long-term health and recovery. In order to study the deleterious effects of administering morphine shortly after trauma, we employed our low thoracic (T13) dorsal root avulsion model (Spinal Neuropathic Avulsion Pain, SNAP). Administering a weeklong course of 10 mg/kg/day morphine beginning 24 hr after SNAP resulted in amplified mechanical allodynia. Co-administering the non-opioid toll-like receptor 4 (TLR4) antagonist (+)-naltrexone throughout the morphine regimen prevented morphine-induced amplification of SNAP. Exploration of changes induced by early post-trauma morphine revealed that this elevated gene expression of TLR4, TNF, IL-1β, and NLRP3, as well as IL-1β protein at the site of spinal cord injury. These data suggest that a short course of morphine administered early after spinal trauma can exacerbate CNP in the long term. TLR4 initiates this phenomenon and, as such, may be potential therapeutic targets for preventing the deleterious effects of administering opioids after traumatic injury. PMID:27519154

Peripheral input and its importance for central sensitization.

PubMed

Baron, Ralf; Hans, Guy; Dickenson, Anthony H

2013-11-01

Many pain states begin with damage to tissue and/or nerves in the periphery, leading to enhanced transmitter release within the spinal cord and central sensitization. Manifestations of this central sensitization are windup and long-term potentiation. Hyperexcitable spinal neurons show reduced thresholds, greater evoked responses, increased receptive field sizes, and ongoing stimulus-independent activity; these changes probably underlie the allodynia, hyperalgesia, and spontaneous pain seen in patients. Central sensitization is maintained by continuing input from the periphery, but also modulated by descending controls, both inhibitory and facilitatory, from the midbrain and brainstem. The projections of sensitized spinal neurons to the brain, in turn, alter the processing of painful messages by higher centers. Several mechanisms contribute to central sensitization. Repetitive activation of primary afferent C fibers leads to a synaptic strengthening of nociceptive transmission. It may also induce facilitation of non-nociceptive Aβ fibers and nociceptive Aδ fibers, giving rise to dynamic mechanical allodynia and mechanical hyperalgesia. In postherpetic neuralgia and complex regional pain syndrome, for example, these symptoms are maintained and modulated by peripheral nociceptive input. Diagnosing central sensitization can be particularly difficult. In addition to the medical history, quantitative sensory testing and functional magnetic resonance imaging may be useful, but diagnostic criteria that include both subjective and objective measures of central augmentation are needed. Mounting evidence indicates that treatment strategies that desensitize the peripheral and central nervous systems are required. These should generally involve a multimodal approach, so that therapies may target the peripheral drivers of central sensitization and/or the central consequences. © 2013 American Neurological Association.

Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex.

PubMed

Jasmin, Luc; Rabkin, Samuel D; Granato, Alberto; Boudah, Abdennacer; Ohara, Peter T

2003-07-17

It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter gamma-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold--producing analgesia or hyperalgesia, respectively--in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABA(B)-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.

Inhibition of DOR prevents remifentanil induced postoperative hyperalgesia through regulating the trafficking and function of spinal NMDA receptors in vivo and in vitro.

PubMed

Wang, Chunyan; Li, Yize; Wang, Haiyun; Xie, Keliang; Shu, Ruichen; Zhang, Linlin; Hu, Nan; Yu, Yonghao; Wang, Guolin

2015-01-01

Several studies have demonstrated that intraoperative remifentanil infusions have been associated with opioid-induced hyperalgesia (OIH). Activation of delta opioid receptor (DOR) and augmentation of N-methyl-d-aspartate (NMDA) receptor expression and function may play an important role in the development of OIH. The aim of this study was to investigate whether DOR inhibition could prevent remifentanil-induced hyperalgesia via regulating spinal NMDA receptor expression and function in vivo and in vitro. A rat model of remifentanil-induced postoperative hyperalgesia was performed with the DOR agonist deltorphin-deltorphin II or the DOR antagonist naltrindole injected intrathecally 10 min before remifentanil infusion. Mechanical and thermal hyperalgesia were measured at -24h, 2, 6, 24 and 48 h after remifentanil infusion. Western blot was applied to detect the membrane and total expression of DOR and NMDA receptor subunits (NR1, NR2A and NR2B) in spinal cord L4-L6 segments. In addition, whole-cell patch-clamp recording was used to investigate the effect of DOR inhibition on NMDA receptor-induced current in spinal cord slices in vitro. We found that membrane trafficking of DOR, NR1 and NR2B subunits in the spinal cord increased after remifentanil administration and surgery. The DOR antagonist naltrindole could attenuate mechanical and thermal hyperalgesia without affecting baseline nociceptive threshold, reduce membrane expression of DOR and decrease the membrane and total expressions of NR1 and NR2B subunits. Furthermore, the amplitude and the frequency of NMDA receptor-induced current were significantly increased by remifentanil incubation in neurons of the dorsal horn, which was reversed by the application of naltrindole. The above results indicate that inhibition of DOR could significantly inhibit remifentanil-induced hyperalgesia via modulating the total protein level, membrane trafficking and function of NMDA receptors in the dorsal horn of spinal cord

Intradermal capsaicin as a neuropathic pain model in patients with unilateral sciatica

PubMed Central

Aykanat, Verna; Gentgall, Melanie; Briggs, Nancy; Williams, Desmond; Yap, Sharon; Rolan, Paul

2012-01-01

AIM This study compared the responses between patients with unilateral sciatica and pain-free volunteers following administration of intradermal capsaicin. METHODS Fourteen patients with unilateral sciatica and 12 pain-free volunteers received one injection per hour over 4 h of 1 µg and 10 µg capsaicin, into each calf. For each dose, spontaneous pain (10 cm VAS), area of flare (cm2) and the sum of allodynia and hyperalgesia radii across eight axes (cm) were recorded pre-injection and at 5, 15, 30, 45 and 60 min post injection. RESULTS Sciatica subjects experienced higher spontaneous pain and hyperalgesia responses in both legs compared with pain-free volunteers. The largest mean difference in spontaneous pain was 2.8 cm (95% CI 1.6, 3.9) at 5 min in the unaffected leg following 10 µg. The largest mean difference in hyperalgesia was 19.7 cm (95% CI 12.4, 27.0) at 60 min in the unaffected leg following 10 µg. Allodynia was greater in patients than in controls with the largest mean difference of 2.9 cm (95% CI 1, 4.8) at 5 min following 10 µg in the affected leg. Allodynia was also higher in the affected leg compared with the unaffected leg in sciatica patients with the highest mean difference of 3.0 cm (95% CI 1.2, 4.7) at 5 min following 10 µg. CONCLUSIONS The responses to intradermal capsaicin are quantitatively and qualitatively different in unilateral sciatica patients compared with pain-free controls. PMID:21740458

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

[Pain in humans: experimental facts and hypotheses].

PubMed

Cesaro, P

1994-09-15

The description of painful phenomena in humans has to take into account its different components: sensory component (relevant to nociception), affective and emotional components. Nociceptor's (physiology is best understood with electrophysiological and neurochemical methods allowing a clear description of hyperalgesia, with its peripheral and spinal mechanisms. A functional model is partly available to explain allodynia, spontaneous burning pain and lightning pain, the three main consequences following deafferentation. At the thalamo-cortical level, one can describe nociceptive pathways and other pathways or neuronal networks involved in the affective and emotional components of pain.

Laminar distribution of GABAA- and glycine-receptor mediated tonic inhibition in the dorsal horn of the rat lumbar spinal cord: effects of picrotoxin and strychnine on expression of Fos-like immunoreactivity.

PubMed

Cronin, John N; Bradbury, Elizabeth J; Lidierth, Malcolm

2004-11-01

Inhibitory mechanisms are essential in suppressing the development of allodynia and hyperalgesia in the normal animal and there is evidence that loss of inhibition can lead to the development of neuropathic pain. We used Fos expression to map the distribution of tonically inhibited cells in the healthy rat lumbar spinal cord. In a control group, Fos-like immunoreactive (Fos-LI) cells were rare, averaging 7.5+/-2.2 cells (mean+/-SEM; N=13 sections) per 20 microm thick section of dorsal horn. This rose to 103+/-11 (mean+/-SEM; N=20) in picrotoxin-treated rats and to 88+/-11 (mean+/-SEM; N=18) in strychnine-treated rats. These changes were significant (ANOVA; P<0.001). There were marked regional variations in the distribution of Fos-LI cells between picrotoxin- and strychnine-treated animals. Picrotoxin induced a significant increase in the number of Fos-LI cells throughout the dorsal horn (lamina I-VI) while strychnine significantly elevated Fos-like immunoreactivity only in deep laminae (III-VI). For both picrotoxin and strychnine, the increase in Fos-like immunoreactivity peaked in lamina V (at 3579+/-319 and 3649+/-375% of control, respectively; mean+/-SEM) but for picrotoxin an additional peak was observed in the outer part of lamina II (1959+/-196%). Intrathecal administration of both GABAA and glycine receptor antagonists has been shown elsewhere to induce tactile allodynia. The present data suggest that this allodynia could arise due to blockade of tonic GABAA and glycine-receptor mediated inhibition in the deep dorsal horn. GABAA antagonists also induce hypersensitivity to noxious inputs. The blockade of tonic inhibition in the superficial dorsal horn shown here may underlie this hyperalgesia.

Activation of the nuclear factor E2-related factor 2/anitioxidant response element alleviates the nitroglycerin-induced hyperalgesia in rats.

PubMed

Di, Wei; Shi, Xiaolei; Lv, Hua; Liu, Jun; Zhang, Hong; Li, Zhiwei; Fang, Yannan

2016-12-01

Antioxidants have been proven to weaken hyperalgesia in neuropathic pain. Endogenous antioxidant defense system may have a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) pathway in regulating the activation of the trigeminovascular system (TGVS) and hypersensitivity in nitroglycerin (NTG)-induced hyperalgesia rats. The expression levels of Nrf2, HO, HO1, and NQO1 in the trigeminal nucleus caudalis (TNC) were detected by western blot. Immunofluorescence was used to demonstrate the cell-specific localization of Nrf2 in TNC. Sulforaphane, a Nrf2 activator, was administered to NTG-induced rats. Then, the number of c-Fos- and nNOS-immunoreactive neurons in TNC was evaluated using immunofluorescence, and c-Fos and nNOS protein levels were quantified using western blot. Von Frey hair testing was used to evaluate the tactile thresholds of rats at different time points in different groups. Total cellular and nuclear levels of the proteins Nrf2, HO1, and NQO1 were elevated in TNC after NTG injection, and Nrf2 was found to be located in the nucleus and cytoplasm of the neurons. Sulforaphane pretreatment significantly increased the nuclear Nrf2, HO1, and NQO1 levels in TNC. In addition, sulforaphane exposure effectively inhibited the expression of nNOS and c-Fos, reduced the number of nNOS and c-Fos immunoreactive neurons in TNC, and attenuated the tactile thresholds induced by NTG injection. Oxidative stress was involved in nitroglycerin-induced hyperalgesia. Activation of the Nrf2/ARE pathway inhibited the activation of TGVS and prevented the induction of hyperalgesia. Sulforaphane might therefore be an effective agent for hyperalgesia. Further studies are needed to discover the underlying mechanisms of the process.

Cutaneous allodynia is more frequent in chronic migraine, and its presence and severity seems to be more associated with the duration of the disease.

PubMed

Benatto, Mariana Tedeschi; Florencio, Lidiane Lima; Carvalho, Gabriela Ferreira; Dach, Fabíola; Bigal, Marcelo Eduardo; Chaves, Thaís Cristina; Bevilaqua-Grossi, Débora

2017-03-01

To evaluate cutaneous allodynia among patients with chronic and episodic migraine in a tertiary headache clinic. 80 subjects with episodic migraine and 80 with chronic migraine were assessed in a tertiary hospital. The 12-item Allodynia Symptom Checklist/Brazil questionnaire was applied to classify subjects according to the presence and severity of cutaneous allodynia. Cutaneous allodynia was identified in 81.3% of the episodic migraine group and 92.5% of the chronic migraine group (p = 0.03). No increased association could be attributed to chronic migraine when adjusted by years with disease (PR = 1.12; 95%CI = 0.99 to 1.27; p = 0.06). The groups also did not differ in the severity of allodynia, and severe presentation was the most frequent. Both groups seemed to be similarly affected in the cephalic and extracephalic regions, with the same severity. Cutaneous allodynia is more frequent in chronic migraine, and its presence and severity seems to be more associated with the duration of the disease.

The Effect of Gabapentin and Ketorolac on Allodynia and Conditioned Place Preference in Antibody-Induced Inflammation

PubMed Central

Park, HJ; Sandor, K; McQueen, J; Woller, SA; Svensson, CI; Corr, MP; Yaksh, TL

2018-01-01

Background Glucose-6-phosphate isomerase and collagen type II antibody induced arthritis models (K/BxN and CAIA, respectively) have an inflammatory and a post-inflammatory phase. Both phases display robust tactile allodynia. In previous work, inflammatory phase allodynia was reversed by gabapentin and ketorolac, whereas in late phase only gabapentin was effective. Here we sought to determine if the effects of these two drugs during the early and late phases of the two arthritis models were observed in the conditioned place preference (CPP) paradigm, indicating a differential drug effect on the aversive state. Methods Male C57BL/6 mice received K/BxN serum intraperitoneally, while male BALB/c mice received collagen type II antibody cocktail intravenously. After onset of inflammation and allodynia, we assessed effects of i.p. gabapentin (100 mg/kg) or ketorolac (15 mg/kg) using a CPP paradigm: 2 days adaptation, 2 days conditioning (vehicle in morning and drug in afternoon), preference testing on day 5. Results Consistent with the effects upon allodynia, both gabapentin and ketorolac produced a preference for the drug-paired compartment in the early phase of the K/BxN model, while gabapentin, but not ketorolac, resulted in a place preference during late phase. In the CAIA model, consistent with differential effects upon allodynia, gabapentin produced a preference in the early phase and a trend in the late phase, whereas ketorolac was ineffective at either time. Conclusions CPP validated the aversive state in the inflammatory and post-inflammatory phases of the K/BxN and CAIA arthritis models and correspondence between the anti-hyperpathic pharmacology as defined by thresholds and CPP. PMID:26517300

The effect of gabapentin and ketorolac on allodynia and conditioned place preference in antibody-induced inflammation.

PubMed

Park, H J; Sandor, K; McQueen, J; Woller, S A; Svensson, C I; Corr, M; Yaksh, T L

2016-07-01

Glucose-6-phosphate isomerase and collagen type II antibody-induced arthritis models (K/BxN and CAIA, respectively) have an inflammatory and a post-inflammatory phase. Both phases display robust tactile allodynia. In previous work, inflammatory phase allodynia was reversed by gabapentin and ketorolac, whereas in late phase only gabapentin was effective. Here, we sought to determine if the effects of these two drugs during the early and late phases of the two arthritis models were observed in the conditioned place preference (CPP) paradigm, indicating a differential drug effect on the aversive state. Male C57BL/6 mice received K/BxN serum intraperitoneally, while male BALB/c mice received collagen type II antibody cocktail intravenously. After onset of inflammation and allodynia, we assessed effects of i.p. gabapentin (100 mg/kg) or ketorolac (15 mg/kg) using a CPP paradigm: 2 days adaptation, 2 days conditioning (vehicle in morning and drug in afternoon), preference testing on day 5. Consistent with the effects upon allodynia, both gabapentin and ketorolac produced a preference for the drug-paired compartment in the early phase of the K/BxN model, while gabapentin, but not ketorolac, resulted in a place preference during late phase. In the CAIA model, consistent with differential effects upon allodynia, gabapentin produced a preference in the early phase and a trend in the late phase, whereas ketorolac was ineffective at either time. CPP validated the aversive state in the inflammatory and post-inflammatory phases of the K/BxN and CAIA arthritis models and correspondence between the anti-hyperpathic pharmacology as defined by thresholds and CPP. © 2015 European Pain Federation - EFIC®

Association between pain, central sensitization and anxiety in postherpetic neuralgia.

PubMed

Schlereth, T; Heiland, A; Breimhorst, M; Féchir, M; Kern, U; Magerl, W; Birklein, F

2015-02-01

In postherpetic neuralgia (PHN), dorsal root ganglia neurons are damaged. According to the proposed models, PHN pain might be associated with nociceptive deafferentation, and peripheral (heat hyperalgesia) or central sensitization (allodynia). In 36 PHN patients, afferent nerve fibre function was characterized using quantitative sensory testing and histamine-induced flare analysis. Psychological factors were evaluated with the Hospital Anxiety and Depression Scale (HADS), disease-related quality of life (QoL) with SF-36 and pain with the McGill questionnaire [pain rating index (PRI)]. The patients were also divided into subgroups according to the presence or absence of brush-evoked allodynia as a sign of central sensitization. For all patients, warm, cold and mechanical detection was impaired (p < 0.001 each) and the size of the histamine flare was diminished on the affected side (p < 0.05); pain thresholds with the exception of brush-evoked allodynia (p < 0.05) were unaltered. Correlation analysis revealed allodynia, anxiety, depression, QoL and age as relevant factors associated with pain severity (PRI). Allodynia was present in 23 patients (64%). In these patients, heat pain perception was preserved; the histamine flare was larger; the pinprick pain was increased as were McGill PRI sensory subscore, actual pain rating and almost significantly pain (McGill PRI) over the last 4 weeks. PHN is associated with damage of afferent fibres. Central sensitization (i.e., allodynia) might contribute to PHN pain. There was a striking association between anxiety, depression and age, and the magnitude of PHN pain. © 2014 European Pain Federation - EFIC®

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.

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.

The role of IL-6 and IL-1beta in painful perineural inflammatory neuritis.

PubMed

Eliav, Eli; Benoliel, Rafael; Herzberg, Uri; Kalladka, Mythili; Tal, Michael

2009-05-01

Inflammation along a nerve trunk (perineural inflammation), without detectable axonal damage, has been shown to induce transient pain in the organ supplied by the nerve. The aims of the present study were to study the role IL-6 and IL-1beta, in pain induced by perineural inflammation. IL-6 and IL-1beta secretion from rat's sciatic nerves, L-5 Dorsal Root Ganglia (DRG), and the hind paw skin, 3 and 8 days following exposure of the nerve to Complete Freund's Adjuvant (CFA), were measured using ELISA method. Hind paw tactile-allodynia, mechano-hyperalgesia, heat-allodynia and electrical detection thresholds were tested up to 8 days following the application of CFA, IL-6 or IL-1beta adjacent to the sciatic nerve trunk. Employing electrophysiological recording, saphenous nerve spontaneous activity, nerve trunk mechano-sensitivity and paw tactile detection threshold (determined by recording action potential induced by the lowest mechanical stimulus) were assessed 3 and 8 days following exposure of the nerve trunk to CFA, IL-6, or IL-1beta. IL-6 and IL-1beta secretion from the nerve was significantly elevated on the 3rd day post-operation (DPO). On the 8th DPO, IL-6 levels returned to baseline while IL-1beta levels remained significantly elevated. The DRG cytokine's level was increased on the 3rd and 8th DPOs, contralateral cytokine's level was increased on the 3rd DPO. The skin IL-6 level was increased bilaterally on the 3rd DPO and returned to baseline on the 8th DPO. IL-1beta levels increased in the affected side on the 3rd and bilaterally on the 8th DPO. Direct application of IL-6 or CFA on the sciatic nerve induced significant hind paw tactile-allodynia from the 1st to 5th DPOs, reduced electrical detection threshold from the 1st to 3rd DPOs, mechano-hyperalgesia from 3rd to 5th DPOs and heat-allodynia on the 3rd DPO. Direct application of IL-1beta induced paw tactile and heat-allodynia on the 7-8th DPOs and mechano-hyperalgesia on the 5-8th DPOs. Perineural

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

Allodynia Is Associated With Initial and Sustained Response to Acute Migraine Treatment: Results from the American Migraine Prevalence and Prevention Study.

PubMed

Lipton, Richard B; Munjal, Sagar; Buse, Dawn C; Bennett, Alix; Fanning, Kristina M; Burstein, Rami; Reed, Michael L

2017-07-01

In a population sample of persons with migraine treating with a single category of acute migraine medication, to identify rates and factors associated with acute treatment outcomes, including 2-hour pain freedom (2hPF), 24-hour pain response (24hPR), and 24-hour sustained pain response (24hSPR). Key predictors include acute treatment type (triptans and other medication categories), the influence of allodynia on response to medication, and the interaction between medication category and presence of allodynia in response to treatment among people with migraine. Cutaneous allodynia was previously associated with inadequate 2hPF, 24hPR, and 24hSPR (sustained response at 24 hours among those with adequate 2hPF) among people with migraine in the American Migraine Prevalence and Prevention (AMPP) Study. The AMPP Study obtained data from a representative US sample of persons with migraine by mailed questionnaire. The 2006 survey included 8233 people with migraine aged 18 or over who completed the Migraine Treatment Optimization Questionnaire (mTOQ). mTOQ was used to assess acute treatment outcomes including 2hPF, 24hPR, and 24hSPR. Eligible individuals used only a single category of acute prescription migraine treatments (n  =  5236, 63.6%). This sample was stratified into 5 categories of type of acute prescription headache medication used (triptans, nonsteroidal anti-inflammatory drugs, barbiturate-combinations, opioids, and opioid combinations and ergot alkaloids). Separate binary logistic regression models evaluated: (1) triptans vs other medication types; (2) presence of allodynia vs no allodynia; and (3) the interaction of medication category with allodynia. Sociodemographic variables, health insurance status, over-the-counter and preventive medication use were included as covariates. Odds ratios (OR) and 95% confidence intervals (CI) were generated for each acute treatment outcome. Among eligible participants, the mean age was 46 years, and 82.5% were women

Paclitaxel-induced peripheral neuropathy increases substance P release in rat spinal cord.

PubMed

Chiba, Terumasa; Oka, Yusuke; Kambe, Toshie; Koizumi, Naoya; Abe, Kenji; Kawakami, Kazuyoshi; Utsunomiya, Iku; Taguchi, Kyoji

2016-01-05

Peripheral neuropathy is a common adverse effect of paclitaxel treatment. The major dose-limiting side effect of paclitaxel is peripheral sensory neuropathy, which is characterized by painful paresthesia of the hands and feet. To analyze the contribution of substance P to the development of paclitaxel-induced mechanical hyperalgesia, substance P expression in the superficial layers of the rat spinal dorsal horn was analyzed after paclitaxel treatment. Behavioral assessment using the von Frey test and the paw thermal test showed that intraperitoneal administration of 2 and 4mg/kg paclitaxel induced mechanical allodynia/hyperalgesia and thermal hyperalgesia 7 and 14 days after treatment. Immunohistochemistry showed that paclitaxel (4mg/kg) treatment significantly increased substance P expression (37.6±3.7% on day 7, 43.6±4.6% on day 14) in the superficial layers of the spinal dorsal horn, whereas calcitonin gene-related peptide (CGRP) expression was unchanged. Moreover, paclitaxel (2 and 4mg/kg) treatment significantly increased substance P release in the spinal cord on day 14. These results suggest that paclitaxel treatment increases release of substance P, but not CGRP in the superficial layers of the spinal dorsal horn and may contribute to paclitaxel-induced painful peripheral neuropathy. Copyright © 2015 Elsevier B.V. All rights reserved.

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 (allodynia thresholds. A significant antinociceptive effect (40-50% increase in tactile allodynia thresholds, P<0.05) was observed at the dose of 10 mg/kg, i.p., within 0.5-2-h post-dosing. The antinociceptive effects of ABT-627 (10 mg kg(-1) day(-1), p.o.) were maintained following chronic administration of the antagonist in drinking water for 7 days. In comparison, morphine administered acutely at a dose of 8 mg/kg, i.p., produced a significant 90% increase in streptozotocin-induced tactile allodynia thresholds. The endothelin ET(B) receptor-selective antagonist, 2R-(4-propoxyphenyl)-4S-(1, 3-benzodioxol-5-yl)-1-(N-(2, 6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxy lic acid (A-192621; 20 mg/kg, i.p.), did not significantly alter tactile allodynia thresholds in streptozotocin-treated rats. Although combined i.p. administration

Limonene reduces hyperalgesia induced by gp120 and cytokines by modulation of IL-1 β and protein expression in spinal cord of mice.

PubMed

Piccinelli, Ana Claudia; Morato, Priscila Neder; Dos Santos Barbosa, Marcelo; Croda, Julio; Sampson, Jared; Kong, Xiangpeng; Konkiewitz, Elisabete Castelon; Ziff, Edward B; Amaya-Farfan, Jaime; Kassuya, Cândida Aparecida Leite

2017-04-01

We have investigated the antihyperalgesic effects of limonene in mice that received intrathecal injection of gp120. Male Swiss mice received gp120, IL-1β or TNF-α intrathecally or sterile saline as a control. A mechanical sensitivity test was performed at 2 and 3h after the injection. Spinal cord and blood samples were isolated for protein quantification. Intrathecal administration of gp120 increased mechanical sensitivity measured with an electronic Von Frey apparatus, at 2 and 3h after the injections. Limonene administered orally prior to gp120 administration significantly decreased this mechanical sensitivity at 3h after the gp120 injection. In addition, intrathecal injection of gp120 increased IL-1β and IL-10 in serum, and limonene prevented the ability of gp120 to increase these cytokines. Limonene also inhibited TNF-α and IL-1β-induced mechanical hyperalgesia. Western blot assay demonstrated limonene was capable of increasing SOD expression in the cytoplasm of cells from spinal cord at 4h after intrathecal IL-1β injection. These results demonstrate that gp120 causes mechanical hyperalgesia and a peripheral increase in IL-1β and IL-10, and that prior administration of limonene inhibits these changes. Also limonene modulates the activation of SOD expression in the spinal cord after spinal IL-1β application. The ability of limonene to inhibit the mechanical hyperalgesia induced by gp120, TNF-α and IL-1β emphasizes the anti-inflammatory action of limonene, specifically its ability to inhibit cytokine production and its consequences. Copyright © 2016. Published by Elsevier Inc.

The role of P2X3 receptors in bilateral masseter muscle allodynia in rats

PubMed Central

Tariba Knežević, Petra; Vukman, Robert; Antonić, Robert; Kovač, Zoran; Uhač, Ivone; Simonić-Kocijan, Sunčana

2016-01-01

Aim To determine the relationship between bilateral allodynia induced by masseter muscle inflammation and P2X3 receptor expression changes in trigeminal ganglia (TRG) and the influence of intramasseteric P2X3 antagonist administration on bilateral masseter allodynia. Methods To induce bilateral allodynia, rats received a unilateral injection of complete Freund’s adjuvant (CFA) into the masseter muscle. Bilateral head withdrawal threshold (HWT) was measured 4 days later. Behavioral measurements were followed by bilateral masseter muscle and TRG dissection. Masseter tissue was evaluated histopathologically and TRG tissue was analyzed for P2X3 receptor mRNA expression by using quantitative real-time polymerase chain reaction (PCR) analysis. To assess the P2X3 receptor involvement in nocifensive behavior, two doses (6 and 60 μg/50 μL) of selective P2X3 antagonist A-317491 were administrated into the inflamed masseter muscle 4 days after the CFA injection. Bilateral HWT was measured at 15-, 30-, 60-, and 120-minute time points after A-317491 administration. Results HWT was bilaterally reduced after the CFA injection (P < 0.001). Intramasseteric inflammation was confirmed ipsilaterally to the CFA injection. Quantitative real-time PCR analysis demonstrated enhanced P2X3 expression in TRG ipsilaterally to CFA administration (P < 0.01). In comparison with controls, the dose of 6 μg of A-317491 significantly increased bilateral HWT at 15-, 30-, and 60-minute time points after the A-317491 administration (P < 0.001), whereas the dose of 60 μg of A-317491 was efficient at all time points ipsilaterally (P = 0.004) and at 15-, 30-, and 60-minute time points contralaterally (P < 0.001). Conclusion Unilateral masseter inflammation can induce bilateral allodynia in rats. The study provided evidence that P2X3 receptors can functionally influence masseter muscle allodynia and suggested that P2X3 receptors expressed in TRG neurons are involved in masseter

Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation.

PubMed

Wei, F; Dubner, R; Ren, K

1999-03-01

Previous findings indicate that the brain stem descending system becomes more active in modulating spinal nociceptive processes during the development of persistent pain. The present study further identified the supraspinal sites that mediate enhanced descending modulation of behavior hyperalgesia and dorsal horn hyperexcitability (as measured by Fos-like immunoreactivity) produced by subcutaneous complete Freund's adjuvant (CFA). Selective chemical lesions were produced in the nucleus raphe magnus (NRM), the nuclei reticularis gigantocellularis (NGC), or the locus coeruleus/subcoeruleus (LC/SC). Compared to vehicle-injected animals with injection of vehicle alone, microinjection of a serotoninergic neurotoxin 5,7-dihydroxytryptamine into the NRM significantly increased thermal hyperalgesia and Fos protein expression in lumbar spinal cord after hindpaw inflammation. In contrast, the selective bilateral destruction of the NGC with a soma-selective excitotoxic neurotoxin, ibotenic acid, led to an attenuation of hyperalgesia and a reduction of inflammation-induced spinal Fos expression. Furthermore, if the NGC lesion was extended to involve the NRM, the behavioral hyperalgesia and CFA-induced Fos expression were similar to that in vehicle-injected rats. Bilateral LC/SC lesions were produced by microinjections of a noradrenergic neurotoxin, DSP-4. There was a significant increase in inflammation-induced spinal Fos expression, especially in the ipsilateral superficial dorsal horn following LC/SC lesions. These results demonstrated that multiple specific brain stem sites are involved in descending modulation of inflammatory hyperalgesia. Both NRM and LC/SC descending pathways are major sources of enhanced inhibitory modulation in inflamed animals. The persistent hyperalgesia and neuronal hyperexcitability may be mediated in part by a descending pain facilitatory system involving NGC. Thus, the intensity of perceived pain and hyperalgesia is fine-tuned by descending

A ketogenic diet reduces metabolic syndrome-induced allodynia and promotes peripheral nerve growth in mice.

PubMed

Cooper, Michael A; Menta, Blaise W; Perez-Sanchez, Consuelo; Jack, Megan M; Khan, Zair W; Ryals, Janelle M; Winter, Michelle; Wright, Douglas E

2018-08-01

Current experiments investigated whether a ketogenic diet impacts neuropathy associated with obesity and prediabetes. Mice challenged with a ketogenic diet were compared to mice fed a high-fat diet or a high-fat diet plus exercise. Additionally, an intervention switching to a ketogenic diet following 8 weeks of high-fat diet was performed to compare how a control diet, exercise, or a ketogenic diet affects metabolic syndrome-induced neural complications. When challenged with a ketogenic diet, mice had reduced bodyweight and fat mass compared to high-fat-fed mice, and were similar to exercised, high-fat-fed mice. High-fat-fed, exercised and ketogenic-fed mice had mildly elevated blood glucose; conversely, ketogenic diet-fed mice were unique in having reduced serum insulin levels. Ketogenic diet-fed mice never developed mechanical allodynia contrary to mice fed a high-fat diet. Ketogenic diet fed mice also had increased epidermal axon density compared all other groups. When a ketogenic diet was used as an intervention, a ketogenic diet was unable to reverse high-fat fed-induced metabolic changes but was able to significantly reverse a high-fat diet-induced mechanical allodynia. As an intervention, a ketogenic diet also increased epidermal axon density. In vitro studies revealed increased neurite outgrowth in sensory neurons from mice fed a ketogenic diet and in neurons from normal diet-fed mice given ketone bodies in the culture medium. These results suggest a ketogenic diet can prevent certain complications of prediabetes and provides significant benefits to peripheral axons and sensory dysfunction. Published by Elsevier Inc.

Distinct TrkA and Ret modulated negative and positive neuropathic behaviors in a mouse model of resiniferatoxin-induced small fiber neuropathy.

PubMed

Hsieh, Yu-Lin; Kan, Hung-Wei; Chiang, Hao; Lee, Yi-Chen; Hsieh, Sung-Tsang

2018-02-01

Neurotrophic factors and their corresponding receptors play key roles in the maintenance of different phenotypic dorsal root ganglion (DRG) neurons, the axons of which degenerate in small fiber neuropathy, leading to various neuropathic manifestations. Mechanisms underlying positive and negative symptoms of small fiber neuropathy have not been systematically explored. This study investigated the molecular basis of these seemingly paradoxical neuropathic behaviors according to the profiles of TrkA and Ret with immunohistochemical and pharmacological interventions in a mouse model of resiniferatoxin (RTX)-induced small fiber neuropathy. Mice with RTX neuropathy exhibited thermal hypoalgesia and mechanical allodynia, reduced skin innervation, and altered DRG expression profiles with decreased TrkA(+) neurons and increased Ret(+) neurons. RTX neuropathy induced the expression of activating transcription factor 3 (ATF3), and ATF3(+) neurons were colocalized with Ret but not with TrkA (P<0.001). As a neuroprotectant, 4-Methylcatechol (4MC) promoted skin reinnervation partially with correlated reversal of the neuropathic behaviors and altered neurochemical expression. Gambogic amide, a selective TrkA agonist, normalized thermal hypoalgesia, and GW441756, a TrkA kinase inhibitor, induced thermal hypoalgesia, which was already reversed by 4MC. Mechanical allodynia was reversed by a Ret kinase inhibitor, AST487, which induced thermal hyperalgesia in naïve mice. The activation of Ret signaling by XIB4035 induced mechanical allodynia and thermal hypoalgesia in RTX neuropathy mice in which the neuropathic behaviors were previously normalized by 4MC. Distinct neurotrophic factor receptors, TrkA and Ret, accounted for negative and positive neuropathic behaviors in RTX-induced small fiber neuropathy, respectively: TrkA for thermal hypoalgesia and Ret for mechanical allodynia and thermal hypoalgesia. Copyright © 2017 Elsevier Inc. All rights reserved.

The Effects of Pregabalin and the Glial Attenuator Minocycline on the Response to Intradermal Capsaicin in Patients with Unilateral Sciatica

PubMed Central

Sumracki, Nicole M.; Hutchinson, Mark R.; Gentgall, Melanie; Briggs, Nancy; Williams, Desmond B.; Rolan, Paul

2012-01-01

Background Patients with unilateral sciatica have heightened responses to intradermal capsaicin compared to pain-free volunteers. No studies have investigated whether this pain model can screen for novel anti-neuropathic agents in patients with pre-existing neuropathic pain syndromes. Aim This study compared the effects of pregabalin (300 mg) and the tetracycline antibiotic and glial attenuator minocycline (400 mg) on capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia in patients with unilateral sciatica on both their affected and unaffected leg. Methods/Results Eighteen patients with unilateral sciatica completed this randomised, double-blind, placebo-controlled, three-way cross-over study. Participants received a 10 µg dose of capsaicin into the middle section of their calf on both their affected and unaffected leg, separated by an interval of 75 min. Capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were recorded pre-injection and at 5, 20, 40, 60 and 90 min post-injection. Minocycline tended to reduce pre-capsaicin injection values of hyperalgesia in the affected leg by 28% (95% CI 0% to 56%). The area under the effect time curves for capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were not affected by either treatment compared to placebo. Significant limb differences were observed for flare (AUC) (−38% in affected leg, 95% CI for difference −19% to −52%). Both hand dominance and sex were significant covariates of response to capsaicin. Conclusions It cannot be concluded that minocycline is unsuitable for further evaluation as an anti-neuropathic pain drug as pregabalin, our positive control, failed to reduce capsaicin-induced neuropathic pain. However, the anti-hyperalgesic effect of minocycline observed pre-capsaicin injection is promising pilot information to support ongoing research into glial-mediated treatments for neuropathic pain. The differences in flare response between limbs may

Physiological and pathological characterization of capsaicin-induced reversible nerve degeneration and hyperalgesia.

PubMed

Chiang, H; Chang, K-C; Kan, H-W; Wu, S-W; Tseng, M-T; Hsueh, H-W; Lin, Y-H; Chao, C-C; Hsieh, S-T

2018-07-01

The study aimed to investigate the physiology, psychophysics, pathology and their relationship in reversible nociceptive nerve degeneration, and the physiology of acute hyperalgesia. We enrolled 15 normal subjects to investigate intraepidermal nerve fibre (IENF) density, contact heat-evoked potential (CHEP) and thermal thresholds during the capsaicin-induced skin nerve degeneration-regeneration; and CHEP and thermal thresholds at capsaicin-induced acute hyperalgesia. After 2-week capsaicin treatment, IENF density of skin was markedly reduced with reduced amplitude and prolonged latency of CHEP, and increased warm and heat pain thresholds. The time courses of skin nerve regeneration and reversal of physiology and psychophysics were different: IENF density was still lower at 10 weeks after capsaicin treatment than that at baseline, whereas CHEP amplitude and warm threshold became normalized within 3 weeks after capsaicin treatment. Although CHEP amplitude and IENF density were best correlated in a multiple linear regression model, a one-phase exponential association model showed better fit than a simple linear one, that is in the regeneration phase, the slope of the regression line between CHEP amplitude and IENF density was steeper in the subgroup with lower IENF densities than in the one with higher IENF densities. During capsaicin-induced hyperalgesia, recordable rate of CHEP to 43 °C heat stimulation was higher with enhanced CHEP amplitude and pain perception compared to baseline. There were differential restoration of IENF density, CHEP and thermal thresholds, and changed CHEP-IENF relationships during skin reinnervation. CHEP can be a physiological signature of acute hyperalgesia. These observations suggested the relationship between nociceptive nerve terminals and brain responses to thermal stimuli changed during different degree of skin denervation, and CHEP to low-intensity heat stimulus can reflect the physiology of hyperalgesia. © 2018 European Pain

Protective effect of co-administration of curcumin and sildenafil in alcohol induced neuropathy in rats.

PubMed

Kaur, Maninder; Singh, Amarjeet; Kumar, Bimlesh; Singh, Sachin Kumar; Bhatia, Amit; Gulati, Monica; Prakash, T; Bawa, Palak; Malik, Adil Hussain

2017-06-15

Neuropathic pain associated with chronic alcohol consumption is a medico-socioeconomical problem that affects both central and peripheral nervous system and has no satisfactory treatment till date. The present study was designed to investigate the protective effect of co-administration of curcumin and sildenafil on alcohol induced neuropathic pain in rats. In order to carry out this, ethanol (35% v/v, 10g/kg, p.o.) was administered for 10 weeks to induce neuropathic pain. Curcumin (30 and 60mg/kg, i.p.) and sildenafil (5 and 10mg/kg, i.p.) were given alone and in combination at their lower doses (30mg/kg curcumin and 5mg/kg, sildenafil, i.p.) to investigate the changes in thermal and mechanical hyperalgesia, allodynia and histopathological parameters. Biochemical estimations of thiobarbituric acid reactive species, glutathione and protein was also carried out to evaluate oxidative stress. The results revealed that chronic alcohol consumption for 10 weeks caused significant thermal and mechanical hyperalgesia, allodynia and increased oxidative stress. Individual administration of both the drugs at their low as well as high doses were able to improve the symptoms of alcohol induced neuropathic pain. Whereas co-administration of curcumin and sildenafil at their lower doses itself were found to significantly improve nerve functions, biochemical and histopathological parameters as compared to their individual administration. It is therefore proposed that co-administration of curcumin and sildenafil may bring new dimension towards attenuation of alcohol induced neuropathic pain affecting central as well as peripheral nervous system. Copyright © 2017 Elsevier B.V. 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

Increased brain white matter axial diffusivity associated with fatigue, pain and hyperalgesia in Gulf War illness.

PubMed

Rayhan, Rakib U; Stevens, Benson W; Timbol, Christian R; Adewuyi, Oluwatoyin; Walitt, Brian; VanMeter, John W; Baraniuk, James N

2013-01-01

Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction. Gulf War veterans (n = 31) and sedentary veteran and civilian controls (n = 20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs. Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis. The right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness.

Self-reported sleep duration associated with distraction analgesia, hyperemia, and secondary hyperalgesia in the heat-capsaicin nociceptive model.

PubMed

Campbell, Claudia M; Bounds, Sara C; Simango, Mpepera B; Witmer, Kenneth R; Campbell, James N; Edwards, Robert R; Haythornthwaite, Jennifer A; Smith, Michael T

2011-07-01

Although sleep deprivation is known to heighten pain sensitivity, the mechanisms by which sleep modifies nociception are largely unknown. Few studies of sleep-pain interactions have utilized quantitative sensory testing models that implicate specific underlying physiologic mechanisms. One possibility, which is beginning to receive attention, is that differences in sleep may alter the analgesic effects of distraction. We utilized the heat-capsaicin nociceptive model to examine whether self-reported habitual sleep duration is associated with distraction analgesia, the degree of secondary hyperalgesia and skin flare, markers implicating both central and peripheral processes that heighten pain. Twenty-eight healthy participants completed three experimental sessions in a randomized within subjects design. In the pain only condition, pain was induced for approximately 70-min via application of heat and capsaicin to the dorsum of the non-dominant hand. Verbal pain ratings were obtained at regular intervals. In the distraction condition, identical procedures were followed, but during heat-capsaicin pain, subjects played a series of video games. The third session involved assessing performance on the video games (no capsaicin). Participants indicated their normal self-reported habitual sleep duration over the past month. Individuals who slept less than 6.5 h/night in the month prior to the study experienced significantly less behavioral analgesia, increased skin flare and augmented secondary hyperalgesia. These findings suggest that reduced sleep time is associated with diminished analgesic benefits from distraction and/or individuals obtaining less sleep have a reduced ability to disengage from pain-related sensations. The secondary hyperalgesia finding may implicate central involvement, whereas enhanced skin flare response suggests that sleep duration may also impact peripheral inflammatory mechanisms. Copyright © 2010 European Federation of International Association for

[Effects of intrathecal administration of AM22-52 on mechanical allodynia and CCL2 expression in DRG in bone cancer rats].

PubMed

Chen, Ya-Juan; Huo, Yuan-Hui; Hong, Yanguo

2017-02-25

The pain peptide adrenomedullin (AM) plays a pivotal role in pathological pain. The present study was designed to investigate the effect of blockade of AM receptor on bone cancer pain (BCP) and its mechanism. BCP was developed by inoculation of Walker 256 mammary gland carcinoma cells in the tibia medullary cavity of Sprague Dawley rats. The selective AM receptor antagonist AM 22-52 was administered intrathecally on 15 d after the inoculation. Quantitative real-time PCR was used to detect mRNA level of CC chemokine ligand 2 (CCL2) in dorsal root ganglion (DRG). Double immunofluorescence staining was used to analyze the localizations of CCL2 and AM in DRG of normal rats. The results showed that, from 6 to15 d after the inoculation, the animals showed significant reduction in the mechanical pain threshold in the ipsilateral hindpaw, companied by the decline in bone density of tibia bone. The expression of CCL2 mRNA in DRG of BCP rats was increased by 3 folds (P < 0.001 vs saline group). Intrathecal administration of AM 22-52 abolished bone cancer-induced mechanical allodynia and increase of CCL2 mRNA level (P < 0.001). In normal rats, CCL2 was co-localized with AM in DRG neurons. These results suggest that AM may play a role in the pathogenesis of BCP. The increased AM bioactivity up-regulates CCL2 expression in DRG, which may contribute to the induction of pain hypersensitivity in bone cancer.

Sensory signs in complex regional pain syndrome and peripheral nerve injury.

PubMed

Gierthmühlen, Janne; Maier, Christoph; Baron, Ralf; Tölle, Thomas; Treede, Rolf-Detlef; Birbaumer, Niels; Huge, Volker; Koroschetz, Jana; Krumova, Elena K; Lauchart, Meike; Maihöfner, Christian; Richter, Helmut; Westermann, Andrea

2012-04-01

This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper-limb CRPS-I (n=298), CRPS-II (n=46), and PNI (n=72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66%-69%) exhibited a combination of sensory loss and gain. Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS-II patients shared features of CRPS-I and PNI. CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS-II. In CRPS-I and -II, cold hyperalgesia/allodynia (28%-31%) and dynamic mechanical allodynia (24%-28%) were less frequent than heat or pressure hyperalgesia (36%-44%, 67%-73%), and mechanical hypoesthesia (31%-55%) was more frequent than thermal hypoesthesia (30%-44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

CaMKII Phosphorylation in Primary Somatosensory Cortical Neurons is Involved in the Inhibition of Remifentanil-induced Hyperalgesia by Lidocaine in Male Sprague-Dawley Rats.

PubMed

Cui, Weihua; Wang, Shanshan; Han, Ruquan; Wang, Qiang; Li, Junfa

2016-01-01

Previous clinical studies have shown that lidocaine can alleviate severe postoperative pain after remifentanil-based anesthesia. Experimental studies have also demonstrated that lidocaine can inhibit remifentanil-induced hyperalgesia, yet the mechanism remains unknown. The present study explored the role of the primary somatosensory (S1) cortex in remifentanil-induced hyperalgesia as well as its inhibition by lidocaine through evaluation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation and protein expression levels in S1 cortical neurons. Male Sprague-Dawley rats were randomly allocated to the following 3 groups: remifentanil only (R), lidocaine only (L), and remifentanil+lidocaine (RL). Experimentally naive animals were used as controls for immunoblotting and immunofluorescence evaluations. Via intravenous tail vein administration (24 G catheter), the animals received remifentanil at 2.4 μg/kg/min, lidocaine at 200 μg/kg/min, and remifentanil at 2.4 μg/kg/min plus lidocaine at 200 μg/kg/min for 2 hours. Paw withdrawal threshold (PWT) values for both mechanical and thermal hyperalgesia, along with immunoblotting and immunofluorescence, were used to measure remifentanil-induced hyperalgesia and changes in CaMKII phosphorylation (P-CaMKII) and total protein expression (T-CaMKII). There was a significant decrease in the PWT for mechanical stimulation at 0.5 and 2 hours after discontinuing infusion in groups R and RL (P<0.05, n=10 per group). However, there were no differences in thermal PWT in any group at any time period when compared with that of baseline. There was also a significant increase of P-CaMKII (not T-CaMKII) in S1 cortical neurons of group R (not L and RL groups) at 0 to 2 hours after discontinuing infusion when compared with that of the corresponding control group (P<0.05, n=6 per group) as determined by immunoblotting and immunofluorescence microscopy. These results suggested that the phosphorylation of CaMKII in S1

Epac-protein kinase C alpha signaling in purinergic P2X3R-mediated hyperalgesia after inflammation.

PubMed

Gu, Yanping; Li, Guangwen; Chen, Yong; Huang, Li-Yen Mae

2016-07-01

Sensitization of purinergic P2X3 receptors (P2X3Rs) is a major mechanism contributing to injury-induced exaggerated pain responses. We showed in a previous study that cyclic adenosine monophosphate (cAMP)-dependent guanine nucleotide exchange factor 1 (Epac1) in rat sensory dorsal root ganglia (DRGs) is upregulated after inflammatory injury, and it plays a critical role in P2X3R sensitization by activating protein kinase C epsilon (PKCε) inside the cells. protein kinase C epsilon has been established as the major PKC isoform mediating injury-induced hyperalgesic responses. On the other hand, the role of PKCα in receptor sensitization was seldom considered. Here, we studied the participation of PKCα in Epac signaling in P2X3R-mediated hyperalgesia. The expression of both Epac1 and Epac2 and the level of cAMP in DRGs are greatly enhanced after complete Freund adjuvant (CFA)-induced inflammation. The expression of phosphorylated PKCα is also upregulated. Complete Freund adjuvant (CFA)-induced P2X3R-mediated hyperalgesia is not only blocked by Epac antagonists but also by the classical PKC isoform inhibitors, Go6976, and PKCα-siRNA. These CFA effects are mimicked by the application of the Epac agonist, 8-(4-chlorophenylthio)-2 -O-methyl-cAMP (CPT), in control rats, further confirming the involvement of Epacs. Because the application of Go6976 prior to CPT still reduces CPT-induced hyperalgesia, PKCα is downstream of Epacs to mediate the enhancement of P2X3R responses in DRGs. The pattern of translocation of PKCα inside DRG neurons in response to CPT or CFA stimulation is distinct from that of PKCε. Thus, in contrast to prevalent view, PKCα also plays an essential role in producing complex inflammation-induced receptor-mediated hyperalgesia.

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

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

Agmatine co-treatment attenuates allodynia and structural abnormalities in cisplatin-induced neuropathy in rats.

PubMed

Donertas, Basak; Cengelli Unel, Cigdem; Aydin, Sule; Ulupinar, Emel; Ozatik, Orhan; Kaygisiz, Bilgin; Yildirim, Engin; Erol, Kevser

2018-06-01

Cisplatin is a widely used antineoplastic agent in the treatment of various cancers. Peripheral neuropathy is a well-known side effect of cisplatin and has potential to result in limiting and/or reducing the dose, decreasing the quality of life. Thus, effective treatments are needed. Agmatine is an endogenous neuromodulator that has been shown to exert antiallodynic effects in various animal studies. The first aim of this study was to investigate the in vitro effects of agmatine on cisplatin-induced neurotoxicity. Primary cultures of dorsal root ganglia (DRG) which are the primary target of drug injury were prepared. DRG cells were incubated with cisplatin (100, 200, 500 μm). Then, agmatine (10, 100, 500 μm) was administered with the submaximal concentration of cisplatin. Cisplatin caused concentration-dependent neurotoxicity, and agmatine did not alter this effect. The second aim was to investigate the effects of agmatine on cisplatin-induced peripheral neuropathy in rats and the influence of nitric oxide synthase (NOS) inhibitor, L-NAME, in this effect. Female Sprague Dawley rats received intraperitoneal saline (control), cisplatin (3 mg/kg), cisplatin+agmatine (100 mg/kg), or cisplatin+agmatine+L-NAME (10 mg/kg) once a week for 5 weeks. The mechanical allodynia, hot plate, and tail clip tests were performed, and DRG cells and sciatic nerves were analyzed. Agmatine and agmatine+L-NAME combination attenuated CIS-induced mechanical allodynia and degeneration in DRG cells and sciatic nerves. However, L-NAME did not potentiate the antiallodynic or neuroprotective effect of agmatine. These findings indicate that agmatine co-administration ameliorates cisplatin-induced neuropathy and may be a therapeutic alternative. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers.

PubMed

Kraft, Birgit; Frickey, Nathalie A; Kaufmann, Rainer M; Reif, Marcus; Frey, Richard; Gustorff, Burkhard; Kress, Hans G

2008-07-01

Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with Delta-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing Delta-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.

TRPV1 channel-mediated bilateral allodynia induced by unilateral masseter muscle inflammation in rats.

PubMed

Simonic-Kocijan, Suncana; Zhao, Xuehong; Liu, Wen; Wu, Yuwei; Uhac, Ivone; Wang, KeWei

2013-12-30

Pain in masticatory muscles is among the most prominent symptoms of temperomandibular disorders (TMDs) that have diverse and complex etiology. A common complaint of TMD is that unilateral pain of craniofacial muscle can cause a widespread of bilateral pain sensation, although the underlying mechanism remains unknown. To investigate whether unilateral inflammation of masseter muscle can cause a bilateral allodynia, we generated masseter muscle inflammation induced by unilateral injection of complete Freund's adjuvant (CFA) in rats, and measured the bilateral head withdrawal threshold at different time points using a von Frey anesthesiometer. After behavioral assessment, both right and left trigeminal ganglia (TRG) were dissected and examined for histopathology and transient receptor potential vanilloid 1 (TRPV1) mRNA expression using quantitative real-time PCR analysis. A significant increase in TRPV1 mRNA expression occurred in TRG ipsilateral to CFA injected masseter muscle, whereas no significant alteration in TRPV1 occurred in the contralateral TRG. Interestingly, central injection of TRPV1 antagonist 5-iodoresiniferatoxin into the hippocampus significantly attenuated the head withdrawal response of both CFA injected and non-CFA injected contralateral masseter muscle. Our findings show that unilateral inflammation of masseter muscle is capable of inducing bilateral allodynia in rats. Upregulation of TRPV1 at the TRG level is due to nociception caused by inflammation, whereas contralateral nocifensive behavior in masticatory muscle nociception is likely mediated by central TRPV1, pointing to the involvement of altered information processing in higher centers.

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.

Bilateral hand/wrist heat and cold hyperalgesia, but not hypoesthesia, in unilateral carpal tunnel syndrome.

PubMed

de la Llave-Rincón, Ana Isabel; Fernández-de-las-Peñas, César; Fernández-Carnero, Josué; Padua, Luca; Arendt-Nielsen, Lars; Pareja, Juan A

2009-10-01

The aim of the current study was to evaluate bilaterally warm/cold detection and heat/cold pain thresholds over the hand/wrist in patients with carpal tunnel syndrome (CTS). A total of 25 women with strictly unilateral CTS (mean 42 +/- 10 years), and 20 healthy matched women (mean 41 +/- 8 years) were recruited. Warm/cold detection and heat/cold pain thresholds were assessed bilaterally over the carpal tunnel and the thenar eminence in a blinded design. Self-reported measures included both clinical pain history (intensity, location and area) and Boston Carpal Tunnel Questionnaire. No significant differences between groups for both warm and cold detection thresholds in either carpal tunnel or thenar eminence (P > 0.5) were found. Further, significant differences between groups, but not between sides, for both heat and cold pain thresholds in both the carpal tunnel and thenar eminence were found (all P < 0.001). Heat pain thresholds (P < 0.01) were negatively correlated, whereas cold pain thresholds (P < 0.001) were positively correlated with hand pain intensity and duration of symptoms. Our findings revealed bilateral thermal hyperalgesia (lower heat pain and reduced cold pain thresholds) but not hypoesthesia (normal warm/cold detection thresholds) in patients with strictly unilateral CTS when compared to controls. We suggest that bilateral heat and cold hyperalgesia may reflect impairments in central nociceptive processing in patients with unilateral CTS. The bilateral thermal hyperalgesia associated with pain intensity and duration of pain history supports a role of generalized sensitization mechanisms in the initiation, maintenance and spread of pain in CTS.

Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers: a double-blind, randomized, controlled study.

PubMed

Ragavendran, J Vaigunda; Laferrière, André; Bennett, Gary J; Ware, Mark A; Gandhi, Wiebke; Bley, Keith; Schweinhardt, Petra; Coderre, Terence J

2016-10-01

This double-blind randomized controlled study was designed to evaluate the analgesic effects of topical treatments with clonidine (CLON) and pentoxifylline (PTX) tested alone or as low- and high-dose combinations in a human experimental model of pain. Of 69 healthy subjects aged 18 to 60 years, 23 each were randomly allocated to low-dose (0.04% + 2%) and high-dose (0.1% + 5%) CLON + PTX groups. Both of these groups also received their corresponding placebos in one of 2 treatment periods separated by at least 48 hours. Twenty-three additional subjects received either CLON (0.1%) or PTX (5%) as single drug treatments, in each of 2 treatment periods. Assessment of analgesic efficacy was based on allodynic effects of previous intraepidermal capsaicin injection, as well as postcapsaicin tourniquet-induced pain 50 minutes following capsaicin injection. Visual Analogue Scale (VAS) ratings of pain intensity and the area of dynamic mechanical allodynia were the primary outcome measures, whereas area of punctate mechanical allodynia (PMA) served as a secondary outcome measure. Topical treatments with high- or low-dose combinations significantly reduced VAS ratings compared with corresponding placebo treatments throughout the period of postcapsaicin tourniquet-induced pain. Importantly, the high-dose combination produced lower VAS ratings than CLON alone, which were lower than PTX alone. Results also revealed significant inhibition of postcapsaicin dynamic mechanical allodynia and PMA for the high-dose combination compared with placebo, and of PMA for CLON compared with the low-dose combination. Hence, the present data are supportive of further clinical investigation of the high-dose topical combination of CLON + PTX in complex regional pain syndrome and neuropathic pain patients, for which our preclinical data predict efficacy.

Agmatine attenuates neuropathic pain in sciatic nerve ligated rats: modulation by hippocampal sigma receptors.

PubMed

Kotagale, Nandkishor Ramdas; Shirbhate, Saurabh Haridas; Shukla, Pradeep; Ugale, Rajesh Ramesh

2013-08-15

Present study investigated the influence of the sigma (σ₁ and σ₂) receptors within hippocampus on the agmatine induced antinociception in neuropathic rats. Animals were subjected to sciatic nerve ligation for induction of neuropathic pain and observed the paw withdrawal latency in response to thermal hyperalgesia, cold allodynia and the mechanical hyperalgesia. Intrahippocampal (i.h.) as well as intraperitoneal (i.p.) administration of agmatine attenuated neuropathic pain in sciatic nerve ligated rats. Intrahippocampal administration of σ₁ agonist (+)-pentazocine or σ₂ agonist PB28 sensitized whereas, σ₁ antagonist BD1063 or σ₂ antagonist SM21 potentiated antinociceptive effect of agmatine. The behavioral effects correlated with hippocampal tumor necrosis factor-α (TNF-α) levels observed by western blot analysis. These results suggest that both the σ₁ and σ₂ receptor subunits within hippocampus play an important role in antinociceptive action of agmatine against neuropathic pain. © 2013 Elsevier B.V. All rights reserved.

Assessment of the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia and neuropathic pain. A pilot study.

PubMed

Keizer, D; van Wijhe, M; Post, W J; Uges, D R A; Wierda, J M K H

2007-08-01

Allodynia is a common and disabling symptom in many patients with neuropathic pain. Whereas quantification of pain mostly depends on subjective pain reports, allodynia can also be measured objectively with quantitative sensory testing. In this pilot study, we investigated the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia as a consequence of a neuropathic pain syndrome, by means of correlating subjective pain scores with pain thresholds obtained with quantitative sensory testing. During a 4-week trial, we administered a cannabis extract to 17 patients with allodynia. We quantified the severity of the allodynia with Von Frey monofilaments before, during and after the patients finished the trial. We also asked the patients to rate their pain on a numeric rating scale at these three moments. We found that most of the effect of the cannabis occurred in the last 2 weeks of the trial. In this phase, we observed that the pain thresholds, as measured with Von Frey monofilaments, were inversely correlated with a decrease of the perceived pain intensity. These preliminary findings indicate clinical relevance of quantitative sensory testing with Von Frey monofilaments in the quantification of allodynia in patients with neuropathic pain, although confirmation of our data is still required in further studies to position this method of quantitative sensory testing as a valuable tool, for example, in the evaluation of therapeutic interventions for neuropathic pain.

Sigma 1 receptor mediated HMGB1 expression in spinal cord is involved in the development of diabetic neuropathic pain.

PubMed

Wang, Xiaolei; Feng, Chang; Qiao, Yong; Zhao, Xin

2018-03-06

No study has been conducted to examine the interactions of sigma-1 receptor (Sigma-1R) and high mobility group box 1 protein (HMGB1) in the development of diabetic peripheral neuropathy. Thus, we examined the effects of streptozotocin (STZ) treatment on expression of HMGB1 in subcellular levels in the dorsal root ganglion (DRG) in both wild-type and Sigma-1R -/- mice and evaluated the effects of repeated intrathecal administrations of selective Sigma-1R antagonists BD1047, agonist PRE-084, or HMGB1 inhibitor glycyrrhizin on peripheral neuropathy in wild-type mice. We found that STZ-induced tactile allodynia and thermal hyperalgesia was associated with increased total HMGB1 expression in DRG. STZ treatment promoted the distribution of HMGB1 into cytoplasm. Furthermore, STZ induced modest peripheral neuropathy and did not alter HMGB1 levels in DRG or the distribution of either cytoplasmic or nuclear HMGB1 in Sigma-1R -/- mice compared to sham control mice. Additionally, repeated stimulation of Sigma-1R in the spinal cord induced tactile allodynia and thermal hyperalgesia at 1 week. This phenomenon was associated with increased cytoplasmic HMGB1 translocation and HMGB1 expression in DRG. Finally, we found that repeated blockade of either Sigma-1R or HMGB1 in the spinal cord after STZ treatment prevent the development of tactile allodynia and thermal hyperalgesia at 1 week. These effects were associated with decreased cytoplasmic HMGB1 translocation and HMGB1 expression in DRG. Taken together, our results suggest that Sigma-1R-mediated enhancement of HMGB1 expression in the DRG is critical for the development of peripheral neuropathy in type 1 diabetes. Copyright © 2018 Elsevier B.V. All rights reserved.

Effects of Different Electroacupuncture Scheduling Regimens on Murine Bone Tumor-Induced Hyperalgesia: Sex Differences and Role of Inflammation

PubMed Central

Smeester, Branden A.; Al-Gizawiy, Mona; Beitz, Alvin J.

2012-01-01

Previous studies have shown that electroacupuncture (EA) is able to reduce hyperalgesia in rodent models of persistent pain, but very little is known about the analgesic effects and potential sex differences of different EA treatment regimens. In the present study, we examined the effects of five different EA treatments on tumor-induced hyperalgesia in male and female mice. EA applied to the ST-36 acupoint either twice weekly (EA-2X/3) beginning on postimplantation day (PID) 3 or prophylactically three times prior to implantation produced the most robust and longest lasting antinociceptive effects. EA treatment given once per week beginning at PID 7 only produced an antinociceptive effect in female animals. The analgesic effect of EA-2X/3 began earlier in males, but lasted longer in females indicating sex differences in EA. We further demonstrate that EA-2X/3 elicits a marked decrease in tumor-associated inflammation as evidenced by a significant reduction in tumor-associated neutrophils at PID 7. Moreover, EA-2X/3 produced a significant reduction in tumor-associated PGE2 as measured in microperfusate samples. Collectively, these data provide evidence that EA-2X/3 treatment reduces tumor-induced hyperalgesia, which is associated with a decrease in tumor-associated inflammation and PGE2 concentration at the tumor site suggesting possible mechanisms by which EA reduces tumor nociception. PMID:23320035

Classical conditioning without verbal suggestions elicits placebo analgesia and nocebo hyperalgesia

PubMed Central

Bajcar, Elżbieta A.; Adamczyk, Wacław; Kicman, Paweł; Lisińska, Natalia; Świder, Karolina; Colloca, Luana

2017-01-01

The aim of this study was to examine the relationships among classical conditioning, expectancy, and fear in placebo analgesia and nocebo hyperalgesia. A total of 42 healthy volunteers were randomly assigned to three groups: placebo, nocebo, and control. They received 96 electrical stimuli, preceded by either orange or blue lights. A hidden conditioning procedure, in which participants were not informed about the meaning of coloured lights, was performed in the placebo and nocebo groups. Light of one colour was paired with pain stimuli of moderate intensity (control stimuli), and light of the other colour was paired with either nonpainful stimuli (in the placebo group) or painful stimuli of high intensity (in the nocebo group). In the control group, both colour lights were followed by control stimuli of moderate intensity without any conditioning procedure. Participants rated pain intensity, expectancy of pain intensity, and fear. In the testing phase, when both of the coloured lights were followed by identical moderate pain stimuli, we found a significant analgesic effect in the placebo group, and a significant hyperalgesic effect in the nocebo group. Neither expectancy nor fear ratings predicted placebo analgesia or nocebo hyperalgesia. It appears that a hidden conditioning procedure, without any explicit verbal suggestions, elicits placebo and nocebo effects, however we found no evidence that these effects are predicted by either expectancy or fear. These results suggest that classical conditioning may be a distinct mechanism for placebo and nocebo effects. PMID:28750001

Effect of flavonol and its dimethoxy derivatives on paclitaxel-induced peripheral neuropathy in mice.

PubMed

Sayeli, Vijaykumar; Nadipelly, Jagan; Kadhirvelu, Parimala; Cheriyan, Binoy Varghese; Shanmugasundaram, Jaikumar; Subramanian, Viswanathan

2018-04-13

Peripheral neuropathy is the dose limiting side effect of many anticancer drugs. Flavonoids exhibit good antinociceptive effect in animal models. Their efficacy against different types of nociception has been documented. The present study investigated the effect of flavonol (3-hydroxy flavone), 3',4'-dimethoxy flavonol, 6,3'-dimethoxy flavonol, 7,2'-dimethoxy flavonol and 7,3'-dimethoxy flavonol against paclitaxel-induced peripheral neuropathy in mice. A single dose of paclitaxel (10 mg/kg, i.p.) was administered to induce peripheral neuropathy in mice and the manifestations of peripheral neuropathy such as tactile allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later by employing Von Frey hair aesthesiometer test, acetone bubble test and hot water tail immersion test, respectively. The test compounds were prepared as a suspension in 0.5% carboxymethyl cellulose and were administered s.c. in various doses (25, 50, 100 and 200 mg/kg). The above behavioral responses were assessed prior to and 30 min after drug treatment. In addition, the effect of test compounds on proinflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β) and free radicals was investigated by using suitable in vitro assays. A dose-dependent attenuation of tactile allodynia, cold allodynia and thermal hyperalgesia was evidenced in mice treated with flavonol derivatives. The test compounds inhibited TNF-α, IL-1β and free radicals in a concentration-dependent manner. These results revealed that flavonol and its dimethoxy derivatives ameliorated the manifestations of paclitaxel-induced peripheral neuropathy in mice. The inhibition of proinflammatory cytokines and free radicals could contribute to this beneficial effect.

Subcutaneous, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia in the rat.

PubMed

Caram-Salas, Nadia L; Reyes-García, Gerardo; Bartoszyk, Gerd D; Araiza-Saldaña, Claudia I; Ambriz-Tututi, Mónica; Rocha-González, Héctor I; Arreola-Espino, Rosaura; Cruz, Silvia L; Granados-Soto, Vinicio

2007-11-14

The purpose of this study was to assess the possible antiallodynic effect of asimadoline ([N-methyl-N-[1S)-1-phenyl)-2-(13S))-3-hydroxypyrrolidine-1-yl)-ethyl]-2,2-diphenylacetamide HCl]) and ICI-20448 ([2-[3-(1-(3,4-Dichlorophenyl-N-methylacetamido)-2-pyrrolidinoethyl)-phenoxy]acetic acid HCl]), two peripheral selective kappa opioid receptor agonists, after subcutaneous, spinal and periaqueductal grey administration to neuropathic rats. Twelve days after spinal nerve ligation tactile allodynia was observed, along with an increase in kappa opioid receptor mRNA expression in dorsal root ganglion and dorsal horn spinal cord. A non-significant increase in periaqueductal grey was also seen. Subcutaneous (s.c.) administration of asimadoline and ICI-204448 (1-30 mg/kg) dose-dependently reduced tactile allodynia. This effect was partially blocked by s.c., but not intrathecal, naloxone. Moreover, intrathecal administration of asimadoline or ICI-204448 (1-30 mug) reduced tactile allodynia in a dose-dependent manner and this effect was completely blocked by intrathecal naloxone. Microinjection of both kappa opioid receptor agonists (3-30 mug) into periaqueductal grey also produced a naloxone-sensitive antiallodynic effect in rats. Our results indicate that systemic, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia. This effect may be a consequence of an increase in kappa opioid receptor mRNA expression in dorsal root ganglion, dorsal horn spinal cord and, to some extent, in periaqueductal grey. Finally, our data suggest that these drugs could be useful to treat neuropathic pain in human beings.

Failure of intrathecal ketorolac to reduce remifentanil-induced postinfusion hyperalgesia in humans.

PubMed

Eisenach, James C; Tong, Chuanyao; Curry, Regina S

2015-01-01

In rodents, acute exposure to opioids results in transient antinociception followed by longer lasting hypersensitivity to tactile or thermal stimuli, a phenomenon termed opioid-induced hyperalgesia. This hypersensitivity can be blocked or reversed by intrathecally administered cyclooxygenase inhibitors, including ketorolac, suggesting a role for spinal prostaglandins. In surgical patients, the dose of intraoperative opioid, particularly the short-acting drug, remifentanil, is directly related to increased pain and opioid requirements for many hours postoperatively. In addition, experimentally induced tactile hypersensitivity in humans is exaggerated after cessation of remifentanil infusions. The degree of this experimental opioid-induced hyperalgesia is reduced by systemic treatment with cyclooxygenase inhibitors, and investigators have speculated that this reduction reflects the actions in the central nervous system, most likely in the spinal cord. To test this hypothesis, we measured cerebrospinal fluid prostaglandin E2 concentrations during and after remifentanil infusion in 30 volunteers. These volunteers received intrathecal ketorolac or saline in a random, blinded manner during intravenous remifentanil infusion after generation of hypersensitivity by topical capsaicin. Remifentanil reduced pain to noxious heat stimuli and reduced areas of capsaicin-induced hypersensitivity similarly in those receiving intrathecal ketorolac or saline. The primary outcome measure, area of capsaicin-induced hypersensitivity after stopping remifentanil, showed a similar increase in those receiving ketorolac as in those receiving saline. Cerebrospinal fluid prostaglandin E2 concentrations did not increase during postinfusion hyperalgesia compared with those during infusion, and they were not increased during infusion compared with those in historical controls. These data fail to support the hypothesis that acute opioid-induced hyperalgesia reflects spinal cyclooxygenase activation

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

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.

Sensory-motor responses to mechanical stimulation of the esophagus after sensitization with acid.

PubMed

Drewes, Asbjørn-Mohr; Reddy, Hariprasad; Staahl, Camilla; Pedersen, Jan; Funch-Jensen, Peter; Arendt-Nielsen, Lars; Gregersen, Hans

2005-07-28

Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization. Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine. The sensitization resulted in allodynia and hyperalgesia to the distension volumes, and the degree of sensitization was related to the infused volume of acid. Furthermore, a nearly 50% increase in the evoked referred pain was seen after sensitization. The mechanical analysis demonstrated hyper-reactivity of the esophagus following acid perfusion, with an increased number and force of the phasic contractions, but the muscle tone did not change. Acid perfusion of the esophagus sensitizes the sensory pathways and facilitates secondary contractions. The new model can be used to study abnormal sensory-motor mechanisms in visceral organs.

Sensory-motor responses to mechanical stimulation of the esophagus after sensitization with acid

PubMed Central

Drewes, Asbjorn Mohr; Reddy, Hariprasad; Staahl, Camilla; Pedersen, Jan; Funch-Jensen, Peter; Arendt-Nielsen, Lars; Gregersen, Hans

2005-01-01

AIM: Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization. METHODS: Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine. RESULTS: The sensitization resulted in allodynia and hyperalgesia to the distension volumes, and the degree of sensitization was related to the infused volume of acid. Furthermore, a nearly 50% increase in the evoked referred pain was seen after sensitization. The mechanical analysis demonstrated hyper-reactivity of the esophagus following acid perfusion, with an increased number and force of the phasic contractions, but the muscle tone did not change. CONCLUSION: Acid perfusion of the esophagus sensitizes the sensory pathways and facilitates secondary contractions. The new model can be used to study abnormal sensory-motor mechanisms in visceral organs. PMID:16038036

Self-reported Recovery is Associated With Improvement in Localized Hyperalgesia Among Adolescent Females With Patellofemoral Pain: Results From a Cluster Randomized Trial.

PubMed

Rathleff, Michael S; Roos, Ewa M; Olesen, Jens L; Rasmussen, Sten; Arendt-Nielsen, Lars

2016-05-01

Adolescent females with patellofemoral pain (PFP) have localized (around the knee) and distal (tibialis anterior muscle) hyperalgesia assessed by decreased pressure pain thresholds (PPT). This may have implications for treating PFP as both localized and central pain mechanisms may contribute to the manifestations of pain. The objective of this study was to compare the change in localized and distal hyperalgesia among female adolescents with PFP deeming themselves recovered compared with those not recovered 3 months after patient education with or without exercise therapy. This is an ancillary analysis of a cluster randomized controlled trial investigating the effect of patient education with or without exercise therapy on self-reported recovery in 121 adolescents with PFP. PPTs were measured at 4 sites around the knee and on tibialis anterior in a random subsample of 57 female adolescents. Changes in localized and distal hyperalgesia from baseline to follow-up were compared with self-reported recovery. Adolescents were categorized as recovered if they rated themselves as "completely recovered" or "strongly recovered" on a 7-point Likert scale. Thirty-nine adolescents (68%) were available for follow-up at 3 months and 10 adolescents reported being recovered. Recovered adolescents had a 68 kPa (95% CI, 1, 136; P=0.047) larger improvement in PPT around the knee and a 76 kPa (95% CI, -29, 181; P=0.16) nonsignificant improvement in PPT on the tibialis anterior compared with adolescents not recovered. Female adolescents with PFP who rated themselves as recovered had a larger reduction in localized hyperalgesia compared with those not recovered.

N-hexane neuropathy with vertigo and cold allodynia in a silk screen printer: A case study.

PubMed

Pradhan, Sunil; Tandon, Ruchika

2015-01-01

N-hexane neuropathy is an occupational disease caused by exposure to n-hexane, which is used as a solvent in silk screen printing. Here, we describe a 35-year-old man, a silk screen printer by profession, who presented with dizziness, distal swelling of both lower limbs for 10 months and tingling and burning sensation in both feet for 9.5 months along with cold allodynia. The patient had normal results of a motor and sensory system examination, apart from an impaired temperature sense. Nerve conduction tests showed a conduction block in bilateral common peroneal nerves and absence of conduction in bilateral sural nerves. These symptoms resolved when further exposure to n-hexane was ceased but cold allodynia remained. Thus, cold allodynia and impaired temperature sense can be a manifestation of n-hexane neuropathy. Hence, abnormalities on nerve conduction studies can be detected in n-hexane neuropathy patients, even before clinical examination detects any such abnormalities. In the case of the patients presenting with sensory motor neuropathy, history of occupational exposure to n-hexane becomes important, as the sooner the disease is detected, the better the chances of recovery. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Cell cycle inhibition limits development and maintenance of neuropathic pain following spinal cord injury

PubMed Central

Wu, Junfang; Zhao, Zaorui; Zhu, Xiya; Renn, Cynthia L.; Dorsey, Susan G.; Faden, Alan I.

2016-01-01

Chronic pain after spinal cord injury (SCI) may present as hyperalgesia, allodynia, and/or spontaneous pain and is often resistant to conventional pain medications. Identifying more effective interventions to manage SCI-Pain requires improved understanding of the pathophysiological mechanisms involved. Cell cycle activation (CCA) has been implicated as a key pathophysiological event following SCI. We have shown that early central or systemic administration of a cell cycle inhibitor reduces CCA, prevents glial changes, and limits SCI-induced hyperesthesia. Here we compared the effects of early versus late treatment with the pan-cyclin dependent kinase inhibitor flavopiridol on allodynia as well as spontaneous pain. Adult C57BL/6 male mice subjected to moderate SCI were treated with intraperitoneal injections of flavopiridol (1 mg/kg), daily for 7 days beginning either 3 h or 5 weeks after injury. Mechanical/thermal allodynia was evaluated, as well as spontaneous pain using the mouse grimace scale (MGS). We show that sensitivity to mechanical and thermal stimulation, and locomotor dysfunction were significantly reduced by early flavopiridol treatment compared to vehicle treated controls. SCI caused robust and extended increases of MGS up to 3 weeks after trauma. Early administration of flavopiridol significantly shortened duration of MGS changes. Late flavopiridol intervention significantly limited hyperesthesia at 7 days after treatment, associated with reduced glial changes, but without effect on locomotion. Thus, our data suggest that cell cycle modulation may provide an effective therapeutic strategy to reduce hyperesthesia after SCI, with a prolonged therapeutic window. PMID:26797506

Generalized Hyperalgesia in Children and Adults Diagnosed With Hypermobility Syndrome and Ehlers-Danlos Syndrome Hypermobility Type: A Discriminative Analysis.

PubMed

Scheper, M C; Pacey, V; Rombaut, L; Adams, R D; Tofts, L; Calders, P; Nicholson, L L; Engelbert, R H H

2017-03-01

Lowered pressure-pain thresholds have been demonstrated in adults with Ehlers-Danlos syndrome hypermobility type (EDS-HT), but whether these findings are also present in children is unclear. Therefore, the objectives of the study were to determine whether generalized hyperalgesia is present in children with hypermobility syndrome (HMS)/EDS-HT, explore potential differences in pressure-pain thresholds between children and adults with HMS/EDS-HT, and determine the discriminative value of generalized hyperalgesia. Patients were classified in 1 of 3 groups: HMS/EDS-HT, hypermobile (Beighton score ≥4 of 9), and healthy controls. Descriptive data of age, sex, body mass index, Beighton score, skin laxity, and medication usage were collected. Generalized hyperalgesia was quantified by the average pressure-pain thresholds collected from 12 locations. Confounders collected were pain locations/intensity, fatigue, and psychological distress. Comparisons between children with HMS/EDS-HT and normative values, between children and adults with HMS/EDS-HT, and corrected confounders were analyzed with multivariate analysis of covariance. The discriminative value of generalized hyperalgesia employed to differentiate between HMS/EDS-HT, hypermobility, and controls was quantified with logistic regression. Significantly lower pressure-pain thresholds were found in children with HMS/EDS-HT compared to normative values (range -22.0% to -59.0%; P ≤ 0.05). When applying a threshold of 30.8 N/cm 2 for males and 29.0 N/cm 2 for females, the presence of generalized hyperalgesia discriminated between individuals with HMS/EDS-HT, hypermobility, and healthy controls (odds ratio 6.0). Children and adults with HMS/EDS-HT are characterized by hypermobility, chronic pain, and generalized hyperalgesia. The presence of generalized hyperalgesia may indicate involvement of the central nervous system in the development of chronic pain. © 2016, American College of Rheumatology.

Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia

PubMed Central

Taché, Yvette; Million, Mulugeta

2015-01-01

The corticotropin-releasing factor (CRF) signaling systems encompass CRF and the structurally related peptide urocortin (Ucn) 1, 2, and 3 along with 2 G-protein coupled receptors, CRF1 and CRF2. CRF binds with high and moderate affinity to CRF1 and CRF2 receptors, respectively while Ucn1 is a high-affinity agonist at both receptors, and Ucn2 and Ucn3 are selective CRF2 agonists. The CRF systems are expressed in both the brain and the colon at the gene and protein levels. Experimental studies established that the activation of CRF1 pathway in the brain or the colon recaptures cardinal features of diarrhea predominant irritable bowel syndrome (IBS) (stimulation of colonic motility, activation of mast cells and serotonin, defecation/watery diarrhea, and visceral hyperalgesia). Conversely, selective CRF1 antagonists or CRF1/CRF2 antagonists, abolished or reduced exogenous CRF and stress-induced stimulation of colonic motility, defecation, diarrhea and colonic mast cell activation and visceral hyperalgesia to colorectal distention. By contrast, the CRF2 signaling in the colon dampened the CRF1 mediated stimulation of colonic motor function and visceral hyperalgesia. These data provide a conceptual framework that sustained activation of the CRF1 system at central and/or peripheral sites may be one of the underlying basis of IBS-diarrhea symptoms. While targeting these mechanisms by CRF1 antagonists provided a relevant novel therapeutic venue, so far these promising preclinical data have not translated into therapeutic use of CRF1 antagonists. Whether the existing or newly developed CRF1 antagonists will progress to therapeutic benefits for stress-sensitive diseases including IBS for a subset of patients is still a work in progress. PMID:25611064

Vinpocetine Reduces Carrageenan-Induced Inflammatory Hyperalgesia in Mice by Inhibiting Oxidative Stress, Cytokine Production and NF-κB Activation in the Paw and Spinal Cord

PubMed Central

Ruiz-Miyazawa, Kenji W.; Zarpelon, Ana C.; Pinho-Ribeiro, Felipe A.; Pavão-de-Souza, Gabriela F.; Casagrande, Rubia; Verri, Waldiceu A.

2015-01-01

Vinpocetine is a safe nootropic agent used for neurological and cerebrovascular diseases. The anti-inflammatory activity of vinpocetine has been shown in cell based assays and animal models, leading to suggestions as to its utility in analgesia. However, the mechanisms regarding its efficacy in inflammatory pain treatment are still not completely understood. Herein, the analgesic effect of vinpocetine and its anti-inflammatory and antioxidant mechanisms were addressed in murine inflammatory pain models. Firstly, we investigated the protective effects of vinpocetine in overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone (PBQ) and formalin. The intraplantar injection of carrageenan was then used to induce inflammatory hyperalgesia. Mechanical and thermal hyperalgesia were evaluated using the electronic von Frey and the hot plate tests, respectively, with neutrophil recruitment to the paw assessed by a myeloperoxidase activity assay. A number of factors were assessed, both peripherally and in the spinal cord, including: antioxidant capacity, reduced glutathione (GSH) levels, superoxide anion, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels, as well as nuclear factor kappa B (NF-κB) activation. Vinpocetine inhibited the overt pain-like behavior induced by acetic acid, PBQ and formalin (at both phases), as well as the carrageenan-induced mechanical and thermal hyperalgesia and associated neutrophil recruitment. Both peripherally and in the spinal cord, vinpocetine also inhibited: antioxidant capacity and GSH depletion; increased superoxide anion; IL-1β and TNF-α levels; and NF-κB activation. As such, vinpocetine significantly reduces inflammatory pain by targeting oxidative stress, cytokine production and NF-κB activation at both peripheral and spinal cord levels. PMID:25822523

Vinpocetine reduces carrageenan-induced inflammatory hyperalgesia in mice by inhibiting oxidative stress, cytokine production and NF-κB activation in the paw and spinal cord.

PubMed

Ruiz-Miyazawa, Kenji W; Zarpelon, Ana C; Pinho-Ribeiro, Felipe A; Pavão-de-Souza, Gabriela F; Casagrande, Rubia; Verri, Waldiceu A

2015-01-01

Vinpocetine is a safe nootropic agent used for neurological and cerebrovascular diseases. The anti-inflammatory activity of vinpocetine has been shown in cell based assays and animal models, leading to suggestions as to its utility in analgesia. However, the mechanisms regarding its efficacy in inflammatory pain treatment are still not completely understood. Herein, the analgesic effect of vinpocetine and its anti-inflammatory and antioxidant mechanisms were addressed in murine inflammatory pain models. Firstly, we investigated the protective effects of vinpocetine in overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone (PBQ) and formalin. The intraplantar injection of carrageenan was then used to induce inflammatory hyperalgesia. Mechanical and thermal hyperalgesia were evaluated using the electronic von Frey and the hot plate tests, respectively, with neutrophil recruitment to the paw assessed by a myeloperoxidase activity assay. A number of factors were assessed, both peripherally and in the spinal cord, including: antioxidant capacity, reduced glutathione (GSH) levels, superoxide anion, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels, as well as nuclear factor kappa B (NF-κB) activation. Vinpocetine inhibited the overt pain-like behavior induced by acetic acid, PBQ and formalin (at both phases), as well as the carrageenan-induced mechanical and thermal hyperalgesia and associated neutrophil recruitment. Both peripherally and in the spinal cord, vinpocetine also inhibited: antioxidant capacity and GSH depletion; increased superoxide anion; IL-1β and TNF-α levels; and NF-κB activation. As such, vinpocetine significantly reduces inflammatory pain by targeting oxidative stress, cytokine production and NF-κB activation at both peripheral and spinal cord levels.

"Curcumin-loaded Poly (d, l-lactide-co-glycolide) nanovesicles induce antinociceptive effects and reduce pronociceptive cytokine and BDNF release in spinal cord after acute administration in mice".

PubMed

Pieretti, Stefano; Ranjan, Amalendu P; Di Giannuario, Amalia; Mukerjee, Anindita; Marzoli, Francesca; Di Giovannandrea, Rita; Vishwanatha, Jamboor K

2017-10-01

Given the poor bioavailability of curcumin, its antinociceptive effects are produced after chronic intravenous administration of high doses, while poly (d,l-lactide-co-glycolide)-loaded vesicles (PLGA) can improve drug delivery. This paper investigates the antinociceptive effects of curcumin-loaded PLGA nanovesicles (PLGA-CUR) administered via intravenous (i.v.) or intrathecal (i.t.) routes at low and high doses. The following models of pain were used: formalin test, zymosan-induced hyperalgesia and sciatic nerve ligation inducing neuropathic allodynia and hyperalgesia. PLGA-CUR administered intravenously was able to reduce the response to nociceptive stimuli in the formalin test and hyperalgesia induced by zymosan. Curcumin, instead, was inactive. Low-dose i.t. administration of PLGA-CUR significantly reduced allodynia produced by sciatic nerve ligation, whereas low doses of curcumin did not change the response to nociceptive stimuli. Long-lasting antinociceptive effects were observed when high doses of PLGA-CUR were administered intrathecally. At high doses, i.t. administration of curcumin only exerted rapid and transient antinociceptive effects. Measurement of cytokine and BDNF in the spinal cord of neuropathic mice demonstrate that the antinociceptive effects of PLGA-CUR depend on the reduction in cytokine release and BDNF in the spinal cord. The results demonstrate the effectiveness of PLGA-CUR and suggest that PLGA-CUR nanoformulation might be a new potential drug in the treatment of pain. Copyright © 2017 Elsevier B.V. All rights reserved.

P2X3 and P2X2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis.

PubMed

Teixeira, Juliana Maia; Bobinski, Franciane; Parada, Carlos Amílcar; Sluka, Kathleen A; Tambeli, Cláudia Herrera

2017-10-01

Osteoarthritis (OA) is a degenerative and progressive disease characterized by cartilage breakdown and by synovial membrane inflammation, which results in disability, joint swelling, and pain. The purinergic P2X3 and P2X2/3 receptors contribute to development of inflammatory hyperalgesia, participate in arthritis processes in the knee joint, and are expressed in chondrocytes and nociceptive afferent fibers innervating the knee joint. In this study, we hypothesized that P2X3 and P2X2/3 receptors activation by endogenous ATP (adenosine 5'-triphosphate) induces articular hyperalgesia in the knee joint of male and female rats through an indirect sensitization of primary afferent nociceptors dependent on the previous release of pro-inflammatory cytokines and/or on neutrophil migration. We found that the blockade of articular P2X3 and P2X2/3 receptors significantly attenuated carrageenan-induced hyperalgesia in the knee joint of male and estrus female rats in a similar manner. The carrageenan-induced knee joint inflammation increased the expression of P2X3 receptors in chondrocytes of articular cartilage. Further, the blockade of articular P2X3 and P2X2/3 receptors significantly reduced the increased concentration of TNF-α, IL-6, and CINC-1 and the neutrophil migration induced by carrageenan. These findings indicate that P2X3 and P2X2/3 receptors activation by endogenous ATP is essential to hyperalgesia development in the knee joint through an indirect sensitization of primary afferent nociceptors dependent on the previous release of pro-inflammatory cytokines and/or on neutrophil migration.

Phase-locked and non-phase-locked EEG responses to pinprick stimulation before and after experimentally-induced secondary hyperalgesia.

PubMed

van den Broeke, Emanuel N; de Vries, Bart; Lambert, Julien; Torta, Diana M; Mouraux, André

2017-08-01

Pinprick-evoked brain potentials (PEPs) have been proposed as a technique to investigate secondary hyperalgesia and central sensitization in humans. However, the signal-to-noise (SNR) of PEPs is low. Here, using time-frequency analysis, we characterize the phase-locked and non-phase-locked EEG responses to pinprick stimulation, before and after secondary hyperalgesia. Secondary hyperalgesia was induced using high-frequency electrical stimulation (HFS) of the left/right forearm skin in 16 volunteers. EEG responses to 64 and 96mN pinprick stimuli were elicited from both arms, before and 20min after HFS. Pinprick stimulation applied to normal skin elicited a phase-locked low-frequency (<5Hz) response followed by a reduction of alpha-band oscillations (7-10Hz). The low-frequency response was significantly increased when pinprick stimuli were delivered to the area of secondary hyperalgesia. There was no change in the reduction of alpha-band oscillations. Whereas the low-frequency response was enhanced for both 64 and 96mN intensities, PEPs analyzed in the time domain were only significantly enhanced for the 64mN intensity. Time-frequency analysis may be more sensitive than conventional time-domain analysis in revealing EEG changes associated to secondary hyperalgesia. Time-frequency analysis of PEPs can be used to investigate central sensitization in humans. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Neutrophil Recruitment and Articular Hyperalgesia in Antigen-Induced Arthritis are Modulated by the Cholinergic Anti-Inflammatory Pathway.

PubMed

Kanashiro, Alexandre; Talbot, Jhimmy; Peres, Raphael S; Pinto, Larissa G; Bassi, Gabriel S; Cunha, Thiago M; Cunha, Fernando Q

2016-11-01

The cholinergic anti-inflammatory pathway (CAP) is a complex neuroimmune mechanism triggered by the central nervous system to regulate peripheral inflammatory responses. Understanding the role of CAP in the pathogenesis of rheumatoid arthritis (RA) could help develop new therapeutic strategies for this disease. Therefore, we investigated the participation of this neuroimmune pathway on the progression of experimental arthritis. Using antigen-induced arthritis (AIA) model, we investigated in mice the effects of vagotomy or the pharmacological treatments with hexamethonium (peripheral nicotinic receptor antagonist), methylatropine (peripheral muscarinic receptor antagonist) or neostigmine (peripheral acetylcholinesterase inhibitor) on AIA progression. Unilateral cervical vagotomy was performed 1 week before the immunization protocol with methylated bovine serum albumin (mBSA), while drug administration was conducted during the period of immunization. On day 21, 6 hr after the challenge with mBSA injection in the femur-tibial joint, the local neutrophil migration and articular mechanical hyperalgesia were assessed. Herein, we observed that vagotomy or blockade of peripheral nicotinic (but not muscarinic) receptors exacerbated the clinical parameters of this disease. Moreover, peripheral acetylcholinesterase inhibition by neostigmine treatment promoted a reduction of neutrophil recruitment in the knee joint and articular hyperalgesia. Our results demonstrated that peripheral activation of CAP modulates experimental arthritis, providing a pre-clinical evidence of a potential therapeutic strategy for RA. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Pharmacology of Intracisternal or Intrathecal Glycine, Muscimol, and Baclofen in Strychnine-induced Thermal Hyperalgesia of Mice

PubMed Central

Son, Jin Kook; Lim, Eui-Sung; Kim, Yeon-Soo

2011-01-01

Glycine and γ-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABAA receptor agonist), baclofen (a GABAB receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system. PMID:22022192

Pharmacology of intracisternal or intrathecal glycine, muscimol, and baclofen in strychnine-induced thermal hyperalgesia of mice.

PubMed

Lee, Il Ok; Son, Jin Kook; Lim, Eui-Sung; Kim, Yeon-Soo

2011-10-01

Glycine and γ-aminobutyric acid (GABA) are localized and released by the same interneurons in the spinal cord. Although the effects of glycine and GABA on analgesia are well known, little is known about the effect of GABA in strychnine-induced hyperalgesia. To investigate the effect of GABA and the role of the glycine receptor in thermal hyperalgesia, we designed an experiment involving the injection of muscimol (a GABA(A) receptor agonist), baclofen (a GABA(B) receptor agonist) or glycine with strychnine (strychnine sensitive glycine receptor antagonist). Glycine, muscimol, or baclofen with strychnine was injected into the cisterna magna or lumbar subarachnoidal spaces of mice. The effects of treatment on strychnine-induced heat hyperalgesia were observed using the pain threshold index via the hot plate test. The dosages of experimental drugs and strychnine we chose had no effects on motor behavior in conscious mice. Intracisternal or intrathecal administration of strychnine produced thermal hyperalgesia in mice. Glycine antagonize the effects of strychnine, whereas, muscimol or baclofen does not. Our results indicate that glycine has anti-thermal hyperalgesic properties in vivo; and GABA receptor agonists may lack the binding abilities of glycine receptor antagonists with their sites in the central nervous system.

Evaluating the Analgesic Effect of the GLS Inhibitor 6-Diazo-5-Oxo-L-Norleucine in Vivo

PubMed Central

Crosby, Heith A; Miller, Kenneth E

2018-01-01

Glutamate is an excitatory neurotransmitter, produced by its synthetic enzyme, glutaminase (GLS), and packaged by vesicular transporters (VGluT2) into synaptic vesicles. Primary sensory peripheral nerve and spinal synaptic terminals release glutamate during nociceptive (pain) signaling. In post-incisional and inflammation models in rats, GLS and VGluT2 production is elevated in dorsal root ganglion neuronal cell bodies and transported to peripheral and spinal terminals for increased glutamate synthesis and release. 6-Diazo-5-oxo-l-norleucine (DON) is a GLS inhibitor that produces long lasting pain relief when applied to the inflamed paw of arthritic rats, but its effect in a post-incisional model has not been evaluated. In this study, we examined the analgesic efficacy of DON in a surgical incision model by measuring thermal latency and mechanical allodynia. Following behavioral evaluation, we examined the skin for VGluT2, GLS and glutamate immunoreactivity (ir). Our findings revealed that VGluT2-ir is elevated in the stratum lucidum by approximately 19%, 64 hours post-surgical incision and attenuated by approximately 5.4% after the administration of DON. During that same period GLS-ir was elevated in dermal nerve fibers by 52% and was attenuated by approximately 27.9% after the application of DON. Additionally, glutamate-ir was elevated in epidermal nerve fibers by 35% after incision and attenuated by approximately 23% after the administration of DON. Behavioral testing 24 and 48 hours after a single local administration of DON showed five out of six animals having an analgesic response to mechanical allodynia, but not to thermal hyperalgesia. Following a surgical incision, the area of injury shows increased VGluT2-, GLS-, glutamate-ir, mechanical allodynia and no change in thermal latency. After the application of the GLS inhibitor, DON, nerve fiber of the skin showed decreased VGluT2, GLS, and glutamate-ir. Furthermore, post-incision DON treated animals

Fatigue-enhanced hyperalgesia in response to muscle insult: induction and development occur in a sex-dependent manner

PubMed Central

Gregory, N. S.; Gibson-Corley, K.; Frey-Law, L.; Sluka, K. A.

2014-01-01

Chronic muscle pain affects 20–50% of the population, is more common in women than men, and is associated with increased pain during physical activity and exercise. Muscle fatigue is common in people with chronic muscle pain, occurs in response to exercise and is associated with release of fatigue metabolites. Fatigue metabolites can sensitize muscle nociceptors which could enhance pain with exercise. Using a mouse model we tested whether fatigue of a single muscle, induced by electrical stimulation, resulted in enhanced muscle hyperalgesia and if the enhanced hyperalgesia was more pronounced in female mice. Muscle fatigue was induced in combination with a sub-threshold muscle insult (2 injections of pH 5.0 saline) in male and female mice. We show that male and female mice, fatigued immediately prior to muscle insult in the same muscle, develop similar muscle hyperalgesia 24h later. However, female mice also develop hyperalgesia when muscle fatigue and muscle insult occur in different muscles, and when muscle insult is administered 24 hours after fatigue in the same muscle. Further, hyperalgesia lasts significantly longer in females. Finally, muscle insult with or without muscle fatigue results in minimal inflammatory changes in the muscle itself, and sex differences are not related to estradiol (ovariectomy) or changes in brainstem activity (pNR1). Thus, the current model mimics muscle fatigue-induced enhancement of pain observed in chronic muscle pain conditions in the human population. Interactions between fatigue and muscle insult may underlie the development of chronic widespread pain with an associated female predominance observed in human subjects. PMID:23906552

Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain.

PubMed

Lomazzo, Ermelinda; Bindila, Laura; Remmers, Floor; Lerner, Raissa; Schwitter, Claudia; Hoheisel, Ulrich; Lutz, Beat

2015-01-01

The occurrence of chronic stress, depression, and anxiety can increase nociception in humans and may facilitate the transition from localized to chronic widespread pain. The mechanisms underlying chronic widespread pain are still unknown, hindering the development of effective pharmacological therapies. Here, we exposed C57BL/6J mice to chronic unpredictable stress (CUS) to investigate how persistent stress affects nociception. Next, mice were treated with multiple intramuscular nerve growth factor (NGF) injections, which induced chronic widespread nociception. Thus, combination of CUS and NGF served as a model where psychophysiological impairment coexists with long-lasting hyperalgesia. We found that CUS increased anxiety- and depression-like behavior and enhanced basal nociception in mice. When co-applied with repeated NGF injections, CUS elicited a sustained long-lasting widespread hyperalgesia. In order to evaluate a potential therapeutic strategy for the treatment of chronic pain associated with stress, we hypothesized that the endocannabinoid system (ECS) may represent a target signaling system. We found that URB597, an inhibitor of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), and JZL184, an inhibitor of the 2-arachidonoyl glycerol-degrading enzyme monoacylglycerol lipase (MAGL), increased eCB levels in the brain and periphery and were both effective in reducing CUS-induced anxiety measured by the light-dark test and CUS-induced thermal hyperalgesia. Remarkably, the long-lasting widespread hyperalgesia induced by combining CUS and NGF was effectively reduced by URB597, but not by JZL184. Simultaneous inhibition of FAAH and MAGL did not improve the overall therapeutic response. Therefore, our findings indicate that enhancement of anandamide signaling with URB597 is a promising pharmacological approach for the alleviation of chronic widespread nociception in stress-exposed mice, and thus, it could represent a potential treatment strategy

The release of spinal prostaglandin E2 and the effect of nitric oxide synthetase inhibition during strychnine-induced allodynia.

PubMed

Milne, B; Hall, S R; Sullivan, M E; Loomis, C

2001-09-01

The removal of spinal glycinergic inhibition by intrathecal strychnine produces an allodynia-like state in rodents. Our objective was to measure spinal prostaglandin E2 (PGE2) release during strychnine-allodynia and examine the effects of Nomega-nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide synthetase. Under halothane, rats were fitted with intrathecal and spinal microdialysis catheters, and microelectrodes implanted into the locus coeruleus for measurement of catechol oxidation current (CAOC) using voltammetry. Animals were then administered urethane and treated as follows: 1) baseline control 10 min, intrathecal strychnine (40 microg) 10 min, 10 min of hair deflection, and 2) 10-min control followed by intrathecal strychnine (40 microg) with hair deflection for 60 min. Spinal dialysate samples were collected for PGE2 levels determined by using immunoassay. In separate experiments, the effect of intrathecal strychnine (40 microg) followed by hair deflection was studied in rats pretreated with intrathecal l-NOARG (50 nmol). After intrathecal strychnine, hair deflection significantly increased spinal PGE2 release (619% +/- 143%), locus coeruleus CAOC (181% +/- 6%), and mean arterial pressure (123% +/- 2%) P < 0.05. Pretreatment with intrathecal l-NOARG significantly inhibited strychnine-allodynia. In this model, hair deflection evokes spinal PGE2 release, locus coeruleus activation, and an increase in mean arterial pressure. L-NOARG pretreatment attenuated the locus coeruleus CAOC, a biochemical index of strychnine-allodynia, suggesting a mediator role of nitric oxide. A mediator role of nitric oxide is also implicated, helping to explain the pathophysiology of this allodynic pain.

Implication of surgical procedure in the induction of headache and generalized painful sensation in a fluid percussion injury model in rats.

PubMed

da SilvaFiorin, Fernando; do Espírito Santo, Caroline Cunha; Santos, Adair Roberto Soares; Fighera, Michele Rechia; Royes, Luiz Fernando Freire

2018-06-13

This study demonstrated the effects of traumatic brain injury (TBI) and each step of the surgical procedure for a fluid percussion injury (FPI) model on periorbital allodynia. Adult male Wistar rats were divided in naive, incision, scraping, sham-TBI and TBI groups. Periorbital allodynia was evaluated using von Frey filaments, and heat hyperalgesia of the hindpaws was evaluated by a Plantar Test Apparatus. The statistical analyses revealed that the surgical procedure decreased von Frey filaments thresholds twenty-four hours after the surgery in all groups when compared to the naive group (p < 0.0001). Scraping, sham-TBI and TBI groups showed a decrease in the periorbital mechanical threshold for 35 days compared with the naive and incision groups (p < 0.0001). Only the TBI group demonstrated a significant difference in periorbital allodynia at 45 and 60 days after the injury (p < 0.01). A significant decrease in the thermal withdrawal latency of the hindpaw contralateral to the lesion was observed in the TBI group compared with the naïve group at 7 days and 28 days after the lesion (p < 0.05). This study presented in detail the effects of each stage of the surgical procedure for a FPI model on periorbital allodynia over time and characterized the TBI model for this evaluation. The FPI model is relevant for the study of headache and generalized pain in both acute and chronic phases after an injury. Copyright © 2018 Elsevier B.V. All rights reserved.

Involvement of NO-cGMP pathway in anti-hyperalgesic effect of PDE5 inhibitor tadalafil in experimental hyperalgesia.

PubMed

Otari, K V; Upasani, C D

2015-08-01

The association of elevated level of cyclic guanosine monophosphate (cGMP) with inhibition of hyperalgesia and involvement of nitric oxide (NO)-cGMP pathway in the modulation of pain perception was previously reported. Phosphodiesterases 5 (PDE5) inhibitors, sildenafil and tadalafil (TAD) used in erectile dysfunction, are known to act via the NO-cGMP pathway. TAD exerts its action by increasing the levels of intracellular cGMP. Hence, the present study investigated the effect of TAD 5, 10, or 20 mg/kg, per os (p.o.) or L-NAME 20 mg/kg, intraperitoneally (i.p.) and TAD (20 mg/kg, p.o.) in carrageenan- and diabetes-induced hyperalgesia in rats using hot plate test at 55 ± 2 °C. In carrageenan- and diabetes-induced hyperalgesia, TAD (10 and 20 mg/kg, p.o.) significantly increased paw withdrawal latencies (PWLs) as compared to the control group. L-NAME significantly decreased PWLs as compared to the normal group and aggravated the hyperalgesia. Moreover, significant difference in PWLs of L-NAME and TAD 20 was evident. Co-administration of L-NAME (20 mg/kg) with TAD (20 mg/kg) showed significant difference in PWLs as compared to the TAD (20 mg/kg), indicating L-NAME reversed and antagonized TAD-induced anti-hyperalgesia. This suggested an important role of NO-cGMP pathway in TAD-induced anti-hyperalgesic effect.

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.

Effect of painless diabetic neuropathy on pressure pain hypersensitivity (hyperalgesia) after acute foot trauma

PubMed Central

Wienemann, Tobias; Chantelau, Ernst A.; Koller, Armin

2014-01-01

Introduction and objective Acute injury transiently lowers local mechanical pain thresholds at a limb. To elucidate the impact of painless (diabetic) neuropathy on this post-traumatic hyperalgesia, pressure pain perception thresholds after a skeletal foot trauma were studied in consecutive persons without and with neuropathy (i.e. history of foot ulcer or Charcot arthropathy). Design and methods A case–control study was done on 25 unselected clinical routine patients with acute unilateral foot trauma (cases: elective bone surgery; controls: sprain, toe fracture). Cases were 12 patients (11 diabetic subjects) with severe painless neuropathy and chronic foot pathology. Controls were 13 non-neuropathic persons. Over 1 week after the trauma, cutaneous pressure pain perception threshold (CPPPT) and deep pressure pain perception threshold (DPPPT) were measured repeatedly, adjacent to the injury and at the opposite foot (pinprick stimulators, Algometer II®). Results In the control group, post-traumatic DPPPT (but not CPPPT) at the injured foot was reduced by about 15–25%. In the case group, pre- and post-operative CPPPT and DPPPT were supranormal. Although DPPPT fell post-operatively by about 15–20%, it remained always higher than the post-traumatic DPPPT in the control group: over musculus abductor hallucis 615 kPa (kilopascal) versus 422 kPa, and over metatarsophalangeal joint 518 kPa versus 375 kPa (medians; case vs. control group); CPPPT did not decrease post-operatively. Conclusion Physiological nociception and post-traumatic hyperalgesia to pressure are diminished at the foot with severe painless (diabetic) neuropathy. A degree of post-traumatic hypersensitivity required to ‘pull away’ from any one, even innocuous, mechanical impact in order to avoid additional damage is, therefore, lacking. PMID:25397867

Strychnine-sensitive modulation is selective for non-noxious somatosensory input in the spinal cord of the rat.

PubMed

Sherman, S E; Loomis, C W

1996-08-01

Touch-evoked allodynia, an important symptom of clinical neural injury pain, can be modelled acutely and reversibly in the urethane-anesthetized rat using intrathecal (i.t.) strychnine (STR). Allodynia, after i.t. STR (40 micrograms), is manifest as a significant enhancement of cardiovascular and motor responses evoked by normally innocuous brushing of the hair (hair deflection), as compared to responses evoked by either hair deflection after i.t. saline (SAL), or to i.t. STR (40 micrograms) with no tactile stimulus. The present study investigated: (1) the pharmacology of afferent neural inputs involved in STR-dependent allodynia using neonatal capsaicin and the non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX); and (2) the effect of i.t. STR on responses evoked by peripheral noxious stimulation. Neonatal capsaicin (25 mg/kg, s.c., post-natal day (PND) 1, and 50 mg/kg, s.c., PND 2, 3, 4, 11, 25, 55 and 85) significantly attenuated the responses evoked by noxious mechanical, thermal or chemical stimuli, but had no effect on STR-dependent allodynia. All hair deflection-evoked, STR-dependent responses were dose-dependently inhibited by i.t. NBQX. The ED50 values and 95% confidence intervals were 10.4 micrograms (5.5-19.6) for the motor withdrawal response, 14.4 micrograms (8.6-24.0) for changes in MAP and 12.2 micrograms (6.8-21.8) for changes in HR. Cortical EEG synchrony was unchanged by i.t. NBQX confirming its spinal locus of action. Intrathecal STR neither reduced nor enhanced the responses elicited by noxious stimuli in capsaicin- or vehicle-pretreated rats. These results indicate that STR-dependent allodynia is initiated by primary afferents not normally involved in nociception (possibly A beta-fibers), and that STR-sensitive modulation in the spinal cord is selective for non-noxious sensory input. The sensitivity of STR-dependent allodynia to non-NMDA receptor antagonists, and the failure of i.t. STR to produce

Antinociceptive effectiveness of Tithonia tubaeformis in a vincristine model of chemotherapy-induced painful neuropathy in mice.

PubMed

Nawaz, Noor Ul Ain; Saeed, Muhammad; Rauf, Khalid; Usman, Muhammad; Arif, Mehreen; Ullah, Zaki; Raziq, Naila

2018-04-25

Chemotherapy induced peripheral neuropathy (CIPN) is a painful side-effect of commonly used chemotherapeutic agents that profoundly impair the quality of life of patients as the current pharmacotherapeutic strategies are inefficient in providing adequate pain relief. Complementary and alternative medicine (CAM) therapies are preferred by patients with neuropathic pain as they experience insufficient control of pain with conventional medications. This study describes the antinociceptive effect of Tithonia tubaeformis (Jacq.) Cass. in a vincristine mouse model of established CIPN. Tithonia tubaeformis hydromethanolic extract was tested for preliminary qualitative phytochemical analysis and acute oral toxicity test in mice. The antinociceptive effect was investigated using the abdominal constriction (writhing) and tail immersion tests (25-200 mg/kg). The anti-neuropathic effect was determined in the vincristine mouse model, established by daily administration of vincristine (0.1 mg/kg/day, i.p) for consecutive 14 days. Acute treatment with Tithonia tubaeformis (100 and 200 mg/kg) and the positive control, gabapentin (75 mg/kg) was carried out on the 15th day of the last vincrsitine dose and the animals were tested for allodynia and thermal hyperalgesia at 30-120 min post extract/drug administration. Vincristine produced significant temporal tactile allodynia and thermal hyperalgesia (P < 0.01 and P < 0.001 on day 7 and 14) and was maintained for the subsequent day (P < 0.001 during 30-120 min). Tithonia tubaeformis was effective in attenuating the vincristine-induced allodynia and thermal hyperalgesia at 100 mg/kg (P < 0.05, P < 0.01) and 200 mg/kg (P < 0.01, P < 0.001). Similarly, gabapentin also showed a robust antinociceptive effect in counteracting the vincristine associated behavioral alterations. Tithonia tubaeformis can be an effective CAM therapeutic remedy for established CIPN due to its potential antinociceptive

Nefopam hydrochloride loaded microspheres for post-operative pain management: synthesis, physicochemical characterization and in-vivo evaluation.

PubMed

Sharma, Neelam; Arora, Sandeep; Madan, Jitender

2018-02-01

Once-daily oral dosage of nefopam hydrochloride loaded sustained release microspheres (NPH-MS) was investigated as novel therapeutic strategy for post-operative pain management. Microspheres were synthesized using poly-3-hydroxybutyrate and poly-(ɛ-caprolactone) by double emulsion solvent evaporation technique. NPH-MS were characterized through FTIR, PXRD and SEM. In-vitro drug release study revealed sustained behavior till 24 h. Haemolysis was <5% which signified haemocompatibility of formulation. ED50 in rat tail-flick anti-nociceptive test was found ∼18.12 mg/kg. In post-operative pain model, reversal of mechanical allodynia and thermal hyperalgesia by NPH-MS was statistically significant (p < .001) as compared with NPH till 24 h post-dose.

Biologic poisons for pain.

PubMed

Reisner, Lori

2004-12-01

Pain therapies from natural sources date back thousands of years to the use of plant and animal extracts for a variety of painful conditions and injuries. We certainly are all familiar with modern uses of plant-derived analgesic compounds such as opium derivatives from papaverum somniferum and salicylates from willow bark (Salix species). Local anesthetics were isolated from coca leaves in the late 1800s. Sarapin, derived from carnivorous pitcher plants, has been injected for regional analgesia in human and veterinary medicine, but efficacy is controversial. Biologic organisms can play important roles in developing an understanding of pain mechanisms, either from isolation of compounds that are analgesic or of compounds that produce pain, hyperalgesia, and allodynia.

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.

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

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.

Endogenous Prolactin Generated During Peripheral Inflammation Contributes to Thermal Hyperalgesia

PubMed Central

Scotland, Phoebe E.; Patil, Mayur; Belugin, Sergei; Henry, Michael A.; Goffin, Vincent; Hargreaves, Kenneth M.; Akopian, Armen N.

2011-01-01

Prolactin (PRL) is a hormone and a neuromodulator. PRL sensitizes TRPV1 responses in sensory neurons, but it is not clear whether peripheral inflammation results in the release of endogenous PRL, or whether endogenous PRL is capable of acting as an inflammatory mediator in a sex-dependent manner. To address these questions, we examined inflammation-induced release of endogenous PRL, and its regulation of thermal hyperalgesia in female and male rats. PRL is expressed in several types of peripheral neuronal and non-neuronal cells, including TRPV1-positive nerve fibers, preadipocytes and activated macrophages/monocytes localized in the vicinity of nerves. Evaluation of PRL levels in hindpaws and plasma indicated that complete Freund’s adjuvant (CFA) stimulates release of peripheral, but not systemic PRL within 6–48h in both ovariectomized females with estradiol replacement (OVX-E) and male rats. The time course of release varies in OVX-E and male rats. We next employed the prolactin receptor (PRL-R) antagonist, Δ1-9-G129R-hPRL to assess the role of locally-produced PRL in nociception. Applied at a ratio of 1:1 (PRL:Δ1-9-G129R-hPRL; 40nM each), this antagonist was able to nearly (≈80%) reverse PRL-induced sensitization of capsaicin responses in rat sensory neurons. CFA-induced inflammatory thermal hyperalgesia in OVX-E rat hindpaws was significantly reduced in a dose-dependent manner by the PRL-R antagonist at the 6h, but not the 24h time point. In contrast, PRL contributed to inflammatory thermal hyperalgesia in male rats at 24h, but not 6h. In summary, these findings indicate that inflammation leads to accumulation of endogenous PRL in female and male rats. Further, PRL acts as an inflammatory mediator at different time points for female and male rats. PMID:21777304

Assessment of incising ethology in the absence and presence of jaw muscle hyperalgesia in a mouse home cage environment.

PubMed

Widmer, C G; Morris-Wiman, J

2015-10-01

Assessment of oral motor behavior in a mouse is challenging due to the lack of currently available techniques that are non-invasive and allow long-term assessment in a home cage environment. The purpose of this study was to evaluate incising behavior using mouse chow attached to a three-dimensional force transducer that was mounted on the existing home cage. In addition, a persistent hyperalgesia condition was introduced to evaluate the sensitivity of the technique to identify incising behavioral changes. Incising activity of CD-1 male and female mice (n=48) was evaluated over a 24 hour recording session during four baseline and six longitudinal hyperalgesia assessment sessions using custom written software. A pre-clinical persistent pain model was used to induce hyperalgesia in the masseter muscle by repetitive acidic saline injections. Sex and age differences were evaluated for multiple incising variables during both light and dark cycles during baseline and hyperalgesia conditions. Significant sex differences were found for multiple incising variables but not for age. Discrete incising frequencies were identified in the range of 4.6-10.4 Hz and were reproducibly found in both female and male mice. A significant shift to lower incising frequencies was observed after repetitive acidic saline injections compared to neutral saline injections. This shift to lower frequencies of incising returned to baseline levels after approximately four weeks but was statistically longer in female compared to male mice. Significant differences were also found for chow intake (reduced) and weight change during the hyperalgesia condition. No significant differences were found for total number of incisions or number of incising episodes per day or incising force. The findings from this study support the use of recording three dimensional incising forces as a sensitive measure of incising behavior. This novel technique allowed the identification of specific incising variables that were

Pathophysiological mechanisms of neuropathic pain: comparison of sensory phenotypes in patients and human surrogate pain models.

PubMed

Vollert, Jan; Magerl, Walter; Baron, Ralf; Binder, Andreas; Enax-Krumova, Elena K; Geisslinger, Gerd; Gierthmühlen, Janne; Henrich, Florian; Hüllemann, Philipp; Klein, Thomas; Lötsch, Jörn; Maier, Christoph; Oertel, Bruno; Schuh-Hofer, Sigrid; Tölle, Thomas R; Treede, Rolf-Detlef

2018-06-01

As an indirect approach to relate previously identified sensory phenotypes of patients suffering from peripheral neuropathic pain to underlying mechanisms, we used a published sorting algorithm to estimate the prevalence of denervation, peripheral and central sensitization in 657 healthy subjects undergoing experimental models of nerve block (NB) (compression block and topical lidocaine), primary hyperalgesia (PH) (sunburn and topical capsaicin), or secondary hyperalgesia (intradermal capsaicin and electrical high-frequency stimulation), and in 902 patients suffering from neuropathic pain. Some of the data have been previously published. Randomized split-half analysis verified a good concordance with a priori mechanistic sensory profile assignment in the training (79%, Cohen κ = 0.54, n = 265) and the test set (81%, Cohen κ = 0.56, n = 279). Nerve blocks were characterized by pronounced thermal and mechanical sensory loss, but also mild pinprick hyperalgesia and paradoxical heat sensations. Primary hyperalgesia was characterized by pronounced gain for heat, pressure and pinprick pain, and mild thermal sensory loss. Secondary hyperalgesia was characterized by pronounced pinprick hyperalgesia and mild thermal sensory loss. Topical lidocaine plus topical capsaicin induced a combined phenotype of NB plus PH. Topical menthol was the only model with significant cold hyperalgesia. Sorting of the 902 patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering (65% identity, Cohen κ = 0.44), but the denervation phenotype was more frequent than in heuristic clustering. These data suggest that sorting according to human surrogate models may be useful for mechanism-based stratification of neuropathic pain patients for future clinical trials, as encouraged by the European Medicines Agency.

Constriction of the buccal branch of the facial nerve produces unilateral craniofacial allodynia.

PubMed

Lewis, Susannah S; Grace, Peter M; Hutchinson, Mark R; Maier, Steven F; Watkins, Linda R

2017-08-01

Despite pain being a sensory experience, studies of spinal cord ventral root damage have demonstrated that motor neuron injury can induce neuropathic pain. Whether injury of cranial motor nerves can also produce nociceptive hypersensitivity has not been addressed. Herein, we demonstrate that chronic constriction injury (CCI) of the buccal branch of the facial nerve results in long-lasting, unilateral allodynia in the rat. An anterograde and retrograde tracer (3000MW tetramethylrhodamine-conjugated dextran) was not transported to the trigeminal ganglion when applied to the injury site, but was transported to the facial nucleus, indicating that this nerve branch is not composed of trigeminal sensory neurons. Finally, intracisterna magna injection of interleukin-1 (IL-1) receptor antagonist reversed allodynia, implicating the pro-inflammatory cytokine IL-1 in the maintenance of neuropathic pain induced by facial nerve CCI. These data extend the prior evidence that selective injury to motor axons can enhance pain to supraspinal circuits by demonstrating that injury of a facial nerve with predominantly motor axons is sufficient for neuropathic pain, and that the resultant pain has a neuroimmune component. Copyright © 2016 Elsevier Inc. All rights reserved.

IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats.

PubMed

Zhang, Rui-Xin; Li, Aihui; Liu, Bing; Wang, Linbo; Ren, Ke; Zhang, Haiqing; Berman, Brian M; Lao, Lixing

2008-04-01

Although it has been shown that pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) facilitate perception of noxious inputs at the spinal level, the mechanisms have not been understood. This study determined the cell type that produces IL-1beta, the co-localization of IL-1 receptor type I (IL-1RI) and Fos and NR1 in the spinal cord, and the effects of IL-1 receptor antagonist (IL-1ra) on NR1 phosphorylation and hyperalgesia in a rat model of inflammatory pain. Phosphorylation of NR1, an essential subunit of the NMDA receptor (NMDAR), is known to modulate NMDAR activity and facilitate pain. Hyperalgesia was induced by injecting complete Freund's adjuvant (CFA, 0.08ml, 40microg Mycobacterium tuberculosis) into one hind paw of each rat. Paw withdrawal latency (PWL) was tested before CFA (-48h) for baseline and 2 and 24h after CFA to assess hyperalgesia. IL-1ra was given (i.t.) 24h before CFA to block the action of basal IL-1beta and 2h prior to each of two PWL tests to block CFA-induced IL-1beta. Spinal cords were removed for double immunostaining of IL-1beta/neuronal marker and IL-1beta/glial cell markers, IL-1RI/Fos and IL-1RI/NR1, and for Western blot to measure NR1 phosphorylation. The data showed that: (1) astrocytes produce IL-1beta, (2) IL-1RI is localized in Fos- and NR1-immunoreactive neurons within the spinal dorsal horn, and (3) IL-1ra at 0.01mg/rat significantly increased PWL (P<0.05) and inhibited NR1 phosphorylation compared to saline control. The results suggest that spinal IL-1beta is produced by astrocytes and enhances NR1 phosphorylation to facilitate inflammatory pain.

Incidence of persistent postoperative pain after hepatectomies with 2 regimes of perioperative analgesia containing ketamine.

PubMed

Masgoret, Paula; Gomar, Carmen; Tena, Beatriz; Taurá, Pilar; Ríos, José; Coca, Miquel

2017-04-01

Studies designed to assess persistent postoperative pain (PPP) incidence after hepatectomies are lacking. Our aim was to assess PPP incidence 6 months after hepatectomies with intravenous (IV) or epidural (EPI) analgesia containing ketamine.Prospective observational comparative study between 2 cohorts of patients submitted to hepatectomy. Patients received 1 of 2 analgesic regimes containing ketamine: EPI group or IV group. Visual analog scale (VAS), Neuropathic Pain Symptom Inventory (NPSI), Pain Catastrophizing Scale (PCS), and quantitative sensorial testing (QST: to determine area of hyperalgesia/allodynia) were assessed preoperatively and postoperatively at 2 h, 24 h, 7 days, 1 month, and 6 months. VAS ≥ 1 at 1 and 6 months was considered indicative of PPP and VAS > 3 was considered as not controlled pain. Side effects and complications were registered.Forty-four patients were included: 23 in EPI group and 21 in IV group. Patients in IV group were older and had more comorbidities. No patient presented VAS > 3 at 1 or 6 months. VAS ≥ 1 at 1 and 6 months was 36.4% and 22.7%, respectively. No differences in VAS, NPSI, or PCS were found between groups. Allodynia/hyperalgesia area did not differ between groups and was infrequent and slight. Pain pressure threshold in the wound vertical component was significantly higher in EPI group after 7 days. IV group showed more cognitive side effects.Incidence of PPP at 6 months after open hepatectomies with EPI or IV analgesia containing ketamine was lower than previously reported for other abdominal surgeries.Ketamine influence on low PPP incidence and hyperalgesia cannot be discarded.

Alcoholic neuropathy: possible mechanisms and future treatment possibilities

PubMed Central

Chopra, Kanwaljit; Tiwari, Vinod

2012-01-01

Chronic alcohol consumption produces painful peripheral neuropathy for which there is no reliable successful therapy, mainly due to lack of understanding of its pathobiology. Alcoholic neuropathy involves coasting caused by damage to nerves that results from long term excessive drinking of alcohol and is characterized by spontaneous burning pain, hyperalgesia and allodynia. The mechanism behind alcoholic neuropathy is not well understood, but several explanations have been proposed. These include activation of spinal cord microglia after chronic alcohol consumption, oxidative stress leading to free radical damage to nerves, activation of mGlu5 receptors in the spinal cord and activation of the sympathoadrenal and hypothalamo-pituitary-adrenal (HPA) axis. Nutritional deficiency (especially thiamine deficiency) and/or the direct toxic effect of alcohol or both have also been implicated in alcohol-induced neuropathic pain. Treatment is directed towards halting further damage to the peripheral nerves and restoring their normal functioning. This can be achieved by alcohol abstinence and a nutritionally balanced diet supplemented by all B vitamins. However, in the setting of ongoing alcohol use, vitamin supplementation alone has not been convincingly shown to be sufficient for improvement in most patients. The present review is focused around the multiple pathways involved in the development of peripheral neuropathy associated with chronic alcohol intake and the different therapeutic agents which may find a place in the therapeutic armamentarium for both prevention and management of alcoholic neuropathy. PMID:21988193

A Novel Approach for Effectively Treating SCI Pain, Improving Opioid Efficacy, and Preventing Opioid-Induced Constipation: Key Role of Toll-Like Receptor 4 (TLR4)

DTIC Science & Technology

2015-10-01

University of Colorado Boulder, CO 80303 REPORT DATE: October 2015 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel...TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Regents of the University of Colorado Boulder, CO 80303 8...allodynia, hyperalgesia, toll-like receptor 4 OVERALL PROJECT SUMMARY Task 1. Obtain approval from the University of Colorado Institute Animal Care & Use

Amitriptyline reverses hyperalgesia and improves associated mood-like disorders in a model of experimental monoarthritis.

PubMed

Amorim, D; David-Pereira, A; Pertovaara, A; Almeida, A; Pinto-Ribeiro, F

2014-05-15

Affective disorders are common comorbidities of chronic inflammatory pain that are often overlooked in primary care. As the impact of inflammatory pain upon mood-like disorders in animal models is not well known, our objective was to assess whether prolonged experimental monoarthritis (ARTH) induced the development of anxiety and depressive-like behaviours in rodents and if amitriptyline, an antidepressant commonly used in the treatment of chronic pain, could reverse both nociceptive and mood-like impairments. Experimental ARTH was induced through an injection of kaolin/carrageenan into the right knee joint with control (SHAM) animals injected with saline. Four weeks after induction, ARTH animals displayed mechanical hyperalgesia and a depressive-like phenotype as they showed a significant increase in immobility and a decrease in the latency to immobility in the forced-swimming test at the expense of the time spent climbing/swimming. ARTH animals also displayed a decreased sucrose preference, an index of anhedonia and anxiety-like behaviour as time spent exploring the open arms of the elevated-plus-maze was decreased when compared to controls. The anxiety-like phenotype was also supported by an increase in the number of fecal boli left in the open field. In ARTH animals, the administration of amitriptyline decreased mechanical hyperalgesia and increased sucrose preference and the time spent climbing, although it had a deleterious effect in the performance of control animals. Our data show that this model of ARTH can be useful for the study of chronic pain-mood disorders comorbidities and that amitriptyline is able to partly reverse the associated nociceptive and emotional impairments. Copyright © 2014 Elsevier B.V. All rights reserved.

The level of serotonin in the superficial masseter muscle in relation to local pain and allodynia.

PubMed

Ernberg, M; Hedenberg-Magnusson, B; Alstergren, P; Kopp, S

1999-01-01

The aim of this study was to investigate if serotonin is present in the human masseter muscle and if so, whether it is involved in the modulation of local muscle pain or allodynia. Thirty-five patients with pain and tenderness of the masseter muscle as well as ten healthy individuals were included in the study. Of the patients, 18 suffered from fibromyalgia and 17 had localized myalgia, e.g. myofascial pain in the temporomandibular system. The participants were examined clinically with special consideration to the masseter muscle and the pressure pain threshold as well as tolerance levels of this muscle were assessed. Intramuscular microdialysis was performed in order to sample serotonin and a venous blood sample was collected for analysis of the serum level of serotonin. Serotonin was present in the masseter muscle and the level was significantly higher in the initial sample than in the sample collected during steady state. The level of serotonin in the masseter muscle in relation to the level of serotonin in the blood serum was calculated. This fraction of serotonin was higher in the patients with fibromyalgia than in healthy individuals and high level of serotonin was associated with pain as well as allodynia of the masseter muscle. In conclusion, the results of this study show that serotonin is present in the human masseter muscle both immediately following puncture and in a subsequent steady state and that it is associated with pain and allodynia. The origin of the serotonin seems partly to be the blood, but our results indicate that peripheral release also occurs.

Antagonists of toll like receptor 4 maybe a new strategy to counteract opioid-induced hyperalgesia and opioid tolerance.

PubMed

Li, Qian

2012-12-01

Long term opioid treatment results in hyperalgesia and tolerance, which is a troublesome phenomenon in clinic application. Recent studies have revealed a critical role of toll-like receptor 4 (TLR4) in the neuropathological process of opioid-induced hyperalgesia and tolerance. TLR4 is predominantly expressed by microglial cells and is a key modulator in the activation of the innate immune system. Activation of TLR4 may initiate the activation of microglia and hence a number of neurotransmitters and neuromodulators that could enhance neuronal excitability are released. Blockade of TLR4 activation by its antagonists alleviate neuropathic pain. We hypothesized that opioid antagonists such as naloxone and naltrexone, which were also demonstrated to be TLR4 antagonist, may have clinic application value in attenuation of opioid-induced hyperalgesia and tolerance. Copyright © 2012 Elsevier Ltd. All rights reserved.

Protease-activated receptor 2 in dorsal root ganglion contributes to peripheral sensitization of bone cancer pain.

PubMed

Liu, S; Liu, Y-P; Yue, D-M; Liu, G-J

2014-03-01

Treating bone cancer pain continues to be a major clinical challenge, and the underlying mechanisms of bone cancer pain remain elusive. Protease-activated receptor 2 (PAR2) has been reported to be involved in neurogenic inflammation, nociceptive pain and hyperalgesia. Here, we investigated the role of PAR2 in bone cancer pain development. Expression of PAR2, mechanical allodynia, thermal hyperalgesia and neurochemical alterations induced by bone cancer pain were analysed in male, adult C3H/HeJ mice with tumour cell implantation (TCI). To investigate the contribution of PAR2 to bone cancer pain, PAR2 antagonist peptide and PAR2 knockout mice were used. TCI produced bone cancer-related pain behaviours. Production and persistence of these pain behaviours were well correlated with TCI-induced up-regulation of PAR2 in sciatic nerve and dorsal root ganglia (DRG). PAR2 knockout and spinal administration of PAR2 antagonist peptide prevented and/or reversed bone cancer-related pain behaviours and associated neurochemical changes in DRG and dorsal horn (DH). TCI also induced proteases release in tumour-bearing tibia, sciatic nerve and DRG. Plantar injection of supernatant from sarcoma cells induced PAR2 up-regulation and intracellular calcium [Ca(2+) ]i increase in DRG, and calcitonin gene-related peptide accumulation in DH, as well as significant thermal and mechanical hyperalgesia, which were all in PAR2-dependent manners. These findings suggest that PAR2 may be a key mediator for peripheral sensitization of bone cancer pain. Inhibiting PAR2 activation, especially during the early phase, may be a new therapy for preventing/suppressing development of bone cancer pain. © 2013 European Pain Federation - EFIC®

Systemic morphine treatment induces changes in firing patterns and responses of nociceptive afferent fibers in mouse glabrous skin

PubMed Central

Hogan, Dale; Baker, Alyssa L.; Morón, Jose A.; Carlton, Susan M.

2013-01-01

Patients receiving opioids for pain may experience decreased effectiveness of the drug and even abnormal pain sensitivity – either hyperalgesia and/or allodynia. We hypothesize that peripheral nociceptor hyperexcitability contributes to opioid-induced hyperalgesia and test this using an in vitro mouse glabrous skin-nerve preparation. Mice were injected i.p. with escalating doses of morphine (5, 8, 10, 15 mg/kg) or saline every 12 h for 48 h and sacrificed ~12 h following the last injection. Receptive fields of nociceptors were tested for mechanical, heat, and cold sensitivity. Activity was also measured during an initial 2 min period and during 5 min periods between stimuli. Aberrant activity was common in fibers from morphine-treated mice but rare in salinetreated mice. Resting background activity was elevated in C-fibers from morphinetreated mice. Both C- and Aδ -fibers had afterdischarge in response to mechanical, heat and/or cold stimulation of the skin as well as spontaneous, unevoked activity. Compared to saline, morphine treatment increased the proportion of fibers displaying polymodal rather than mechanical-only responses. A significant increase in Aδ-mechanoreceptive fibers responding to cold accounted for most of this change. In agreement with this, morphine-treated mice showed increased sensitivity in the cold tail flick test. In morphine-treated mice, aberrant activity and hyperexcitability of nociceptors could contribute to increased pain sensitivity. Importantly, this activity is likely driving central sensitization, a phenomenon contributing to abnormal sensory processing and chronic pain. If similar changes occur in human patients, aberrant nociceptor activity is likely to be interpreted as pain, and could contribute to opioid-induced hyperalgesia. PMID:23711478

Increased serum IL-6 level time-dependently regulates hyperalgesia and spinal mu opioid receptor expression during CFA-induced arthritis

PubMed Central

Tekieh, E.; Zaringhalam, Jalal; Manaheji, H.; Maghsoudi, N.; Alani, B.; Zardooz, H.

2011-01-01

Interleukin (IL)-6 is known to cause pro- and anti-inflammatory effects during different stages of inflammation. Recent therapeutic investigations have focused on treatment of various inflammatory disorders with anti-cytokine substances. As a result, the aim of this study was to further elucidate the influence of IL-6 in hyperalgesia and edema during different stages of Complete Freund's Adjuvant (CFA)-induced arthritis (AA) in male Wistar rats. AA was induced by a single subcutaneous injection of CFA into the rats' hindpaw. Anti-IL-6 was administered either daily or weekly during the 21 days of study. Spinal mu opioid receptor (mOR) expression was detected by Western blotting. Daily and weekly treatment with an anti-IL-6 antibody significantly decreased paw edema in the AA group compared to the AA control group. Additionally, daily and weekly anti-IL-6 administration significantly reduced hyperalgesia on day 7 in the AA group compared to the AA control group; however, there were significant increases in hyperalgesia in the antibody-treated group on days 14 and 21 compared to the AA control group. IL-6 antibody-induced increases in hyperalgesia on the 14th and 21st days after CFA injection correlated with a time-dependent, significant reduction in spinal mOR expression during anti-IL-6 treatment. Our study confirmed the important time-dependent relationship between serum IL-6 levels and hyperalgesia during AA. These results suggest that the stages of inflammation in AA must be considered for anti-hyperalgesic and anti-inflammatory interventions via anti-IL-6 antibody treatment. PMID:27857662

Increased serum IL-6 level time-dependently regulates hyperalgesia and spinal mu opioid receptor expression during CFA-induced arthritis.

PubMed

Tekieh, E; Zaringhalam, Jalal; Manaheji, H; Maghsoudi, N; Alani, B; Zardooz, H

2011-01-01

Interleukin (IL)-6 is known to cause pro- and anti-inflammatory effects during different stages of inflammation. Recent therapeutic investigations have focused on treatment of various inflammatory disorders with anti-cytokine substances. As a result, the aim of this study was to further elucidate the influence of IL-6 in hyperalgesia and edema during different stages of Complete Freund's Adjuvant (CFA)-induced arthritis (AA) in male Wistar rats. AA was induced by a single subcutaneous injection of CFA into the rats' hindpaw. Anti-IL-6 was administered either daily or weekly during the 21 days of study. Spinal mu opioid receptor (mOR) expression was detected by Western blotting. Daily and weekly treatment with an anti-IL-6 antibody significantly decreased paw edema in the AA group compared to the AA control group. Additionally, daily and weekly anti-IL-6 administration significantly reduced hyperalgesia on day 7 in the AA group compared to the AA control group; however, there were significant increases in hyperalgesia in the antibody-treated group on days 14 and 21 compared to the AA control group. IL-6 antibody-induced increases in hyperalgesia on the 14 th and 21 st days after CFA injection correlated with a time-dependent, significant reduction in spinal mOR expression during anti-IL-6 treatment. Our study confirmed the important time-dependent relationship between serum IL-6 levels and hyperalgesia during AA. These results suggest that the stages of inflammation in AA must be considered for anti-hyperalgesic and anti-inflammatory interventions via anti-IL-6 antibody treatment.

Patients with chronic pain after abdominal surgery show less preoperative endogenous pain inhibition and more postoperative hyperalgesia: a pilot study.

PubMed

Wilder-Smith, Oliver Hamilton; Schreyer, Tobias; Scheffer, Gert Jan; Arendt-Nielsen, Lars

2010-06-01

Chronic pain is common and undesirable after surgery. Progression from acute to chronic pain involves altered pain processing. The authors studied relationships between presence of chronic pain versus preoperative descending pain control (diffuse noxious inhibitory controls; DNICs) and postoperative persistence and spread of skin and deep tissue hyperalgesia (change in electric/pressure pain tolerance thresholds; ePTT/pPTT) up to 6 months postoperatively. In 20 patients undergoing elective major abdominal surgery under standardized anesthesia, we determined ePTT/pPTT (close to [abdomen] and distant from [leg] incision), eDNIC/pDNIC (change in ePTT/pPTT with cold pressor pain task; only preoperatively), and a 100 mm long pain visual analogue scale (VAS) (0 mm = no pain, 100 mm = worst pain imaginable), both at rest and on movement preoperatively, and 1 day and 1, 3, and 6 months postoperatively. Patients reporting chronic pain 6 months postoperatively had more abdominal and leg skin hyperalgesia over the postoperative period. More inhibitory preoperative eDNIC was associated with less late postoperative pain, without affecting skin hyperalgesia. More inhibitory pDNIC was linked to less postoperative leg deep tissue hyperalgesia, without affecting pain VAS. This pilot study for the first time links chronic pain after surgery, poorer preoperative inhibitory pain modulation (DNIC), and greater postoperative degree, persistence, and spread of hyperalgesia. If confirmed, these results support the potential clinical utility of perioperative pain processing testing.

Can treatment success with 5% lidocaine medicated plaster be predicted in cancer pain with neuropathic components or trigeminal neuropathic pain?

PubMed Central

Kern, Kai-Uwe; Nalamachu, Srinivas; Brasseur, Louis; Zakrzewska, Joanna M

2013-01-01

An expert group of 40 pain specialists from 16 countries performed a first assessment of the value of predictors for treatment success with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain. Results were based on the retrospective analysis of 68 case reports (sent in by participants in the 4 weeks prior to the conference) and the practical experience of the experts. Lidocaine plaster treatment was mostly successful for surgery or chemotherapy-related cancer pain with neuropathic components. A dose reduction of systemic pain treatment was observed in at least 50% of all cancer pain patients using the plaster as adjunct treatment; the presence of allodynia, hyperalgesia or pain quality provided a potential but not definitively clear indication of treatment success. In trigeminal neuropathic pain, continuous pain, severe allodynia, hyperalgesia, or postherpetic neuralgia or trauma as the cause of orofacial neuropathic pain were perceived as potential predictors of treatment success with lidocaine plaster. In conclusion, these findings provide a first assessment of the likelihood of treatment benefits with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain and support conducting large, well-designed multicenter studies. PMID:23630431

Pain and sensory disturbances following surgical repair of pectus carinatum.

PubMed

Knudsen, Marie Veje; Pilegaard, Hans K; Grosen, Kasper

2018-04-01

The purpose of this study was to assess the characteristics of persistent postoperative pain and sensory disturbances following surgical repair of pectus carinatum. Using a prospective observational design, 28 patients were assessed before, 6 weeks and 6 months after a modified Ravitch operation for pectus carinatum. Postoperative pain was assessed using the Short Form McGill Pain Questionnaire. Sensory testing was conducted to detect brush-evoked allodynia and pinprick hyperalgesia. Additionally, generic and disease-specific quality of life was assessed using the Short Form-36 Health Survey and the Nuss Questionnaire Modified for Adults before and after surgery. Six weeks after surgery, ten patients reported mild pain or discomfort. Six months after surgery, four patients reported only mild pain. Allodynia was detected in two patients 6 weeks and 6 months after surgery. Hyperalgesia was detected in eight patients 6 weeks after surgery, and in six patients 6 months after surgery. Generic quality of life was significantly improved over time. The study showed no significant pain problems, a tendency to reduced sensory disturbances and significant improvements in quality of life 6 months after surgical repair of pectus carinatum. Future studies should include a longer follow-up period to determine if these positive results are persistent. 1 (Prognosis Study). Copyright © 2017 Elsevier Inc. All rights reserved.

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

Variable transcriptional responsiveness of the P2X3 receptor gene during CFA-induced inflammatory hyperalgesia.

PubMed

Nuñez-Badinez, Paulina; Sepúlveda, Hugo; Diaz, Emilio; Greffrath, Wolfgang; Treede, Rolf-Detlef; Stehberg, Jimmy; Montecino, Martin; van Zundert, Brigitte

2018-05-01

The purinergic receptor P2X3 (P2X3-R) plays important roles in molecular pathways of pain, and reduction of its activity or expression effectively reduces chronic inflammatory and neuropathic pain sensation. Inflammation, nerve injury, and cancer-induced pain can increase P2X3-R mRNA and/or protein levels in dorsal root ganglia (DRG). However, P2X3-R expression is unaltered or even reduced in other pain studies. The reasons for these discrepancies are unknown and might depend on the applied traumatic intervention or on intrinsic factors such as age, gender, genetic background, and/or epigenetics. In this study, we sought to get insights into the molecular mechanisms responsible for inflammatory hyperalgesia by determining P2X3-R expression in DRG neurons of juvenile male rats that received a Complete Freund's Adjuvant (CFA) bilateral paw injection. We demonstrate that all CFA-treated rats showed inflammatory hyperalgesia, however, only a fraction (14-20%) displayed increased P2X3-R mRNA levels, reproducible across both sides. Immunostaining assays did not reveal significant increases in the percentage of P2X3-positive neurons, indicating that increased P2X3-R at DRG somas is not critical for inducing inflammatory hyperalgesia in CFA-treated rats. Chromatin immunoprecipitation (ChIP) assays showed a correlated (R 2  = 0.671) enrichment of the transcription factor Runx1 and the epigenetic active mark histone H3 acetylation (H3Ac) at the P2X3-R gene promoter in a fraction of the CFA-treated rats. These results suggest that animal-specific increases in P2X3-R mRNA levels are likely associated with the genetic/epigenetic context of the P2X3-R locus that controls P2X3-R gene transcription by recruiting Runx1 and epigenetic co-regulators that mediate histone acetylation. © 2017 Wiley Periodicals, Inc.

Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia.

PubMed

Scotland, Phoebe E; Patil, Mayur; Belugin, Sergei; Henry, Michael A; Goffin, Vincent; Hargreaves, Kenneth M; Akopian, Armen N

2011-09-01

Prolactin (PRL) is a hormone and a neuromodulator. It sensitizes TRPV1 (transient receptor potential cation channel subfamily V member 1) responses in sensory neurons, but it is not clear whether peripheral inflammation results in the release of endogenous PRL, or whether endogenous PRL is capable of acting as an inflammatory mediator in a sex-dependent manner. To address these questions, we examined inflammation-induced release of endogenous PRL, and its regulation of thermal hyperalgesia in female and male rats. PRL is expressed in several types of peripheral neuronal and non-neuronal cells, including TRPV1-positive nerve fibers, preadipocytes and activated macrophages/monocytes localized in the vicinity of nerves. Evaluation of PRL levels in hindpaws and plasma indicated that complete Freund's adjuvant (CFA) stimulates release of peripheral, but not systemic, PRL within 6-48 h in both ovariectomized females with estradiol replacement (OVX-E) and intact male rats. The time course of release varies in OVX-E and intact male rats. We next employed the prolactin receptor (PRL-R) antagonist Δ1-9-G129R-hPRL to assess the role of locally produced PRL in nociception. Applied at a ratio of 1 : 1 (PRL:Δ1-9-G129R-hPRL; 40 nm each), this antagonist was able to nearly (≈ 80%) reverse PRL-induced sensitization of capsaicin responses in rat sensory neurons. CFA-induced inflammatory thermal hyperalgesia in OVX-E rat hindpaws was significantly reduced in a dose-dependent manner by the PRL-R antagonist at 6 h but not at 24 h. In contrast, PRL contributed to inflammatory thermal hyperalgesia in intact male rats at 24, but not at 6 h. These findings indicate that inflammation leads to accumulation of endogenous PRL in female and male rats. Furthermore, PRL acts as an inflammatory mediator at different time points for female and intact male rats. © 2011 UT Health Science Center San Antonio. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies

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 �

Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice.

PubMed

Chen, Yong; Boettger, Michael K; Reif, Andreas; Schmitt, Angelika; Uçeyler, Nurcan; Sommer, Claudia

2010-03-02

Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data. These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.

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

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

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

Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review.

PubMed

Kim, Sang Hun; Stoicea, Nicoleta; Soghomonyan, Suren; Bergese, Sergio D

2015-01-01

The use of opioids may seem to be a double-edged sword; they provide straight analgesic and antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental studies and clinical observations. It has been suggested that opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans.

Chronic Compression of the Dorsal Root Ganglion Enhances Mechanically Evoked Pain Behavior and the Activity of Cutaneous Nociceptors in Mice.

PubMed

Wang, Tao; Hurwitz, Olivia; Shimada, Steven G; Qu, Lintao; Fu, Kai; Zhang, Pu; Ma, Chao; LaMotte, Robert H

2015-01-01

Radicular pain in humans is usually caused by intraforaminal stenosis and other diseases affecting the spinal nerve, root, or dorsal root ganglion (DRG). Previous studies discovered that a chronic compression of the DRG (CCD) induced mechanical allodynia in rats and mice, with enhanced excitability of DRG neurons. We investigated whether CCD altered the pain-like behavior and also the responses of cutaneous nociceptors with unmyelinated axons (C-fibers) to a normally aversive punctate mechanical stimulus delivered to the hairy skin of the hind limb of the mouse. The incidence of a foot shaking evoked by indentation of the dorsum of foot with an aversive von Frey filament (tip diameter 200 μm, bending force 20 mN) was significantly higher in the foot ipsilateral to the CCD surgery as compared to the contralateral side on post-operative days 2 to 8. Mechanically-evoked action potentials were electrophysiologically recorded from the L3 DRG, in vivo, from cell bodies visually identified as expressing a transgenically labeled fluorescent marker (neurons expressing either the receptor MrgprA3 or MrgprD). After CCD, 26.7% of MrgprA3+ and 32.1% MrgprD+ neurons exhibited spontaneous activity (SA), while none of the unoperated control neurons had SA. MrgprA3+ and MrgprD+ neurons in the compressed DRG exhibited, in comparison with neurons from unoperated control mice, an increased response to the punctate mechanical stimuli for each force applied (6, 20, 40, and 80 mN). We conclude that CCD produced both a behavioral hyperalgesia and an enhanced response of cutaneous C-nociceptors to aversive punctate mechanical stimuli.

Low doses of dextromethorphan have a beneficial effect in the treatment of neuropathic pain.

PubMed

Morel, Véronique; Pickering, Gisèle; Etienne, Monique; Dupuis, Amandine; Privat, Anne-Marie; Chalus, Maryse; Eschalier, Alain; Daulhac, Laurence

2014-12-01

N-methyl-D-aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y-maze tests and molecular events by Western blot analysis. Spinal nerve-ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr(1336)NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr(1336)NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life. © 2014 Société Française de Pharmacologie et de Thérapeutique.

Hypothalamic GPR40 signaling activated by free long chain fatty acids suppresses CFA-induced inflammatory chronic pain.

PubMed

Nakamoto, Kazuo; Nishinaka, Takashi; Sato, Naoya; Mankura, Mitsumasa; Koyama, Yutaka; Kasuya, Fumiyo; Tokuyama, Shogo

2013-01-01

GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently increased at day 7, but not at days 1, 3 and 14, after CFA injection. GPR40 was co-localized with NeuN, a neuron marker, but not with glial fibrillary acidic protein (GFAP), an astrocyte marker. At day 1 after CFA injection, GFAP protein expression was markedly increased in the hypothalamus. These increases were significantly inhibited by the intracerebroventricular injection of flavopiridol (15 nmol), a cyclin-dependent kinase inhibitor, depending on the decreases in both the increment of GPR40 protein expression and the induction of mechanical allodynia and thermal hyperalgesia at day 7 after CFA injection. Furthermore, the level of DHA in the hypothalamus tissue was significantly increased in a flavopiridol reversible manner at day 1, but not at day 7, after CFA injection. The intracerebroventricular injection of DHA (50 µg) and GW9508 (1.0 µg), a GPR40-selective agonist, significantly reduced mechanical allodynia and thermal hyperalgesia at day 7, but not at day 1, after CFA injection. These effects were inhibited by intracerebroventricular pretreatment with GW1100 (10 µg), a GPR40 antagonist. The protein expression of GPR40 was colocalized with that of β-endorphin and proopiomelanocortin, and a single intracerebroventricular injection of GW9508 (1.0 µg) significantly increased the number of neurons double-stained for c-Fos and proopiomelanocortin in the arcuate nucleus of the hypothalamus. Our findings suggest that hypothalamic GPR40 activated by free long chain fatty

Hypothalamic GPR40 Signaling Activated by Free Long Chain Fatty Acids Suppresses CFA-Induced Inflammatory Chronic Pain

PubMed Central

Nakamoto, Kazuo; Nishinaka, Takashi; Sato, Naoya; Mankura, Mitsumasa; Koyama, Yutaka; Kasuya, Fumiyo; Tokuyama, Shogo

2013-01-01

GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently increased at day 7, but not at days 1, 3 and 14, after CFA injection. GPR40 was co-localized with NeuN, a neuron marker, but not with glial fibrillary acidic protein (GFAP), an astrocyte marker. At day 1 after CFA injection, GFAP protein expression was markedly increased in the hypothalamus. These increases were significantly inhibited by the intracerebroventricular injection of flavopiridol (15 nmol), a cyclin-dependent kinase inhibitor, depending on the decreases in both the increment of GPR40 protein expression and the induction of mechanical allodynia and thermal hyperalgesia at day 7 after CFA injection. Furthermore, the level of DHA in the hypothalamus tissue was significantly increased in a flavopiridol reversible manner at day 1, but not at day 7, after CFA injection. The intracerebroventricular injection of DHA (50 µg) and GW9508 (1.0 µg), a GPR40-selective agonist, significantly reduced mechanical allodynia and thermal hyperalgesia at day 7, but not at day 1, after CFA injection. These effects were inhibited by intracerebroventricular pretreatment with GW1100 (10 µg), a GPR40 antagonist. The protein expression of GPR40 was colocalized with that of β-endorphin and proopiomelanocortin, and a single intracerebroventricular injection of GW9508 (1.0 µg) significantly increased the number of neurons double-stained for c-Fos and proopiomelanocortin in the arcuate nucleus of the hypothalamus. Our findings suggest that hypothalamic GPR40 activated by free long chain fatty

Ameliorative potential of rutin in combination with nimesulide in STZ model of diabetic neuropathy: targeting Nrf2/HO-1/NF-kB and COX signalling pathway.

PubMed

Mittal, Ruchika; Kumar, Anil; Singh, Dhirendra Pratap; Bishnoi, Mahendra; Nag, Tapas Chandra

2018-06-01

Emerging role of Nrf-2/HO-1 in pathogenesis of diabetic neuropathy has been suggested. Diabetic neuropathy is one of the most common complications of diabetes and more than 50% patients of diabetes develop diabetic neuropathy. Rutin has been well documented to show protective effect in various complications, e.g., diabetic neuropathy. However, its mechanistic insight is still not completely understood. The present study has been designed to explore the protective effect of rutin and its interaction with COX-2 inhibitor, nimesulide in diabetic neuropathy. DN (diabetic neuropathy) rats were maintained with or without rutin (100 and 200 mg/kg), nimesulide (5 and 10 mg/kg), and their combinations for 8 weeks. Body weight, serum glucose, pain assessment (mechanical allodynia, cold allodynia, mechanical hyperalgesia, and thermal hyperalgesia), and motor nerve conduction velocity (MNCV) were measured in all groups. Oxidative damage was assessed through biochemical estimation and mitochondrial ROS production, followed by inflammatory and apoptotic markers (TNF-α, caspase-3, Nrf-2, HO-1, and NF-kBp65) for their activity, protein, and gene expression. The structural changes were also reported through transmission electron microscope. Streptozotocin injection (55 mg/kg) induced diabetes reduced body weight, reduced the threshold for pain in various pain assessment parameters. Oxidative damage (increased MDA, decreased SOD, catalase, and GSH levels) increased mitochondrial ROS production followed by increased expression of inflammatory markers and decreased expression of Nrf-2/HO-1 in sciatic nerve. Treatment with rutin (100 and 200 mg/kg) and nimesulide (5 and 10 mg/kg) significantly attenuates these alterations as compared to DN control rats. Furthermore, combination of rutin (200 mg/kg) and nimesulide (10 mg/kg) significantly potentiated their protective effect which was significant as compared to their effect alone in streptozotocin-treated rats. The present study

Analgesic effect of piracetam on peripheral neuropathic pain induced by chronic constriction injury of sciatic nerve in rats.

PubMed

Mehta, Ashish K; Bhati, Yogendra; Tripathi, Chakra D; Sharma, Krishna K

2014-08-01

Despite immense advances in the treatment strategies, management of neuropathic pain remains unsatisfactory. Piracetam is a prototype of nootropic drugs, used to improve cognitive impairment. The present study was designed to investigate the effect of piracetam on peripheral neuropathic pain in rats. Neuropathic pain was induced by the chronic constriction injury of the sciatic nerve. Following this, piracetam was intraperitoneally administered for 2 weeks in doses of 50, 100 and 200 mg/kg, and pain was assessed by employing the behavioural tests for thermal hyperalgesia (hot plate and tail flick tests) and cold allodynia (acetone test). After the induction of neuropathic pain, significant development of thermal hyperalgesia and cold allodynia was observed. The administration of piracetam (50 mg/kg) did not have any significant effect on all the behavioural tests. Further, piracetam (100 mg/kg) also had no effect on the hot plate and tail flick tests; however it significantly decreased the paw withdrawal duration in the acetone test. Piracetam in a dose of 200 mg/kg significantly modulated neuropathic pain as observed from the increased hot plate and tail flick latencies, and decreased paw withdrawal duration (in acetone test). Therefore, the present study suggests the potential use of piracetam in the treatment of neuropathic pain, which merits further clinical investigation.

Cholera toxin B subunit labeling in lamina II of spinal cord dorsal horn following chronic inflammation in rats.

PubMed

Ma, Qing Ping; Tian, Li

2002-07-26

We have investigated the effect of inflammation on the labeling pattern of cholera toxin B subunit (CTB)-conjugated horseradish peroxidase, an A-fiber marker, by an intra-sciatic nerve injection of the tracer. Following chronic inflammation in one hind paw in rats, there was substantial CTB labeling in lamina II of the spinal dorsal horn, which is normally absent. However, there was no change in the labeling pattern of wheat germ agglutinin or fluoride resistant acid phosphatase/thiamine monophosphatase, two C-fiber markers. The CTB labeling in lamina II after peripheral nerve injury has been interpreted as central sprouting of A-fibers or uptake of the tracer by injured C-fibers. Our results suggest that chronic inflammation and nerve injury may share some common mechanisms in generating allodynia and hyperalgesia.

Decreased voltage-gated potassium currents in rat dorsal root ganglion neurons after chronic constriction injury.

PubMed

Xiao, Yun; Wu, Yang; Zhao, Bo; Xia, Zhongyuan

2016-01-20

Voltage-gated potassium channels (KV) regulate pain transmission by controlling neuronal excitability. Changes in KV expression patterns may thus contribute toward hyperalgesia following nerve injury. The aim of this study was to characterize KV current density in dorsal root ganglion (DRG) neurons following chronic constriction injury (CCI) of the right sciatic nerve, a robust model of post-traumatic neuropathic pain. The study examined changes in small-diameter potassium ion currents (<30 µm) in neurons in the L4-L6 DRG following CCI by whole-cell patch-clamping and the association with post-CCI mechanical and thermal nociceptive thresholds. Compared with the control group, 7 days after CCI, the mechanical force and temperature required to elicit ipsilateral foot withdrawal decreased significantly, indicating tactile allodynia and thermal hyperalgesia. Post-CCI neurons had a significantly lower rheobase current and depolarized resting membrane potential than controls, suggesting KV current downregulation. Some ipsilateral DRG neurons also had spontaneous action potentials and repetitive firing. There was a 55% reduction in the total KV current density caused by a 55% decrease in the sustained delayed rectifier potassium ion current (IK) density and a 17% decrease in the transient A-type potassium ion current (IA) density. These results indicated that changes in DRG neuron IK and IA current density and concomitant afferent hyperexcitability may contribute toward neuropathic pain following injury. The rat CCI model may prove valuable for examining pathogenic mechanisms and potential therapies, such as KV channel modulators.

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.

Interaction of hyperalgesia and sensory loss in complex regional pain syndrome type I (CRPS I).

PubMed

Huge, Volker; Lauchart, Meike; Förderreuther, Stefanie; Kaufhold, Wibke; Valet, Michael; Azad, Shahnaz Christina; Beyer, Antje; Magerl, Walter

2008-07-23

Sensory abnormalities are a key feature of Complex Regional Pain Syndrome (CRPS). In order to characterise these changes in patients suffering from acute or chronic CRPS I, we used Quantitative Sensory Testing (QST) in comparison to an age and gender matched control group. 61 patients presenting with CRPS I of the upper extremity and 56 healthy subjects were prospectively assessed using QST. The patients' warm and cold detection thresholds (WDT; CDT), the heat and cold pain thresholds (HPT; CPT) and the occurrence of paradoxical heat sensation (PHS) were observed. In acute CRPS I, patients showed warm and cold hyperalgesia, indicated by significant changes in HPT and CPT. WDT and CDT were significantly increased as well, indicating warm and cold hypoaesthesia. In chronic CRPS, thermal hyperalgesia declined, but CDT as well as WDT further deteriorated. Solely patients with acute CRPS displayed PHS. To a minor degree, all QST changes were also present on the contralateral limb. We propose three pathomechanisms of CRPS I, which follow a distinct time course: Thermal hyperalgesia, observed in acute CRPS, indicates an ongoing aseptic peripheral inflammation. Thermal hypoaesthesia, as detected in acute and chronic CRPS, signals a degeneration of A-delta and C-fibres, which further deteriorates in chronic CRPS. PHS in acute CRPS I indicates that both inflammation and degeneration are present, whilst in chronic CRPS I, the pathomechanism of degeneration dominates, signalled by the absence of PHS. The contralateral changes observed strongly suggest the involvement of the central nervous system.

Anti-Nociceptive Effect of Resveratrol During Inflammatory Hyperalgesia via Differential Regulation of pro-Inflammatory Mediators.

PubMed

Singh, Ajeet Kumar; Vinayak, Manjula

2016-07-01

Sensitization of nociceptive neurons by inflammatory mediators leads to hypersensitivity for normal painful stimuli which is termed hyperalgesia. Oxidative stress is an essential factor in pathological pain; therefore, antioxidants qualify as potential anti-hyperalgesic agents. The present study examines the efficacy of the natural antioxidant resveratrol in complete Freund's adjuvant (CFA) induced hyperalgesic rats. Thermal hyperalgesia was measured at different time points by paw withdrawal latency test and confirmed by c-Fos expression in spinal dorsal horn. The impact of resveratrol treatment on inflammatory mediators at peripheral (paw skin) and central (spinal cord) sites was determined during early (6 h) as well as late phase (48 h) of hyperalgesia. Intraplanter injection of CFA increased the level of cytokines IL-1β, TNF-α and IL-6 as well as inflammatory enzymes COX-2 and iNOS in paw skin in both phases. In case of spinal cord, the level of COX-2 was found to be elevated in both phases, whereas iNOS could not be detected. The cytokines were found to be elevated only in late phase in spinal cord. Administration of resveratrol (20 mg/kg) shifted the level of all inflammatory mediators towards normal, except cytokines in paw skin. The present study suggests that the anti-nociceptive effect of resveratrol is implicated at both peripheral and central sites in a tissue specific manner. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Striatal-enriched protein tyrosine phosphatase modulates nociception: evidence from genetic deletion and pharmacological inhibition

PubMed Central

Azkona, Garikoitz; Saavedra, Ana; Aira, Zigor; Aluja, David; Xifró, Xavier; Baguley, Tyler; Alberch, Jordi; Ellman, Jonathan A.; Lombroso, Paul J.; Azkue, Jon J.; Pérez-Navarro, Esther

2016-01-01

The information from nociceptors is processed in the dorsal horn of the spinal cord by complex circuits involving excitatory and inhibitory interneurons. It is well documented that GluN2B and ERK1/2 phosphorylation contributes to central sensitization. Striatal-enriched protein tyrosine phosphatase (STEP) dephosphorylates GluN2B and ERK1/2, promoting internalization of GluN2B and inactivation of ERK1/2. The activity of STEP was modulated by genetic (STEP knockout mice) and pharmacological (recently synthesized STEP inhibitor, TC-2153) approaches. STEP61 protein levels in the lumbar spinal cord were determined in male and female mice of different ages. Inflammatory pain was induced by complete Freund’s adjuvant injection. Behavioral tests, immunoblotting, and electrophysiology were used to analyze the effect of STEP on nociception. Our results show that both genetic deletion and pharmacological inhibition of STEP induced thermal hyperalgesia and mechanical allodynia, which were accompanied by increased pGluN2BTyr1472 and pERK1/2Thr202/Tyr204 levels in the lumbar spinal cord. Striatal-enriched protein tyrosine phosphatase heterozygous and knockout mice presented a similar phenotype. Furthermore, electrophysiological experiments showed that TC-2153 increased C fiber-evoked spinal field potentials. Interestingly, we found that STEP61 protein levels in the lumbar spinal cord inversely correlated with thermal hyperalgesia associated with age and female gender in mice. Consistently, STEP knockout mice failed to show age-related thermal hyperalgesia, although gender-related differences were preserved. Moreover, in a model of inflammatory pain, hyperalgesia was associated with increased phosphorylation-mediated STEP61 inactivation and increased pGluN2BTyr1472 and pERK1/2Thr202/Tyr204 levels in the lumbar spinal cord. Collectively, the present results underscore an important role of spinal STEP activity in the modulation of nociception. PMID:26270590

Role of spinal p38α and β MAPK in inflammatory hyperalgesia and spinal COX-2 expression

PubMed Central

Fitzsimmons, Bethany L.; Zattoni, Michela; Svensson, Camilla I.; Steinauer, Joanne; Hua, Xiao-Ying; Yaksh, Tony L.

2010-01-01

Pharmacological studies indicate that spinal p38 MAPK plays a role in the development of hyperalgesia. We investigated whether either the spinal isoform p38α or p38β is involved in peripheral inflammation-evoked pain state and increased expression of spinal COX-2. Using intrathecal antisense oligonucleotides, we show that hyperalgesia is prevented by downregulation of p38β but not p38α, while increases in spinal COX-2 protein expression at eight hours is mediated by both p38α and β isoforms. These data suggest that early activation of spinal p38β isoform may affect acute facilitatory processing, and both p38β and α isforms mediate temporally delayed upregulation of spinal COX-2. PMID:20134354

Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms

PubMed Central

Chang, Leon; Luo, Lin; Palmer, James A; Sutton, Steven; Wilson, Sandy J; Barbier, Ann J; Breitenbucher, James Guy; Chaplan, Sandra R; Webb, Michael

2006-01-01

The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect. Elevated brain concentrations of anandamide (350 pmol g−1 of tissue vs 60 pmol g−1 in vehicle-treated controls) were found in brains of rats given OL135 (20 mg kg−1) i.p. 15 min prior to 20 mg kg−1 i.p. anandamide. Predosing rats with OL135 (2–60 mg kg−1 i.p.) 30 min before administration of an irreversible FAAH inhibitor (URB597: 0.3 mg kg−1 intracardiac) was found to protect brain FAAH from irreversible inactivation. The level of enzyme protection was correlated with the OL135 concentrations in the same brains. OL135 (100 mg kg−1 i.p.) reduced by 50% of the maximum possible efficacy (MPE) mechanical allodynia induced by MTI in FAAH+/+mice (von Frey filament measurement) 30 min after dosing, but was without effect in FAAH−/− mice. OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED50 between 6 and 9 mg kg−1. The plasma concentration at the ED50 in both models was 0.7 μM (240 ng ml−1). In the rat SNL model, coadministration of the selective CB2 receptor antagonist SR144528 (5 mg kg−1 i.p.), with 20 mg kg−1 OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB1 antagonist SR141716A (5 mg kg−1 i.p.) was without effect. In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg−1 i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg−1) blocked reversal of mechanical allodynia assessed 30 min after dosing. In both the MTI model and SNL models in rats, naloxone (1 mg kg−1, i.p. 30 min after OL135) reversed the analgesia

Gabapentin alleviates affective pain after traumatic nerve injury.

PubMed

Griggs, Ryan B; Bardo, Michael T; Taylor, Bradley K

2015-06-17

Gabapentin reduces behavioral signs of stimulus-evoked allodynia and hyperalgesia in preclinical studies of traumatic nerve injury, but its effects on more clinically relevant measures of stimulus-independent pain are unclear. To address this gap, we determined whether gabapentin would relieve affective pain after spared nerve injury (SNI). Twelve days after sham or SNI surgery, we administered gabapentin over three consecutive conditioning days and then evaluated conditioned place preference. Gabapentin produced conditioned place preference and reversed mechanical hypersensitivity in SNI but not sham rats at a dose (100 mg/kg) that did not change open-field activity. These results show for the first time that gabapentin provides relief from affective pain without producing sedation, and add to the limited clinical literature suggesting that its use can be extended to treat pain arising from traumatic nerve injury.

The Underestimated Significance of Conditioning in Placebo Hypoalgesia and Nocebo Hyperalgesia

PubMed Central

Witthöft, Michael

2018-01-01

Placebo and nocebo effects are intriguing phenomena in pain perception with important implications for clinical research and practice because they can alleviate or increase pain. According to current theoretical accounts, these effects can be shaped by verbal suggestions, social observational learning, and classical conditioning and are necessarily mediated by explicit expectation. In this review, we focus on the contribution of conditioning in the induction of placebo hypoalgesia and nocebo hyperalgesia and present accumulating evidence that conditioning independent from explicit expectation can cause these effects. Especially studies using subliminal stimulus presentation and implicit conditioning (i.e., without contingency awareness) that bypass the development of explicit expectation suggest that conditioning without explicit expectation can lead to placebo and nocebo effects in pain perception. Because only few studies have investigated clinical samples, the picture seems less clear when it comes to patient populations with chronic pain. However, conditioning appears to be a promising means to optimize treatment. In order to get a better insight into the mechanisms of placebo and nocebo effects in pain and the possible benefits of conditioning compared to explicit expectation, future studies should carefully distinguish both methods of induction. PMID:29670678

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.

Numbness in clinical and experimental pain--a cross-sectional study exploring the mechanisms of reduced tactile function.

PubMed

Geber, Christian; Magerl, Walter; Fondel, Ricarda; Fechir, Marcel; Rolke, Roman; Vogt, Thomas; Treede, Rolf-Detlef; Birklein, Frank

2008-09-30

Pain patients often report distinct numbness of the painful skin although no structural peripheral or central nerve lesion is obvious. In this cross-sectional study we assessed the reduction of tactile function and studied underlying mechanisms in patients with chronic pain and in healthy participants exposed to phasic and tonic experimental nociceptive stimulation. Mechanical detection (MDT) and pain thresholds (MPT) were assessed in the painful area and the non-painful contralateral side in 10 patients with unilateral musculoskeletal pain. Additionally, 10 healthy participants were exposed to nociceptive stimulation applied to the volar forearms (capsaicin; electrical stimulation, twice each). Areas of tactile hypaesthesia and mechanical hyperalgesia were assessed. MDT and MPT were quantified adjacent to the stimulation site. Tactile hypaesthesia in pain patients and in experimental pain (MDT-z-scores: -0.66+/-0.30 and -0.42+/-0.15, respectively, both p<0.01) was paralleled by mechanical hyperalgesia (MPT-z-scores: +0.51+/-0.27, p<0.05; and +0.48+/-0.10, p<0.001). However, hypaesthesia and hyperalgesia were not correlated. Although 9 patients reported numbness, only 3 of them were able to delineate circumscript areas of tactile hypaesthesia. In experimental pain, the area of tactile hypaesthesia could be mapped in 31/40 experiments (78%). Irrespective of the mode of nociceptive stimulation (phasic vs. tonic) tactile hypaesthesia and hyperalgesia developed with a similar time course and disappeared within approximately 1 day. Hypaesthesia (numbness) often encountered in clinical pain can be reproduced by experimental nociceptive stimulation. The time course of effects suggests a mechanism involving central plasticity.

Coadministration of Resveratrol and Rice Oil Mitigates Nociception and Oxidative State in a Mouse Fibromyalgia-Like Model

PubMed Central

Peres Klein, Caroline; Rodrigues Cintra, Marcos; Binda, Nancy; Montijo Diniz, Danuza; Gomez, Marcus Vinicius; Souto, Andre Arigony; de Souza, Alessandra Hubner

2016-01-01

The mechanism underlying pain symptoms in fibromyalgia (FM) is not fully understood. Oxidative stress has emerged as pathophysiological event occurring during the development of the disease. The present study aimed at investigating the efficacy of resveratrol associated with rice bran oil on fibromyalgia-like mice model. Subcutaneous injection of reserpine (0.25 mg/Kg) during 3 days produced fibromyalgia-like symptoms. Resveratrol and/or rice oil or pregabalin were administered through oral route in therapeutic (single dose) and preventive (four doses) schemes. In both schemes, treatment with resveratrol associated with rice bran oil and pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia in animals. The preventive scheme displayed antidepressant effect which was demonstrated by the forced swimming test as well as reduced reactive species in the cerebrospinal fluid of reserpinized animals. Taken together, our data provide evidences that the intake of resveratrol associated with rice bran oil plays antinociceptive and antidepressant actions probably through reducing reactive species and suggests the involvement of oxidative stress in this model of FM as possible underlying mechanism of pathogenesis of the disease. PMID:27069683

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.

Preoperative But Not Postoperative Flurbiprofen Axetil Alleviates Remifentanil-induced Hyperalgesia After Laparoscopic Gynecological Surgery: A Prospective, Randomized, Double-blinded, Trial.

PubMed

Zhang, Linlin; Shu, Ruichen; Zhao, Qi; Li, Yize; Wang, Chunyan; Wang, Haiyun; Yu, Yonghao; Wang, Guolin

2017-05-01

Acute remifentanil exposure during intraoperative analgesia might enhance sensitivity to noxious stimuli and nociceptive responses to innocuous irritation. Cyclooxygenase inhibition was demonstrated to attenuate experimental remifentanil-induced hyperalgesia (RIH) in rodents and human volunteers. The study aimed to compare the effects of preoperative and postoperative flurbiprofen axetil (FA) on RIH after surgery. Ninety patients undergoing elective laparoscopic gynecologic surgery were randomly assigned to receive either intravenous placebo before anesthesia induction (Group C); or intravenous FA (1.0 mg/kg) before anesthesia induction (Group F1) or before skin closure (Group F2). Anesthesia consisted off sevoflurane and remifentanil (0.30 μg/kg/min). Postoperative pain was managed by sufentanil titration in the postanesthetic care unit, followed by sufentanil infusion via patient-controlled analgesia. Mechanical pain threshold (primary outcome), pain scores, sufentanil consumption, and side-effects were documented for 24 hours postoperatively. Postoperative pain score in Group F1 was lower than Group C. Time of first postoperative sufentanil titration was prolonged in Group F1 than Group C (P=0.021). Cumulative sufentanil consumption in Group F1 was lower than Group C (P<0.001), with a mean difference of 8.75 (95% confidence interval, 5.21-12.29) μg. Mechanical pain threshold on the dominant inner forearm was more elevated in Group F1 than Group C (P=0.005), with a mean difference of 17.7 (95% confidence interval, 5.4-30.0) g. Normalized hyperalgesia area was decreased in Group F1 compared to Group C (P=0.007). No statistically significant difference was observed between Group F2 and Group C. Preoperative FA reduces postoperative RIH in patients undergoing laparoscopic gynecologic surgery under sevoflurane-remifentanil anesthesia.

Orofacial complex regional pain syndrome: pathophysiologic mechanisms and functional MRI.

PubMed

Lee, Yeon-Hee; Lee, Kyung Mi; Kim, Hyug-Gi; Kang, Soo-Kyung; Auh, Q-Schick; Hong, Jyung-Pyo; Chun, Yang-Hyun

2017-08-01

Complex regional pain syndrome (CRPS) is one of the most challenging chronic pain conditions and is characterized by burning pain, allodynia, hyperalgesia, autonomic changes, trophic changes, edema, and functional loss involving mainly the extremities. Until recently, very few reports have been published concerning CRPS involving the orofacial area. We report on a 50-year-old female patient who presented with unbearable pain in all of her teeth and hypersensitivity of the facial skin. She also reported intractable pain in both extremities accompanied by temperature changes and orofacial pain that increased when the other pains were aggravated. In the case of CRPS with trigeminal neuropathic pain, protocols for proper diagnosis and prompt treatment have yet to be established in academia or in the clinical field. We performed functional magnetic resonance imaging for a thorough analysis of the cortical representation of the affected orofacial area immediately before and immediately after isolated light stimulus of the affected hand and foot and concluded that CRPS can be correlated with trigeminal neuropathy in the orofacial area. Furthermore, the patient was treated with carbamazepine administration and stellate ganglion block, which can result in a rapid improvement of pain in the trigeminal region. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Enduring prevention and transient reduction of postoperative pain by intrathecal resolvin D1

PubMed Central

Huang, Liang; Wang, Chi-Fei; Serhan, Charles N.; Strichartz, Gary

2013-01-01

Postoperative pain slows surgical recovery, impacting the return of normal function for weeks, months, or longer. Here we report the antihyperalgesic actions of a new compound, resolvin D1 (RvD1), known to reduce inflammation and to suppress pain after peripheral nerve injury, on the acute pain occurring after paw incision and the prolonged pain after skin-muscle retraction. Injection of RvD1 (20–40 ng) into the L5–L6 intrathecal space 30 minutes before surgery reduces the postincisional primary mechanical hypersensitivity, lowering the peak change by approximately 70% (with 40 ng) and reducing the area under the curve (AUC) for the entire 10-day postincisional course by approximately 60%. Intrathecal injection of RvD1 on postoperative day (POD) 1 reduces the hyperalgesia to the same level as that from preoperative injection within a few hours, an effect that persists for the remaining PODs. Tactile allodynia and hyperalgesia following the skin/muscle incision retraction procedure, measured at the maximum values 12 to 14 days, is totally prevented by intrathecal RvD1 (40 ng) given at POD 2. However, delaying the injection until POD 9 or POD 17 results in RvD1 causing only transient and incomplete reversal of hyperalgesia, lasting for <1 day. These findings demonstrate the potent, effective reduction of postoperative pain by intrathecal RvD1 given before or shortly after surgery. The much more limited effect of this compound on retraction-induced pain, when given 1 to 2 weeks later, suggests that the receptors or pathways for resolvins are more important in the early than the later stages of postoperative pain. PMID:21255928

Burning Eye Syndrome: Do Neuropathic Pain Mechanisms Underlie Chronic Dry Eye?

PubMed

Kalangara, Jerry P; Galor, Anat; Levitt, Roy C; Felix, Elizabeth R; Alegret, Ramon; Sarantopoulos, Constantine D

2016-04-01

Dry eye is a multi-factorial disorder that manifests with painful ocular symptoms and visual disturbances, which can only be partly attributed to tear dysfunction. This disorder may also involve neuroplasticity in response to neuronal injury. This review will emphasize the key characteristics of dry eye pain and its pathologic mechanisms, making the argument that a subset of dry eye represents a neuropathic pain disorder of the eye, more appropriately called "burning eye syndrome." A literature review was conducted using a PubMed search focusing on dry eye, corneal nociception, and neuropathic pain. Articles were reviewed and those discussing clinical course, pathophysiology, and neuronal regulation of chronic ocular pain as related to dry eye were summarized. We found that there is a discordance between ocular pain and dryness on the ocular surface. Although tear dysfunction may be one of the initial insults, its persistence may be associated with repeated ocular sensory nerve injury leading to an acute-to-chronic pain transition associated with neuropathologic changes (peripheral and central sensitization), neuronal dysfunction, and spontaneous ocular pain. Dry eye is becoming a major health concern due to its increasing incidence, significant morbidity, and economic burden. Recent evidence suggests that a subset of dry eye may be better represented as a chronic neuropathic pain disorder due to its features of dysesthesia, spontaneous pain, allodynia, and hyperalgesia. Future therapies targeted at the underlying neuroplasticity may yield improved efficacy for patients with this subset of dry eye, which we term "burning eye syndrome." © 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

PubMed Central

Shavit, Yehuda; Grace, Peter M.; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

2011-01-01

Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical. PMID:21752874

Anti-Inflammatory and Analgesic Effects of the Marine-Derived Compound Excavatolide B Isolated from the Culture-Type Formosan Gorgonian Briareum excavatum

PubMed Central

Lin, Yen-You; Lin, Sung-Chun; Feng, Chien-Wei; Chen, Pei-Chin; Su, Yin-Di; Li, Chi-Min; Yang, San-Nan; Jean, Yen-Hsuan; Sung, Ping-Jyun; Duh, Chang-Yih; Wen, Zhi-Hong

2015-01-01

In recent years, several marine-derived compounds have been clinically evaluated. Diterpenes are secondary metabolites from soft coral that exhibit anti-inflammatory, anti-tumor and cytotoxic activities. In the present study, we isolated a natural diterpene product, excavatolide B, from cultured Formosan gorgonian Briareum excavatum and investigated its anti-inflammatory activities. We found that excavatolide B significantly inhibited the mRNA expression of the proinflammatory mediators, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in lipopolysaccharide (LPS)-challenged murine macrophages (RAW 264.7). We also examined the anti-inflammatory and anti-nociceptive effects of excavatolide B on intraplantar carrageenan-induced inflammatory responses. Excavatolide B was found to significantly attenuate carrageenan-induced nociceptive behaviors, mechanical allodynia, thermal hyperalgesia, weight bearing deficits and paw edema. In addition, excavatolide B inhibited iNOS, as well as the infiltration of immune cells in carrageenan-induced inflammatory paw tissue. PMID:25923315

Kv7.2 regulates the function of peripheral sensory neurons.

PubMed

King, Chih H; Lancaster, Eric; Salomon, Daniela; Peles, Elior; Scherer, Steven S

2014-10-01

The Kv7 (KCNQ) family of voltage-gated K(+) channels regulates cellular excitability. The functional role of Kv7.2 has been hampered by the lack of a viable Kcnq2-null animal model. In this study, we generated homozygous Kcnq2-null sensory neurons using the Cre-Lox system; in these mice, Kv7.2 expression is absent in the peripheral sensory neurons, whereas the expression of other molecular components of nodes (including Kv7.3), paranodes, and juxtaparanodes is not altered. The conditional Kcnq2-null animals exhibit normal motor performance but have increased thermal hyperalgesia and mechanical allodynia. Whole-cell patch recording technique demonstrates that Kcnq2-null sensory neurons have increased excitability and reduced spike frequency adaptation. Taken together, our results suggest that the loss of Kv7.2 activity increases the excitability of primary sensory neurons. © 2014 Wiley Periodicals, Inc.

Organization of hyperactive microglial cells in trigeminal spinal subnucleus caudalis and upper cervical spinal cord associated with orofacial neuropathic pain.

PubMed

Shibuta, Kazuo; Suzuki, Ikuko; Shinoda, Masamichi; Tsuboi, Yoshiyuki; Honda, Kuniya; Shimizu, Noriyoshi; Sessle, Barry J; Iwata, Koichi

2012-04-27

The aim of this study was to evaluate spatial organization of hyperactive microglial cells in trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1), and to clarify the involvement in mechanisms underlying orofacial secondary hyperalgesia following infraorbital nerve injury. We found that the head-withdrawal threshold to non-noxious mechanical stimulation of the maxillary whisker pad skin was significantly reduced in chronic constriction injury of the infraorbital nerve (ION-CCI) rats from day 1 to day 14 after ION-CCI. On day 3 after ION-CCI, mechanical allodynia was obvious in the orofacial skin areas innervated by the 1st and 3rd branches of the trigeminal nerve as well as the 2nd branch area. Hyperactive microglial cells in Vc and C1 were observed on days 3 and 7 after ION-CCI. On day 3 after ION-CCI, a large number of phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive (IR) cells were observed in Vc and C1. Many hyperactive microglial cells were also distributed over a wide area of Vc and C1 innervated by the trigeminal nerve. The intraperitoneal administration of minocycline significantly reduced the activation of microglial cells and the number of pERK-IR cells in Vc and C1, and also significantly attenuated the development of mechanical allodynia. Furthermore, enhanced background activity and mechanical evoked responses of Vc wide dynamic range neurons in ION-CCI rats were significantly reversed following minocycline administration. These findings suggest that activation of microglial cells over a wide area of Vc and C1 is involved in the enhancement of Vc and C1 neuronal excitability in the early period after ION-CCI, resulting in the neuropathic pain in orofacial areas innervated by the injured as well as uninjured nerves. Copyright © 2012 Elsevier B.V. All rights reserved.

Effect of curcumin in mice model of vincristine-induced neuropathy.

PubMed

Babu, Anand; Prasanth, K G; Balaji, Bhaskar

2015-06-01

Curcumin exhibits a wide spectrum of biological activities which include neuroprotective, antinociceptive, anti-inflammatory, and antioxidant activity. The present study evaluates the effect of curcumin in vincristine-induced neuropathy in a mice model. Vincristine sulfate (0.1 mg/kg, i.p. for 10 consecutive days) was administered to mice to induce neuropathy. Pain behavior was assessed at different days, i.e., 0, 7, 10, and 14 d. Sciatic nerve total calcium, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), nitric oxide (NO), and lipid peroxidation (LPO) were also estimated after the 14th day of study. Pregabalin (10 mg/kg, p.o.) and curcumin (15, 30, and 60 mg/kg, p.o.) were administered for 14 consecutive days. Curcumin at 60 mg/kg significantly attenuated the vincristine-induced neuropathic pain manifestations in terms of thermal hyperalgesia (p < 0.001) and allodynia (p < 0.001); mechanical hyperalgesia (p < 0.001); functional loss (p < 0.001); and in the delayed phase of formalin test (p < 0.001). Curcumin at 30 and 60 mg/kg exhibited significant changes (p < 0.001) in antioxidant levels and in total calcium levels in vincristine-injected mice. Curcumin at 30 and 60 mg/kg dose levels significantly attenuated vincristine-induced neuropathy which may be due to its multiple actions including antinociceptive, calcium inhibitory, and antioxidant effect.

Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy.

PubMed

Chattopadhyay, Munmun; Zhou, Zhigang; Hao, Shuanglin; Mata, Marina; Fink, David J

2012-03-22

Painful neuropathy is a common complication of diabetes. Previous studies have identified significant increases in the amount of voltage gated sodium channel isoforms Na(V)1.7 and Na(V)1.3 protein in the dorsal root ganglia (DRG) of rats with streptozotocin (STZ)-induced diabetes. We found that gene transfer-mediated release of the inhibitory neurotransmitters enkephalin or gamma amino butyric acid (GABA) from DRG neurons in diabetic animals reduced pain-related behaviors coincident with a reduction in Na(V)1.7 protein levels in DRG in vivo. To further evaluate the role of Na(V)α subunit levels in DRG in the pathogenesis of pain in diabetic neuropathy, we constructed a non-replicating herpes simplex virus (HSV)-based vector expressing a microRNA (miRNA) against Na(V)α subunits. Subcutaneous inoculation of the miRNA-expressing HSV vector into the feet of diabetic rats to transduce DRG resulted in a reduction in Na(V)α subunit levels in DRG neurons, coincident with a reduction in cold allodynia, thermal hyperalgesia and mechanical hyperalgesia. These data support the role of increased Na(V)α protein in DRG in the pathogenesis of pain in diabetic neuropathy, and provide a proof-of-principle demonstration for the development of a novel therapy that could be used to treat intractable pain in patients with diabetic neuropathy.

Pressure pain sensitivity topographical maps reveal bilateral hyperalgesia of the hands in patients with unilateral carpal tunnel syndrome.

PubMed

Fernández-de-Las-Peñas, César; Madeleine, Pascal; Martínez-Perez, Almudena; Arendt-Nielsen, Lars; Jiménez-García, Rodrigo; Pareja, Juan A

2010-08-01

To assess topographical pressure pain sensitivity maps of the hand in patients with unilateral carpal tunnel syndrome (CTS) as compared with healthy subjects. A total of 20 women with CTS (ages 32-52 years) and 20 healthy matched women (ages 32-51 years) were recruited. Pressure pain thresholds (PPTs) were measured bilaterally over 30 locations of the palm of each hand by an assessor blinded to the subjects' conditions. Patients showed lower PPTs in both hands in all of the measurement points as compared with controls (P < 0.001 for all). PPTs were lower in those points over the proximal phalanx of the fingers and the thenar eminency as compared with those points located over the distal phalanx of the fingers (P < 0.001). CTS patients showed lower PPT levels in dermatomes C6, C7, and C8 when compared with healthy controls (P < 0.001 for all), but without differences between dermatomes (P = 0.4). PPT was negatively correlated with both hand pain intensity and duration of symptoms (P < 0.001 for all). Our findings revealed bilateral generalized pressure pain hyperalgesia in unilateral CTS because lower PPT levels were found in all of the points. The pressure pain hyperalgesia was not uniformly distributed since PPTs were lower in points over the proximal phalanx of the fingers and the thenar eminency as compared with those points located over the distal phalanx of the fingers. The decrease in PPT levels was associated with the intensity and the duration of the pain symptoms, supporting a role of both peripheral and central sensitization mechanisms in this pain condition.

The α5 subunit-containing GABAA receptors contribute to chronic pain

PubMed Central

Bravo-Hernández, Mariana; Corleto, José A.; Barragán-Iglesias, Paulino; González-Ramírez, Ricardo; Pineda-Farias, Jorge B.; Felix, Ricardo; Calcutt, Nigel A.; Delgado-Lezama, Rodolfo; Marsala, Martin; Granados-Soto, Vinicio

2016-01-01

It has been recently proposed that α5-subunit containing GABAA receptors (α5-GABAA receptors) that mediate tonic inhibition might be involved in pain. The purpose of this study was to investigate the contribution of α5-GABAA receptors in the loss of GABAergic inhibition and in formalin-, Complete Freund’s adjuvant (CFA)- and L5/L6 spinal nerve ligation-induced long-lasting hypersensitivity. Formalin or CFA injection and L5/L6 spinal nerve ligation produced long-lasting allodynia and hyperalgesia. Moreover, formalin injection impaired the rate-dependent depression (RDD) of the Hofmann reflex. Peripheral and intrathecal pre-treatment or post-treatment with the α5-GABAA receptor antagonist, L-655,708 (0.15–15 nmol) prevented and reversed, respectively, these long-lasting behaviors. Formalin injection increased α5-GABAA receptors mRNA expression in the spinal cord and dorsal root ganglia (DRG) mainly at 3 days. α5-GABAA receptors were localized in the dorsal spinal cord and DRG co-labeling with NeuN, CGRP and IB4 suggesting their presence in peptidergic and non-peptidergic neurons. These receptors were found mainly in small- and medium-size neurons. Formalin injection enhanced α5-GABAA receptors fluorescence intensity in spinal cord and DRG at 3 and 6 days. Intrathecal administration of L-655,708 (15 nmol) prevented and reversed formalin-induced impairment of RDD. These results suggest that α5-GABAA receptors play a role in the loss of GABAergic inhibition and contribute to long-lasting secondary allodynia and hyperalgesia. PMID:26545088

Downregulation of the spinal NMDA receptor NR2B subunit during electro-acupuncture relief of chronic visceral hyperalgesia.

PubMed

Liu, Hongping; Zhang, Yuhua; Qi, Debo; Li, Weimin

2017-01-01

The involvement of spinal NR2B, a N-methyl-D-aspartate (NMDA) receptor subunit, in the therapeutic effect of electro-acupuncture (EA) on chronic visceral hyperalgesia was investigated. Chronic visceral hyperalgesia was induced using an irritable bowel syndrome (IBS) model in rats. Graded colorectal distention (CRD) stimuli at strengths of 20, 40, 60 and 80 mmHg were applied, and behavioral tests were performed to measure the abdominal withdrawal reflex (AWR) in response to the CRD stimuli and assess the severity of the visceral hyperalgesia. Rats were randomly divided into four groups: normal intact (control) group, IBS model (model) group, EA-treated IBS rats (EA) group and sham EA-treated IBS rats (sham EA) group. For the EA treatment, electric stimuli were applied through needles inserted into two acupoints [Zu-san-li (ST-36) and Shang-ju-xu (ST-37)] in both hind limbs, while the sham EA treatment consisted of only the insertion of needles into these same acupoints without an application of electric stimuli. Our results showed that AWR scores of the model group responding to CRD stimuli of 20, 40, 60 and 80 mmHg were significantly increased. These increased scores subsequently decreased following EA treatment (P < 0.05) compared with those for the other groups. The expression of NR2B in the superficial laminae (SDH, laminae I and II), nucleus proprius (NP, laminae III and IV), neck of the dorsal horn (NECK, laminae V and VI) and central canal region (lamina X) at thoracolumbar (T13-L2) and lumbosacral (L6-S2) segmental level significantly increased in the model group versus the control group (P < 0.05) and significantly decreased after EA treatment (P < 0.05). There were no significant changes in neither AWR scores nor expression of the NR2B subunit in these spinal regions after the sham EA treatment. These results confirm that EA can relieve chronic visceral hyperalgesia in IBS model rats and suggest that such an effect is possibly mediated through the

Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen).

PubMed

Vellani, Vittorio; Giacomoni, Chiara

2017-01-01

Gabapentin is a well-established anticonvulsant drug which is also effective for the treatment of neuropathic pain. Although the exact mechanism leading to relief of allodynia and hyperalgesia caused by neuropathy is not known, the blocking effect of gabapentin on voltage-dependent calcium channels has been proposed to be involved. In order to further evaluate its analgesic mechanisms, we tested the efficacy of gabapentin on protein kinase C epsilon (PKC ε ) translocation in cultured peripheral neurons isolated from rat dorsal root ganglia (DRGs). We found that gabapentin significantly reduced PKC ε translocation induced by the pronociceptive peptides bradykinin and prokineticin 2, involved in both inflammatory and chronic pain. We recently showed that paracetamol (acetaminophen), a very commonly used analgesic drug, also produces inhibition of PKC ε . We tested the effect of the combined use of paracetamol and gabapentin, and we found that the inhibition of translocation adds up. Our study provides a novel mechanism of action for gabapentin in sensory neurons and suggests a mechanism of action for the combined use of paracetamol and gabapentin, which has recently been shown to be effective, with a cumulative behavior, in the control of postoperative pain in human patients.

Methylprednisolone prevents nerve injury-induced hyperalgesia in neprilysin knockout mice.

PubMed

He, Lan; Uçeyler, Nurcan; Krämer, Heidrun H; Colaço, Maria Nandini; Lu, Bao; Birklein, Frank; Sommer, Claudia

2014-03-01

The pathophysiology of the complex regional pain syndrome involves enhanced neurogenic inflammation mediated by neuropeptides. Neutral endopeptidase (neprilysin, NEP) is a key enzyme in neuropeptide catabolism. Our previous work revealed that NEP knock out (ko) mice develop more severe hypersensitivity to thermal and mechanical stimuli after chronic constriction injury (CCI) of the sciatic nerve than wild-type (wt) mice. Because treatment with glucocorticoids is effective in early complex regional pain syndrome, we investigated whether methylprednisolone (MP) reduces pain and sciatic nerve neuropeptide content in NEP ko and wt mice with nerve injury. After CCI, NEP ko mice developed more severe thermal and mechanical hypersensitivity and hind paw edema than wt mice, confirming previous findings. Hypersensitivity was prevented by MP treatment in NEP ko but not in wt mice. MP treatment had no effect on protein levels of calcitonin-gene related peptide, substance P, and bradykinin in sciatic nerves of NEP ko mice. Endothelin-1 (ET-1) levels were higher in naïve and nerve-injured NEP ko than in wt mice, without an effect of MP treatment. Gene expression of the ET-1 receptors ETAR and ETBR was not different between genotypes and was not altered after CCI, but was increased after additional MP treatment. The ETBR agonist IRL-1620 was analgesic in NEP ko mice after CCI, and the ETBR antagonist BQ-788 showed a trend to reduce the analgesic effect of MP. The results provide evidence that MP reduces CCI-induced hyperalgesia in NEP ko mice, and that this may be related to ET-1 via analgesic actions of ETBR. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain.

PubMed

Lim, Eun Yeong; Kim, Yun Tai

2016-01-01

Neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory nervous system, is characterized by dysesthesia, hyperalgesia, and allodynia. The number of patients with this type of pain has increased rapidly in recent years. Yet, available neuropathic pain medicines have undesired side effects, such as tolerance and physical dependence, and do not fully alleviate the pain. The mechanisms of neuropathic pain are still not fully understood. Injury causes inflammation and immune responses and changed expression and activity of receptors and ion channels in peripheral nerve terminals. Additionally, neuroinflammation is a known factor in the development and maintenance of neuropathic pain. During neuropathic pain development, the C-C motif chemokine receptor 2 (CCR2) acts as an important signaling mediator. Traditional plant treatments have been used throughout the world for treating diseases. We and others have identified food-derived compounds that alleviate neuropathic pain. Here, we review the natural compounds for neuropathic pain relief, their mechanisms of action, and the potential benefits of natural compounds with antagonistic effects on GPCRs, especially those containing CCR2, for neuropathic pain treatment.

Antinociceptive effects of oxymatrine from Sophora flavescens, through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling in a mice model of neuropathic pain.

PubMed

Wang, Haiyan; Li, Yuxiang; Dun, Linglu; Xu, Yaqiong; Jin, Shaojv; Du, Juan; Ma, Lin; Li, Juan; Zhou, Ru; He, Xiaoliang; Sun, Tao; Yu, Jianqiang

2013-08-15

In this study we investigated antinociceptive effects of oxymatrine through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling in a chronic neuropathic pain model induced by chronic constrictive injury (CCI) of the sciatic nerve. The von Frey and plantar tests were performed to assess the degree of mechanical and thermal changes respectively. Immunohistochemistry assay was used to evaluate the expressions of NR2B. Western blotting assay were used to evaluate the expressions of NR2B, tERK, p-ERK, tCREB and p-CREB. The intraperitoneal administration of OMT (160, 80 mg/kg) could prevent the development of mechanical allodynia, thermal hyperalgesia induced by CCI. Intraperitoneal administration of OMT decreased the mean IOD of NR2B in the dorsal horn and expression of NR2B, p-ERK and p-CREB protein. Regulation of NMDA NR2B receptor-ERK/CREB signaling maybe the targets for the antinociceptive effects of OMT on a chronic neuropathic pain model induced by chronic constrictive injury of the sciatic nerve. Copyright © 2013 Elsevier GmbH. All rights reserved.

Bromodomain-containing Protein 4 Activates Voltage-gated Sodium Channel 1.7 Transcription in Dorsal Root Ganglia Neurons to Mediate Thermal Hyperalgesia in Rats.

PubMed

Hsieh, Ming-Chun; Ho, Yu-Cheng; Lai, Cheng-Yuan; Wang, Hsueh-Hsiao; Lee, An-Sheng; Cheng, Jen-Kun; Chau, Yat-Pang; Peng, Hsien-Yu

2017-11-01

Bromodomain-containing protein 4 binds acetylated promoter histones and promotes transcription; however, the role of bromodomain-containing protein 4 in inflammatory hyperalgesia remains unclear. Male Sprague-Dawley rats received hind paw injections of complete Freund's adjuvant to induce hyperalgesia. The dorsal root ganglia were examined to detect changes in bromodomain-containing protein 4 expression and the activation of genes involved in the expression of voltage-gated sodium channel 1.7, which is a key pain-related ion channel. The intraplantar complete Freund's adjuvant injections resulted in thermal hyperalgesia (4.0 ± 1.5 s; n = 7). The immunohistochemistry and immunoblotting results demonstrated an increase in the bromodomain-containing protein 4-expressing dorsal root ganglia neurons (3.78 ± 0.38 fold; n = 7) and bromodomain-containing protein 4 protein levels (2.62 ± 0.39 fold; n = 6). After the complete Freund's adjuvant injection, histone H3 protein acetylation was enhanced in the voltage-gated sodium channel 1.7 promoter, and cyclin-dependent kinase 9 and phosphorylation of RNA polymerase II were recruited to this area. Furthermore, the voltage-gated sodium channel 1.7-mediated currents were enhanced in neurons of the complete Freund's adjuvant rats (55 ± 11 vs. 19 ± 9 pA/pF; n = 4 to 6 neurons). Using bromodomain-containing protein 4-targeted antisense small interfering RNA to the complete Freund's adjuvant-treated rats, the authors demonstrated a reduction in the expression of bromodomain-containing protein 4 (0.68 ± 0.16 fold; n = 7), a reduction in thermal hyperalgesia (7.5 ± 1.5 s; n = 7), and a reduction in the increased voltage-gated sodium channel 1.7 currents (21 ± 4 pA/pF; n = 4 to 6 neurons). Complete Freund's adjuvant triggers enhanced bromodomain-containing protein 4 expression, ultimately leading to the enhanced excitability of nociceptive neurons and thermal hyperalgesia. This effect is

Altered spinal arachidonic acid turnover after peripheral nerve injury regulates regional glutamate concentration and neuropathic pain behaviors in rats.

PubMed

Sung, Backil; Wang, Shuxing; Zhou, Bei; Lim, Grewo; Yang, Liling; Zeng, Qing; Lim, Jeong-Ae; Wang, Jing Dong; Kang, Jing X; Mao, Jianren

2007-09-01

Spinal glutamate transporters (GT) have been implicated in the mechanisms of neuropathic pain; however, how spinal GT uptake activity is regulated remains unclear. Here we show that alteration of spinal arachidonic acid (AA) turnover after peripheral nerve injury regulated regional GT uptake activity and glutamate homeostasis. Chronic constriction nerve injury (CCI) in rats significantly reduced spinal GT uptake activity ((3)H-glutamate uptake) with an associated increase in extracellular AA and glutamate concentration from spinal microdialysates on postoperative day 8. AACOCF3 (a cytosolic phospholipase A2 inhibitor, 30mug) given intrathecally twice a day for postoperative day 1-7 reversed this CCI-induced spinal AA production, prevented the reduced spinal GT uptake activity and increased extracellular glutamate concentration. Conversely, alteration of spinal AA metabolism by diclofenac (a cyclooxygenase 1/2 inhibitor, 200mug) further reduced spinal GT uptake activity and increased extracellular glutamate concentration in CCI rats. GT uptake activity was also attenuated when AA (10 or 100nM) was directly added into spinal samples of naïve rats in an in vitro(3)H-glutamate uptake assay, indicating a direct inhibitory effect of AA on GT uptake activity. Consistent with these findings, AACOCF3 reduced the development of both thermal hyperalgesia and mechanical allodynia, whereas diclofenac exacerbated thermal hyperalgesia, in CCI rats. Thus, spinal AA turnover may serve as a regulator in CCI-induced changes in regional GT uptake activity, glutamate homeostasis, and neuropathic pain behaviors. These data suggest that regulating spinal AA turnover may be a useful approach to improving the clinical management of neuropathic pain.

A novel human surrogate model of noninjurious sharp mechanical pain.

PubMed

Shabes, Polina; Schloss, Natalie; Magerl, Walter; Schmahl, Christian; Treede, Rolf-Detlef; Baumgärtner, Ulf

2016-01-01

We propose a blade as a noninjurious nociceptive stimulus modeling sharp mechanical pain and yielding acute pain and hyperalgesia responses with closer proximity to incision-induced pain/hyperalgesia than punctate or blunt pressure mechanical pain models. Twenty-six healthy men and women were investigated to compare a small incision in the left forearm with noninvasive stimuli of different shapes and modalities to the right forearm. The magnitude and time course of incisional and blade-induced pain were assessed by numerical rating scales. Affective vs sensory components of pain experience were differentiated using a pain sensation questionnaire. The magnitude and time course of the axon reflex vasodilator response and of secondary hyperalgesia following a 7-second blade application were assessed. The maximum blade or incisional pain was similar (visual analogue scale [mean ± SD]: 32.9 ± 22.5 [blade] vs. 33.6 ± 29.8 [incision]), and both time courses matched closely in the first 10 seconds (paired t test; P = 0.5-1.0), whereas incision but not blade was followed by a second phase of pain, probably related to the tissue injury (decrease to half maximum pain 8 ± 2 vs. 33 ± 35 seconds; P < 0.01). Affective pain scores were significantly lower than sensory scores for all stimuli (P < 0.001). Comparing blade and incision, patterns of affective and sensory pain descriptors exhibited a remarkably similar pattern. Hence, we suggest the blade as novel model of sharp mechanical pain, which will be useful in investigating postoperative/mechanical pain and the role of self-injurious behavior in, eg, patients with borderline personality disorder.

Widespread Pressure Pain Hyperalgesia in Chronic Nonspecific Neck Pain with Neuropathic Features: A Descriptive Cross-Sectional Study.

PubMed

Lopez-de-Uralde-Villanueva, Ibai; Beltran-Alacreu, Hector; Fernandez-Carnero, Josue; Kindelan-Calvo, Paula; La Touche, Roy

2016-02-01

Neck pain has an elevated prevalence worldwide. Most people with neck pain are diagnosed as nonspecific neck pain patients. Poor recovery in neck disorders, as well as high levels of pain and disability, are associated with widespread sensory hypersensitivity. Nevertheless, there is controversy regarding the presence of widespread hyperalgesia in chronic nonspecific neck pain (CNSNP); this lack of agreement could be due to the presence of different pathophysiological mechanisms in CNSNP. To determinate differences in pressure pain thresholds (PPTs) over extracervical and cervical regions, and differences in cervical range of motion (ROM) between patients with CNSNP with and without neuropathic features (NF and No-NF, respectively). In addition, this study expected to observe correlations in these 2 types of CNSNP of psychosocial factors with PPTs and with cervical ROM separately. Descriptive, cross-sectional study. A hospital physiotherapy outpatient department. This research involved 53 patients with CNSNP that had obtained a Self-completed Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS) score = 12 (pain with NF, NF group); 54 that had obtained a S-LANSS score < 12 (pain with No-NF, No-NF group), and 53 healthy controls (control group, CG). Measures included: PPTs (suboccipital muscle, upper fibers trapezius muscle, lateral epicondyle, and anterior tibial muscle), cervical ROM (flexion, extension, rotation, and latero-flexion), pain intensity (Visual Analog Scale [VAS]), neck disability index (NDI), kinesiophobia (Tampa Scale of Kinesiophobia-11 [TSK-11]), and Pain Catastrophizing Scale (PCS). A statistically significant effect was observed for the group factor in all assessed measures (P < 0.01). Both CNSNP groups showed statistically significant differences compared to the CG for PPTs in the cervical region (suboccipital and upper fibers trapezius muscles), but only the NF group demonstrated statistically significant differences for PPTs

Contralateral Hyperalgesia from Injection of Endothelin-1 into the Ipsilateral Paw Requires Efferent Conduction into the Contralateral Paw.

PubMed

Strichartz, Gary R; Khodorova, Alla; Wang, Jeffrey Chi-Fei; Chen, Yu-Wen; Huang, Chuan-Chin

2015-10-01

Contralateral hyperalgesia, occurring after unilateral injury, is usually explained by central sensitization in spinal cord and brain. We previously reported that injection of endothelin-1 (ET-1) into one rat hindpaw induces prolonged mechanical and chemical sensitization of the contralateral hindpaw. Here, we examined the role of contralateral efferent activity in this process. ET-1 (2 nmol, 10 μL) was injected subcutaneously into the plantar surface of right (ipsilateral) hindpaw (ILP), and the thermal response latency and mechanical threshold for nocifensive withdrawal were determined by the use of, respectively, plantar radiant heating and von Frey filaments, for both ILP and contralateral hindpaws (CLP). Either paw was anesthetized for 60 minutes by direct injection of bupivacaine (0.25%, 40 μL), 30 minutes before ET-1. Alternatively, the contralateral sciatic nerve was blocked for 6 to 12 hours by percutaneous injection of bupivacaine-releasing microspheres 30 minutes before injection of ET-1. Systemic actions of these bupivacaine formulations were simulated by subcutaneous injection at the nuchal midline. After the injection of ET-1, the mechanical threshold of both ILP and CLP decreased by 2 hours, appeared to be lowest around 24 hours, and recovered through 48 hours to preinjection baseline at 72 hours. These hypersensitive responses were suppressed by bupivacaine injected into the ipsilateral paw before ET-1. Injection of the CLP by bupivacaine also suppressed the hypersensitivity of the CLP at all test times, and that of the ILP, except at 2 hours when it increased the sensitivity. This same pattern of change occurred when the contralateral sciatic nerve was blocked by bupivacaine-releasing microspheres. The systemic actions of these bupivacaine formulations were much smaller and only reached significance at 24 hours post-ET-1. Thermal hypersensitivity after ET-1 injection also occurred in both ILP and CLP and showed the same pattern in response to the

Mice overexpressing chemokine ligand 2 (CCL2) in astrocytes display enhanced nociceptive responses.

PubMed

Menetski, J; Mistry, S; Lu, M; Mudgett, J S; Ransohoff, R M; Demartino, J A; Macintyre, D E; Abbadie, C

2007-11-09

Recent findings demonstrate that chemokines, and more specifically CC chemokine ligand 2 (CCL2 or monocyte chemoattractant protein-1), play a major role in pain processing. In the present study, we assess nociceptive responses of mice that overexpressed CCL2 under control of glial fibrillary acidic protein promoter (CCL2 tg). In models of acute nociception CCL2 tg mice demonstrated significantly enhanced nociceptive behavior relative to wild-type controls in responses to both thermal (hot plate) and chemical (formalin test) stimulus modalities. There were no differences in mechanical allodynia in the partial sciatic nerve ligation model, in terms of either magnitude or duration of the allodynic response; however, both groups responded to the maximal extent measurable. In a model of inflammatory pain, elicited by intraplantar administration of complete Freund's adjuvant (CFA), CCL2 tg mice displayed both greater edema and thermal hyperalgesia compared with control mice. In control mice, edema and hyperalgesia returned to baseline values 5-7 days post CFA. However, in CCL2 tg mice, thermal hyperalgesia was significantly different from baseline up to 3 weeks post CFA. Parallel to these enhanced behavioral responses CCL2 serum levels were significantly greater in CCL2 overexpressing mice and remained elevated 7 days post CFA. Consequently, proinflammatory cytokine mRNA expression (IL-1beta, IL-6, and TNFalpha) levels were greater in skin, dorsal root ganglia (DRG), and spinal cord, whereas the anti-inflammatory cytokine (IL-10) level was lower in skin and DRG in CCL2 overexpressing mice than in control mice. Taken together with data from CCR2-deficient mice, these present data confirm a key role of CCL2/CCR2 axis in pain pathways and suggest that inhibiting this axis may result in novel pain therapies.

Repeated forced swim stress enhances CFA-evoked thermal hyperalgesia and affects the expressions of pCREB and c-Fos in the insular cortex.

PubMed

Imbe, H; Kimura, A; Donishi, T; Kaneoke, Y

2014-02-14

Stress affects brain activity and promotes long-term changes in multiple neural systems. Exposure to stressors causes substantial effects on the perception and response to pain. In several animal models, chronic stress produces lasting hyperalgesia. The insular (IC) and anterior cingulate cortices (ACC) are the regions exhibiting most reliable pain-related activity. And the IC and ACC play an important role in pain modulation via the descending pain modulatory system. In the present study we examined the expression of phospho-cAMP response element-binding protein (pCREB) and c-Fos in the IC and ACC after forced swim stress (FS) and complete Freund's adjuvant (CFA) injection to clarify changes in the cerebral cortices that affect the activity of the descending pain modulatory system in the rats with stress-induced hyperalgesia. FS (day 1, 10min; days 2-3, 20min) induced an increase in the expression of pCREB and c-Fos in the anterior IC (AIC). CFA injection into the hindpaw after the FS shows significantly enhanced thermal hyperalgesia and induced a decrease in the expression of c-Fos in the AIC and the posterior IC (PIC). Quantitative image analysis showed that the numbers of c-Fos-immunoreactive neurons in the left AIC and PIC were significantly lower in the FS+CFA group (L AIC, 95.9±6.8; L PIC, 181.9±23.1) than those in the naive group (L AIC, 151.1±19.3, p<0.05; L PIC, 274.2±37.3, p<0.05). These findings suggest a neuroplastic change in the IC after FS, which may be involved in the enhancement of CFA-induced thermal hyperalgesia through dysfunction of the descending pain modulatory system. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Mechanical allodynia induced by nucleoside reverse transcriptase inhibitor is suppressed by p55TNFSR mediated by herpes simplex virus vector through the SDF1α/CXCR4 system in rats.

PubMed

Huang, Wan; Zheng, Wenwen; Ouyang, Handong; Yi, Hyun; Liu, Shue; Zeng, Weian; Levitt, Roy C; Candiotti, Keith A; Lubarsky, David A; Hao, Shuanglin

2014-03-01

In the human immunodeficiency virus (HIV)-associated sensory neuropathy, neuropathic pain associated with the use of nucleoside reverse transcriptase inhibitors (NRTIs) in patients with HIV/acquired immunodeficiency syndrome is clinically common. While evidence demonstrates that neuropathic pain is influenced by neuroinflammatory events that include the proinflammatory molecules, tumor necrosis factor-α (TNF-α), stromal cell-derived factor 1-α (SDF1-α), and C-X-C chemokine receptor type 4 (CXCR4), the detailed mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In this study, we investigated the role of these proinflammatory molecules in the dorsal root ganglion (DRG) and the spinal dorsal horn in NRTIs-mediated neuropathic pain state. Neuropathic pain was induced by intraperitoneal administration of 2',3'-dideoxycytidine (ddC, one of the NRTIs). Mechanical threshold was tested using von Frey filament fibers. Nonreplicating herpes simplex virus (HSV) vectors expressing p55 TNF soluble receptor (p55TNFSR) were inoculated into hindpaw of rats. The expression of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG was examined using Western blots. Intrathecal CXCR4 antagonist was administered. The present study demonstrated that (1) systemic ddC induced upregulation of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG; (2) p55TNFSR mediated by a nonreplicating HSV vector reversed mechanical allodynia induced by systemic ddC; (3) intrathecal administration of the CXCR4 antagonist AMD3100 increased mechanical threshold; and (4) HSV vector expressing p55TNFSR reversed upregulation of TNF-α, SDF1-α, and CXCR4 induced by ddC in the lumbar spinal dorsal horn and the DRG. Our studies demonstrate that TNF-α through the SDF1/CXCR4 system is involved in the NRTIs-related neuropathic pain state and that blocking the signaling of these proinflammatory molecules is able to reduce NRTIs

Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms.

PubMed

Klafke, J Z; da Silva, M A; Rossato, M F; de Prá, S Dal Toé; Rigo, F K; Walker, C I B; Bochi, G V; Moresco, R N; Ferreira, J; Trevisan, G

2016-02-01

Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain.

Intra-Articular Blockade of P2X7 Receptor Reduces the Articular Hyperalgesia and Inflammation in the Knee Joint Synovitis Especially in Female Rats.

PubMed

Teixeira, Juliana Maia; Dias, Elayne Vieira; Parada, Carlos Amílcar; Tambeli, Cláudia Herrera

2017-02-01

Synovitis is a key factor in joint disease pathophysiology, which affects a greater proportion of women than men. P2X7 receptor activation contributes to arthritis, but whether it plays a role in articular inflammatory pain in a sex-dependent manner is unknown. We investigated whether the P2X7 receptor blockade in the knee joint of male and female rats reduces the articular hyperalgesia and inflammation induced by a carrageenan knee joint synovitis model. Articular hyperalgesia was quantified using the rat knee joint incapacitation test and the knee joint inflammation, characterized by the concentration of cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cytokine-induced neutrophil chemoattractant-1, and by neutrophil migration, was quantified using enzyme-linked immunosorbent assay and by myeloperoxidase enzyme activity measurement, respectively. P2X7 receptor blockade by the articular coadministration of selective P2X7 receptor antagonist A740003 with carrageenan significantly reduced articular hyperalgesia, pro-inflammatory cytokine concentrations, and myeloperoxidase activity induced by carrageenan injection into the knee joint of male and estrus female rats. However, a lower dose of P2X7 receptor antagonist was sufficient to significantly induce the antihyperalgesic and anti-inflammatory effects in estrus female but not in male rats. These results suggest that P2X7 receptor activation by endogenous adenosine 5'-triphosphate is essential to articular hyperalgesia and inflammation development in the knee joint of male and female rats. However, female rats are more responsive than male rats to the antihyperalgesic and anti-inflammatory effects induced by P2X7 receptor blockade. P2X7 receptors could be promising therapeutic targets in the treatment of knee joint disease symptoms, especially in women, who are more affected than men by these conditions. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Analgesic effect of the neuropeptide cortistatin in murine models of arthritic inflammatory pain.

PubMed

Morell, Maria; Souza-Moreira, Luciana; Caro, Marta; O'Valle, Francisco; Forte-Lago, Irene; de Lecea, Luis; Gonzalez-Rey, Elena; Delgado, Mario

2013-05-01

To investigate the role of the antiinflammatory neuropeptide cortistatin in chronic pain evoked by joint inflammation. Thermal and mechanical hyperalgesia was evoked in mouse knee joints by intraplantar injection of tumor necrosis factor α and intraarticular infusion of Freund's complete adjuvant, and the analgesic effects of cortistatin, administered centrally, peripherally, and systemically, were assessed. In addition, the effects of cortistatin on the production of nociceptive peptides and the activation of pain signaling were assayed in dorsal root ganglion cultures and in inflammatory pain models. The role of endogenous cortistatin in pain sensitization and perpetuation of chronic inflammatory states was evaluated in cortistatin-deficient mice. Finally, the effect of noxious/inflammatory stimuli in the production of cortistatin by the peripheral nociceptive system was assayed in vitro and in vivo. Expression of cortistatin was observed in peptidergic nociceptors of the peripheral nociceptive system, and endogenous cortistatin was found to participate in the tuning of pain sensitization, especially in pathologic inflammatory conditions. Results showed that cortistatin acted both peripherally and centrally to reduce the tactile allodynia and heat hyperalgesia evoked by arthritis and peripheral tissue inflammation in mice, via mechanisms that were independent of its antiinflammatory action. These mechanisms involved direct action on nociceptive neurons and regulation of central sensitization. The analgesic effects of cortistatin in murine arthritic pain were linked to binding of the neuropeptide to somatostatin and ghrelin receptors, activation of the G protein subunit Gαi , impairment of ERK signaling, and decreased production of calcitonin gene-related peptide in primary nociceptors. These findings indicate that cortistatin is an antiinflammatory factor with potent analgesic effects that may offer a new approach to pain therapy in pathologic inflammatory

Aloperine attenuated neuropathic pain induced by chronic constriction injury via anti-oxidation activity and suppression of the nuclear factor kappa B pathway

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

Xu, Ya-Qiong; Jin, Shao-Ju; Luohe Medical College, Luohe 462002, Henan Province

Highlights: • Aloperine has anti-nociceptive effects on neuropathic pain induced CCI. • Aloperine reduces ROS in neuropathic pain mice. • Aloperine down-regulates the expression of NF-κB and its downstream pro-inflammatory cytokines in neuropathic pain mice. - Abstract: Objective: To investigate whether aloperine (ALO) has antinociceptive effects on neuropathic pain induced by chronic constriction injury, whether ALO reduces ROS against neuropathic pain, and what are the mechanisms involved in ALO attenuated neuropathic pain. Methods: Mechanical and cold allodynia, thermal and mechanical hyperalgesia and spinal thermal hyperalgesia were estimated by behavior methods such as Von Frey filaments, cold-plate, radiant heat, paw pressuremore » and tail immersion on one day before surgery and days 7, 8, 10, 12 and 14 after surgery, respectively. In addition, T-AOC, GSH-PX, T-AOC and MDA in the spinal cord (L4/5) were measured to evaluate anti-oxidation activity of ALO on neuropathic pain. Expressions of NF-κB and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in the spinal cord (L4/5) were analyzed by using Western blot. Results: Administration of ALO (80 mg/kg and 40 mg/kg, i.p.) significantly increased paw withdrawal threshold, paw pressure, paw withdrawal latencies, tail-curling latencies, T-AOC, GSH-PX and T-SOD concentration, reduced the numbers of paw lifts and MDA concentration compared to CCI group. ALO attenuated CCI induced up-regulation of expressions of NF-κB, TNF-α, IL-6, IL-1β at the dose of 80 mg/kg (i.p.). Pregabalin produced similar effects serving as positive control at the dose of 10 mg/kg (i.p.). Conclusion: ALO has antinociceptive effects on neuropathic pain induced by CCI. The antinociceptive effects of ALO against neuropathic pain is related to reduction of ROS, via suppression of NF-κB pathway.« less

Clinical descriptors for the recognition of central sensitization pain in patients with knee osteoarthritis.

PubMed

Lluch, Enrique; Nijs, Jo; Courtney, Carol A; Rebbeck, Trudy; Wylde, Vikki; Baert, Isabel; Wideman, Timothy H; Howells, Nick; Skou, Søren T

2017-08-02

Despite growing awareness of the contribution of central pain mechanisms to knee osteoarthritis pain in a subgroup of patients, routine evaluation of central sensitization is yet to be incorporated into clinical practice. The objective of this perspective is to design a set of clinical descriptors for the recognition of central sensitization in patients with knee osteoarthritis that can be implemented in clinical practice. A narrative review of original research papers was conducted by nine clinicians and researchers from seven different countries to reach agreement on clinically relevant descriptors. It is proposed that identification of a dominance of central sensitization pain is based on descriptors derived from the subjective assessment and the physical examination. In the former, clinicians are recommended to inquire about intensity and duration of pain and its association with structural joint changes, pain distribution, behavior of knee pain, presence of neuropathic-like or centrally mediated symptoms and responsiveness to previous treatment. The latter includes assessment of response to clinical test, mechanical hyperalgesia and allodynia, thermal hyperalgesia, hypoesthesia and reduced vibration sense. This article describes a set of clinically relevant descriptors that might indicate the presence of central sensitization in patients with knee osteoarthritis in clinical practice. Although based on research data, the descriptors proposed in this review require experimental testing in future studies. Implications for Rehabilitation Laboratory evaluation of central sensitization for people with knee osteoarthritis is yet to be incorporated into clinical practice. A set of clinical indicators for the recognition of central sensitization in patients with knee osteoarthritis is proposed. Although based on research data, the clinical indicators proposed require further experimental testing of psychometric properties.

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.

GABAergic Transmission in Rat Pontine Reticular Formation Regulates the Induction Phase of Anesthesia and Modulates Hyperalgesia Caused by Sleep Deprivation

PubMed Central

Vanini, Giancarlo; Nemanis, Kriste; Baghdoyan, Helen A.; Lydic, Ralph

2014-01-01

The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia, and pain. The role of PnO GABA in modulating these states remains incompletely understood. The present study used time to Loss and time to Resumption of Righting Response (LoRR and RoRR) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (1) pharmacologically manipulating GABA levels in rat PnO alters LoRR, RoRR, and nociception; (2) propofol decreases GABA levels in the PnO; and (3) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis inhibitor (3-MPA) or a GABA uptake inhibitor (NPA) into rat PnO significantly altered LoRR caused by propofol. 3-MPA significantly decreased LoRR for propofol (−18%). NPA significantly increased LoRR during administration of propofol (36%). Neither 3-MPA nor NPA altered RoRR following cessation of propofol or isoflurane delivery. The finding that LoRR was decreased by 3-MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3-MPA and increased by NPA, and 3-MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABAergic transmission in the PnO mediates hyperalgesia caused by sleep loss. PMID:24674578

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain

PubMed Central

Lim, Eun Yeong

2016-01-01

Neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory nervous system, is characterized by dysesthesia, hyperalgesia, and allodynia. The number of patients with this type of pain has increased rapidly in recent years. Yet, available neuropathic pain medicines have undesired side effects, such as tolerance and physical dependence, and do not fully alleviate the pain. The mechanisms of neuropathic pain are still not fully understood. Injury causes inflammation and immune responses and changed expression and activity of receptors and ion channels in peripheral nerve terminals. Additionally, neuroinflammation is a known factor in the development and maintenance of neuropathic pain. During neuropathic pain development, the C-C motif chemokine receptor 2 (CCR2) acts as an important signaling mediator. Traditional plant treatments have been used throughout the world for treating diseases. We and others have identified food-derived compounds that alleviate neuropathic pain. Here, we review the natural compounds for neuropathic pain relief, their mechanisms of action, and the potential benefits of natural compounds with antagonistic effects on GPCRs, especially those containing CCR2, for neuropathic pain treatment. PMID:27891521

Rapamycin ameliorates neuropathic pain by activating autophagy and inhibiting interleukin-1β in the rat spinal cord.

PubMed

Feng, Tao; Yin, Qin; Weng, Ze-lin; Zhang, Jian-cheng; Wang, Kun-feng; Yuan, Shi-ying; Cheng, Wei

2014-12-01

Autophagy acts as an important homoeostatic mechanism by degradation of cytosolic constituents and plays roles in many physiological processes. Recent studies demonstrated that autophagy can also regulate the production and secretion of the proinflammatory cytokine interleukin-1β (IL-1β), which plays a critical role in the development and maintenance of neuropathic pain. In the present study, the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were significantly decreased after spinal nerve ligation (SNL), and the changes were accompanied by inhibited autophagy in the spinal microglia and increased mRNA and protein levels of IL-1β in the ipsilateral spinal cord. We then investigated the antinociceptive effect of rapamycin, a widely used autopahgy inducer, on SNL-induced neuropathic pain in rats and found that treatment with intrathecal rapamycin significantly attenuated the mechanical allodynia and thermal hyperalgesia. Moreover, rapamycin significantly enhanced autophagy in the spinal microglia, whereas it reduced the mRNA and protein levels of IL-1β in the ipsilateral spinal cord. Our results showed that rapamycin could ameliorate neuropathic pain by activating autophagy and inhibiting IL-1β in the spinal cord.

Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition

PubMed Central

van Helmond, Noud; Steegers, Monique A.; Filippini-de Moor, Gertie P.; Vissers, Kris C.; Wilder-Smith, Oliver H.

2016-01-01

Background Persistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia. Methods 138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months. Results 48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively. Conclusions Perioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of

GluN2B/CaMKII mediates CFA-induced hyperalgesia via HDAC4-modified spinal COX2 transcription.

PubMed

Lai, Cheng-Yuan; Hsieh, Ming-Chun; Ho, Yu-Cheng; Chen, Gin-Den; Chou, Dylan; Ruan, Ting; Lee, An-Sheng; Wang, Hsueh-Hsiao; Chau, Yat-Pang; Peng, Hsien-Yu; Lai, Cheng-Hung

2018-06-01

Histone deacetylase 4 (HDAC4), which actively shuttles between the nucleus and cytoplasm, is an attractive candidate for a repressor mechanism in epigenetic modification. However, the potential role of HDAC4-dependent epigenetics in the neural plasticity underlying the development of inflammatory pain has not been well established. By injecting complete Freund's adjuvant (CFA) into the hind-paw of Sprague-Dawley rats (200-250 g), we found animals displayed behavioral hyperalgesia was accompanied with HDAC4 phosphorylation and cytoplasmic redistribution in the dorsal horn neurons. Cytoplasmic HDAC4 retention led to its uncoupling with the COX2 promoter, hence prompting spinal COX2 transcription and expression in the dorsal horn. Moreover, the GluN2B-bearing N-methyl-d-aspartate receptor (GluN2B-NMDAR)/calmodulin-dependent protein kinase II (CaMKII) acted as an upstream cascade to facilitate HDAC4 phosphorylation/redistribution-associated spinal COX2 expression after inflammatory insults. The results of this pilot study demonstrated that the development and/or maintenance of inflammatory pain involved the spinal HDAC4-dependent epigenetic mechanisms. Our findings open up a new avenue for the development of a novel medical strategy for the relief of inflammatory pain. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Operative treatment of painful neuromas].

PubMed

Stokvis, Annemieke; Coert, J Henk

2011-01-01

3-5% of patients with traumatic or iatrogenic peripheral nerve injury develop a painful neuroma, especially following trauma of small cutaneous sensory nerve branches. Neuroma pain is difficult to treat and often leads to loss of function and reduction of quality of life. Patients with a painful neuroma present with spontaneous electric, shooting or burning pain, allodynia, hyperalgesia and cold intolerance. The diagnosis is based on the medical history and physical examination, supplemented by Tinel's test and a diagnostic nerve blockade. Lasting pain relief is possible by means of surgical neuroma treatment performed by a plastic surgeon. Surgical treatment consists of repair or denervation of the nerve with relocation of the nerve stump in bone or muscle tissue or a vein. Referral of neuroma patients without delay to a plastic surgeon or multidisciplinary consultation is important, because the symptoms become increasingly difficult to treat over time. 3-5% of patients with traumatic or iatrogenic peripheral nerve injury develop a painful neuroma, especially following trauma of small cutaneous sensory nerve branches. Neuroma pain is difficult to treat and often leads to loss of function and reduction of quality of life. Patients with a painful neuroma present with spontaneous electric, shooting or burning pain, allodynia, hyperalgesia and cold intolerance. The diagnosis is based on the medical history and physical examination, supplemented by Tinel's test and a diagnostic nerve blockade. Lasting pain relief is possible by means of surgical neuroma treatment performed by a plastic surgeon. Surgical treatment consists of repair or denervation of the nerve with relocation of the nerve stump in bone or muscle tissue or a vein. Referral of neuroma patients without delay to a plastic surgeon or multidisciplinary consultation is important, because the symptoms become increasingly difficult to treat over time.

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

Abdominal pain in Irritable Bowel Syndrome: a review of putative psychological, neural and neuro-immune mechanisms.

PubMed

Elsenbruch, Sigrid

2011-03-01

Chronic abdominal pain is a common symptom of great clinical significance in several areas of medicine. In many cases no organic cause can be established resulting in the classification as functional gastrointestinal disorder. Irritable Bowel Syndrome (IBS) is the most common of these conditions and is considered an important public health problem because it can be disabling and constitutes a major social and economic burden given the lack of effective treatments. IBS aetiology is most likely multi-factorial involving biological, psychological and social factors. Visceral hyperalgesia (or hypersensitivity) and visceral hypervigilance, which could be mediated by peripheral, spinal, and/or central pathways, constitute key concepts in current research on pathophysiological mechanisms of visceral hyperalgesia. The role of central nervous system mechanisms along the "brain-gut axis" is increasingly appreciated, owing to accumulating evidence from brain imaging studies that neural processing of visceral stimuli is altered in IBS together with long-standing knowledge regarding the contribution of stress and negative emotions to symptom frequency and severity. At the same time, there is also growing evidence suggesting that peripheral immune mechanisms and disturbed neuro-immune communication could play a role in the pathophysiology of visceral hyperalgesia. This review presents recent advances in research on the pathophysiology of visceral hyperalgesia in IBS, with a focus on the role of stress and anxiety in central and peripheral response to visceral pain stimuli. Together, these findings support that in addition to lower pain thresholds displayed by a significant proportion of patients, the evaluation of pain appears to be altered in IBS. This may be attributable to affective disturbances, negative emotions in anticipation of or during visceral stimulation, and altered pain-related expectations and learning processes. Disturbed "top-down" emotional and cognitive pain

[Stress-induced hyperalgesia (SIH) as a consequence of emotional deprivation and psychosocial traumatization in childhood : Implications for the treatment of chronic pain].

PubMed

Egle, U T; Egloff, N; von Känel, R

2016-12-01

It is now widely recognized that in many chronic pain syndromes the intensity and severity of individually perceived pain does not correlate consistently with the degree of peripheral nervous system tissue damage or with the intensity of primary afferent or spinal nociceptive neurone activity. In particular, stress and anxiety exert modulatory influences on pain depending on the nature, duration and intensity of the stressor and developmental influences on the maturation of the stress as well as the pain system. In some chronic pain syndromes, e. g. fibromyalgia, TMD or somatoform disorders, no nociceptive or neuropathic input is detectable. We summarise the studies investigating the neural substrates and neurobiological mechanisms of stress-induced hyperalgesia (SIH) in animals and humans. The review provides new perspectives and challenges for the current and future treatment of chronic pain.

GABAergic transmission in rat pontine reticular formation regulates the induction phase of anesthesia and modulates hyperalgesia caused by sleep deprivation.

PubMed

Vanini, Giancarlo; Nemanis, Kriste; Baghdoyan, Helen A; Lydic, Ralph

2014-07-01

The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia and pain. The role of PnO γ-aminobutyric acid (GABA) in modulating these states remains incompletely understood. The present study used time to loss and time to resumption of righting response (LoRR and RoRR) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (i) pharmacologically manipulating GABA levels in rat PnO alters LoRR, RoRR and nociception; (ii) propofol decreases GABA levels in the PnO; and (iii) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis inhibitor [3-mercaptopropionic acid (3-MPA)] or a GABA uptake inhibitor [nipecotic acid (NPA)] into rat PnO significantly altered LoRR caused by propofol. 3-MPA significantly decreased LoRR for propofol (-18%). NPA significantly increased LoRR during administration of propofol (36%). Neither 3-MPA nor NPA altered RoRR following cessation of propofol or isoflurane delivery. The finding that LoRR was decreased by 3-MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3-MPA and increased by NPA, and 3-MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABAergic transmission in the PnO mediates hyperalgesia caused by sleep loss. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Long-Term Treatment by Vitamin B1 and Reduction of Serum Proinflammatory Cytokines, Hyperalgesia, and Paw Edema in Adjuvant-Induced Arthritis

PubMed Central

Zaringhalam, Jalal; Akbari, Akhtar; Zali, Alireza; Manaheji, Homa; Nazemian, Vida; Shadnoush, Mahdi; Ezzatpanah, Somayeh

2016-01-01

Introduction: Immune system is involved in the etiology and pathophysiology of inflammation and vitamins are important sources of substances inducing nonspecific immunomodulatory effects. Given the proinflammatory role of cytokines in the inflammation and pain induction, this study aimed to assess the effects of long-term administration of vitamin B1 on the proinflammatory cytokines, edema, and hyperalgesia during the acute and chronic phases of adjuvant-induced arthritis. Methods: On the first day of study, inflammation was induced by intraplantar injection of complete Freund's adjuvant (CFA) in the hindpaws of rats. Vitamin B1 at doses of 100, 150, and 200 mg/kg was administrated intraperitoneally during 21 days of the study. Antinociceptive and anti-inflammatory effects of vitamin B1 were also compared to indomethacin (5 mg/kg). Inflammatory symptoms such as thermal hyperalgesia and paw edema were measured by radiant heat and plethysmometer, respectively. Serum TNF-α and IL-1β levels were checked by rat standard enzyme-linked immune sorbent assay (ELISA) specific kits. Results: The results indicated that vitamin B1(150 and 200 mg/kg) attenuated the paw edema, thermal hyperalgesia, and serum levels of TNF-α and IL-1β during both phases of CFA-induced inflammation in a dose-dependent manner. Effective dose of vitamin B1(150 mg/kg) reduced inflammatory symptoms and serum levels of TNF-α and IL-1β compare to indomethacin during the chronic phase of inflammation. Conclusion: Anti-inflammatory and antihyperalgesic effects of vitamin B1 during CFA-induced arthritis, more specifically after chronic vitamin B1 administration, suggest its therapeutic property for inflammation. PMID:27872694

Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review.

PubMed

Kim, Sang Hun; Stoicea, Nicoleta; Soghomonyan, Suren; Bergese, Sergio D

2014-01-01

The use of opioids has been increasing in operating room and intensive care unit to provide perioperative analgesia as well as stable hemodynamics. However, many authors have suggested that the use of opioids is associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) in experimental studies and clinical observations in dose and/or time dependent exposure even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management during anesthesia as well as in the intensive care units because of its rapid onset and offset. Search of the available literature to assess remifentanil AOT and OIH based on available published data. We reviewed articles analyzing remifentanil AOT and OIH, and focused our literature search on evidence based information. Experimental and clinical studies were identified using electronic searches of Medline (PubMed, Ovid, Springer, and Elsevier, ClinicalKey). Our results showed that the development of remifentanil AOT and OIH is a clinically significant phenomenon requiring further research. AOT - defined as an increase in the required opioid dose to maintain adequate analgesia, and OIH - defined as decreased pain threshold after chronic opioid treatment, should be suspected with any unexplained pain report unassociated with the disease progression. The clinical significance of these findings was evaluated taking into account multiple methodological issues including the dose and duration of opioids administration, the different infusion mode, the co-administrated anesthetic drug's effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion. Future studies need to investigate the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process.

Perioperative epidural or intravenous ketamine does not improve the effectiveness of thoracic epidural analgesia for acute and chronic pain after thoracotomy.

PubMed

Tena, Beatriz; Gomar, Carmen; Rios, Jose

2014-06-01

Persistent postsurgical pain (PPP) after thoracotomy effect 50% to 80%. Nerve damage and central sensitization involving NDMDAr activation may play an important role. This study evaluates the efficacy of adding intravenous (IV) or epidural ketamine to thoracic epidural analgesia (TEA) after thoracotomy. Double-blind randomized study on patients undergoing thoracotomy allocated to one of the following: group Kiv (IV racemic ketamine 0.5 mg/kg preincisional +0.25 mg/kg/h for 48 h), group Kep (epidural racemic ketamine 0.5 mg/kg preincisional +0.25 mg/kg/h for 48 h), or group S (saline). Postoperative analgesia was ensured by TEA with ropivacaine and fentanyl. Pain visual analog scales (VAS), Neuropathic Pain Symptom Inventory, Catastrophizing Scale, and Quantitative Sensory Testing, measuring both the peri-incisional and distant hyperalgesia area, were conducted preoperatively and postoperatively until 6 months. Plasma ketamine levels and stability of the analgesic solutions were analyzed. A total of 104 patients were included. PPP incidence was 20% at 6 months. Pain scores on coughing were significantly lower in Kiv and Kep than in S at 24 and 72 hours, but there were no differences afterwards. There were no significant differences in pain at rest, Neuropathic Pain Symptom Inventory, and Catastrophizing Scale, or in the area of mechanical allodynia at any time. Adverse effects were mild. Plasma ketamine levels did not differ significantly between groups. Analgesic solutions were stable. Adding epidural or IV racemic ketamine to TEA after thoracotomy did not lead to any reduction in PPP or allodynia. Epidural administration produced similar plasma ketamine levels to the IV route.

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.

Stress-related psychological symptoms contribute to axial pain persistence after motor vehicle collision: path analysis results from a prospective longitudinal study.

PubMed

Feinberg, Rose K; Hu, JunMei; Weaver, Mark A; Fillingim, Roger B; Swor, Robert A; Peak, David A; Jones, Jeffrey S; Rathlev, Niels K; Lee, David C; Domeier, Robert M; Hendry, Phyllis L; Liberzon, Israel; McLean, Samuel A

2017-04-01

Posttraumatic stress disorder (PTSD) symptoms and pain after traumatic events such as motor vehicle collision (MVC) have been proposed to be mutually promoting. We performed a prospective multicenter study that enrolled 948 individuals who presented to the emergency department within 24 hours of MVC and were discharged home after evaluation. Follow-up evaluations were completed 6 weeks, 6 months, and 1 year after MVC. Path analysis results supported the hypothesis that axial pain after MVC consistently promotes the maintenance of hyperarousal and intrusive symptoms, from the early weeks after injury through 1 year. In addition, path analysis results supported the hypothesis that one or more PTSD symptom clusters had an influence on axial pain outcomes throughout the year after MVC, with hyperarousal symptoms most influencing axial pain persistence in the initial months after MVC. The influence of hyperarousal symptoms on pain persistence was only present among individuals with genetic vulnerability to stress-induced pain, suggesting specific mechanisms by which hyperarousal symptoms may lead to hyperalgesia and allodynia. Further studies are needed to better understand the specific mechanisms by which pain and PTSD symptoms enhance one another after trauma, and how such mechanisms vary among specific patient subgroups, to better inform the development of secondary preventive interventions.

Effects of paclitaxel on mechanical sensitivity and morphine reward in male and female C57Bl6 mice

PubMed Central

Neelakantan, Harshini; Ward, Sara Jane; Walker, Ellen Ann

2016-01-01

This study evaluated the hypothesis that a paclitaxel treatment regimen sufficient to produce mechanical allodynia would alter sensitivities of male and female mice to the conditioned rewarding and reinforcing effects of morphine. Saline or paclitaxel were administered on days 1, 3, 5, and 7 in male and female C57Bl/6 mice to induce morphine-reversible mechanical allodynia as measured by the Von Frey filament test. Paclitaxel treatment did not change sensitivity to morphine conditioned place preference (CPP) relative to saline treatment in either male or female mice. Morphine produced peak self-administration under a fixed ratio-1 schedule of reinforcement for 0.03 mg/kg morphine per infusion in female mice and 0.1 mg/kg morphine per infusion in male mice. During the progressive ratio experiments, saline treatment in male mice decreased the number of morphine infusions for 12 days whereas the paclitaxel-treated male mice maintained responding for morphine similar to baseline levels during the same time period. However, paclitaxel did not have an overall effect on the reinforcing efficacy of morphine assessed over a limited dose range during the course of the repeated self-administration. These results suggest that the reward-related behavioral effects of morphine are overall not robustly altered by the presence of paclitaxel treatment under the current dosing regimen, with the exception of maintaining a small yet significant higher baseline than saline treatment during the development of allodynia in male mice. PMID:27929349

Adiponectin regulates thermal nociception in a mouse model of neuropathic pain.

PubMed

Sun, L; Li, H; Tai, L W; Gu, P; Cheung, C W

2018-06-01

Adiponectin, a cytokine secreted by adipocytes, plays an important role in regulating glucose and lipid metabolism. However, the role of adiponectin in pain conditions is largely unknown. This study aimed to identify the role and mechanism of adiponectin in nociceptive sensitivity under physiological and pathological states utilising adiponectin knockout (KO) mice. Wild type (WT) and adiponectin KO mice were subjected to partial sciatic nerve ligation (pSNL) or sham operation. Pain-like behavioural tests, including thermal allodynia, hyperalgesia, and mechanical allodynia, were performed before and after pSNL from Day 3-21. Dorsal root ganglions (DRGs), lumbar spinal segments at L3-5, and somatosensory cortex were collected for protein measurement via western blotting and immunofluorescence staining. Compared with WT mice, KO mice had significantly lower (40-50%) paw withdrawal latency to innocuous and noxious stimuli before and after pSNL. In DRG neurones from KO mice, where adiponectin receptor (AdipoR) 2 is located, phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and heat-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1) were significantly higher (by two- to three-fold) than from WT mice. In spinal microglia and somatosensory cortical neurones, where AdipoR1 is mainly located, p-p38 MAPK and TRPV1 were also higher (by two- to three-fold) in KO compared with WT mice, and altered signalling of these molecules was exacerbated (1.2- to 1.3-fold) by pSNL. Our results show that adiponectin regulates thermal nociceptive sensitivity by inhibiting activation of DRG neurones, spinal microglia, and somatosensory cortical neurones in physiological and neuropathic pain states. This study has relevance for patients with adiponectin disorders, such as obesity and diabetes. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Sub-paresthesia spinal cord stimulation reverses thermal hyperalgesia and modulates low frequency EEG in a rat model of neuropathic pain.

PubMed

Koyama, Suguru; Xia, Jimmy; Leblanc, Brian W; Gu, Jianwen Wendy; Saab, Carl Y

2018-05-08

Paresthesia, a common feature of epidural spinal cord stimulation (SCS) for pain management, presents a challenge to the double-blind study design. Although sub-paresthesia SCS has been shown to be effective in alleviating pain, empirical criteria for sub-paresthesia SCS have not been established and its basic mechanisms of action at supraspinal levels are unknown. We tested our hypothesis that sub-paresthesia SCS attenuates behavioral signs of neuropathic pain in a rat model, and modulates pain-related theta (4-8 Hz) power of the electroencephalogram (EEG), a previously validated correlate of spontaneous pain in rodent models. Results show that sub-paresthesia SCS attenuates thermal hyperalgesia and power amplitude in the 3-4 Hz range, consistent with clinical data showing significant yet modest analgesic effects of sub-paresthesia SCS in humans. Therefore, we present evidence for anti-nociceptive effects of sub-paresthesia SCS in a rat model of neuropathic pain and further validate EEG theta power as a reliable 'biosignature' of spontaneous pain.

Anti-inflammatory effects of vitamin E on adjuvant-induced arthritis in rats.

PubMed

Rossato, Mateus Fortes; Hoffmeister, Carin; Tonello, Raquel; de Oliveira Ferreira, Ana Paula; Ferreira, Juliano

2015-04-01

Vitamin E (vit-E) is a lipophilic antioxidant, and its anti-inflammatory activity is still not full characterized. Thus, our goal was to investigate the anti-inflammatory effect of repeated vit-E treatment in the arthritis induced by the intraplantar injection of complete Freund's adjuvant (CFA). We observed an increase in arthritis scores, interleukin-1β and H2O2 levels, neutrophil and macrophage infiltration, thermal hyperalgesia, mechanical allodynia, and loss of function induced by intraplantar CFA injection. These effects were unaltered after 1 day, partially reversed after 3 days, and inhibited after 9 days after vit-E treatment. Furthermore, the concentration of vit-E was reduced and that of tumor necrosis factor-alpha was increased in the CFA-injected paw. Both effects were reversed from 1 to 9 days after vit-E treatment. However, vit-E treatment did not alter CFA-induced edema at any time. Thus, vit-E treatment produced an anti-inflammatory effect of slow onset in CFA, which demonstrates a disease-modifying drug profile.

Synergistic anti-hyperalgesia of electroacupuncture and low dose of celecoxib in monoarthritic rats: involvement of the cyclooxygenase activity in the spinal cord.

PubMed

Mi, Wen-Li; Mao-Ying, Qi-Liang; Liu, Qiong; Wang, Xiao-Wei; Wang, Yan-Qing; Wu, Gen-Cheng

2008-09-30

Electroacupuncture (EA) can effectively control the exaggerated pain in humans with inflammatory disease and animals with experimental inflammatory pain. However, there have been few investigations on the effect of co-administration of EA and analgesics and the underlying synergistic mechanism. Using behavioral test, RT-PCR analysis, enzyme immunoassay (EIA) and enzyme-linked immunosorbent assay (ELISA), the present study demonstrated that (1) Unilateral intra-articular injection of complete Freund's adjuvant (CFA) produced a constant hyperalgesia and an up-regulation of the prostaglandin E(2) (PGE(2)) level as well as the tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 levels in the spinal cord; (2) Celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2), at a dose of 2, 10, and 20 mg/kg (twice daily, p.o.), presented a dose-dependent anti-hyperalgesic effect; (3) Repeated EA stimulation of ipsilateral 'Huan-Tiao' (GB30) and 'Yang-Ling-Quan' (GB34) acupoints significantly suppressed CFA-induced hyperalgesia, and markedly inhibited the CFA-induced increase of the level of PGE(2) as well as IL-1beta, IL-6, and TNF-alpha in the spinal cord; (4) EA combined with low dose of celecoxib (2 mg/kg, twice daily, p.o.) greatly enhanced the anti-hyperalgesic effects of EA, with a synergistic reversing effect on CFA-induced up-regulation of spinal PGE(2), but not on the IL-1beta, IL-6, or TNF-alpha. These data indicated that repeated EA combined with low dose of celecoxib produced synergistic anti-hyperalgesic effect in the CFA-induced monoarthritic rats, which could be made possible by regulating the activity of spinal COX, hence the spinal PGE(2) level. Thus, this combination may provide an effective strategy for pain management.

Neuropeptide Y in the rostral ventromedial medulla reverses inflammatory and nerve injury hyperalgesia in rats via non-selective excitation of local neurons

PubMed Central

Cleary, Daniel R.; Roeder, Zachary; Elkhatib, Rania; Heinricher, Mary M.

2014-01-01

Chronic pain reflects not only sensitization of the ascending nociceptive pathways, but also changes in descending modulation. The rostral ventromedial medulla (RVM) is a key structure in a well-studied descending pathway, and contains two classes of modulatory neurons, the ON-cells and the OFF-cells. Disinhibition of OFF-cells depresses nociception; increased ON-cell activity facilitates nociception. Multiple lines of evidence show that sensitization of ON-cells contributes to chronic pain, and reversing or blocking this sensitization is of interest as a treatment of persistent pain. Neuropeptide Y (NPY) acting via the Y1 receptor has been shown to attenuate hypersensitivity in nerve-injured animals without affecting normal nociception when microinjected into the RVM, but the neural basis for this effect was unknown. We hypothesized that behavioral anti-hyperalgesia was due to selective inhibition of ON-cells by NPY at the Y1 receptor. To explore the possibility of Y1 selectivity on ON-cells, we stained for the NPY-Y1 receptor in the RVM, and found it broadly expressed on both serotonergic and non-serotonergic neurons. In subsequent behavioral experiments, NPY microinjected into the RVM in lightly anesthetized animals reversed signs of mechanical hyperalgesia following either nerve injury or chronic hindpaw inflammation. Unexpectedly, rather than decreasing ON-cell activity, NPY increased spontaneous activity of both ON- and OFF-cells without altering noxious-evoked changes in firing. Based on these results, we conclude that the anti-hyperalgesic effects of NPY in the RVM are not explained by selective inhibition of ON-cells, but rather by increased spontaneous activity of OFF-cells. Although ON-cells undoubtedly facilitate nociception and contribute to hypersensitivity, the present results highlight the importance of parallel OFF-cell mediated descending inhibition in limiting the expression of chronic pain. PMID:24792711

Effectiveness of Epidural Analgesia, Continuous Surgical Site Analgesia, and Patient-Controlled Analgesic Morphine for Postoperative Pain Management and Hyperalgesia, Rehabilitation, and Health-Related Quality of Life After Open Nephrectomy: A Prospective, Randomized, Controlled Study.

PubMed

Capdevila, Xavier; Moulard, Sebastien; Plasse, Christian; Peshaud, Jean-Luc; Molinari, Nicolas; Dadure, Christophe; Bringuier, Sophie

2017-01-01

There is no widely recognized effective technique to optimally reduce pain scores and prevent persistent postoperative pain after nephrectomy. We compared continuous surgical site analgesia (CSSA), epidural analgesia (EA), and a control group (patient-controlled analgesic morphine) in patients undergoing open nephrectomy. Sixty consecutive patients were randomized to be part of EA, CSSA, or control groups postoperatively for 72 hours. All patients received patient-controlled analgesic morphine, if needed. Hyperalgesia was assessed on the first, second, and third postoperative days. Chronic pain characteristics and quality of life were analyzed at 1 and 3 months. The primary outcome was the pain score at 24 hours. Secondary outcomes were morphine consumption, postoperative rehabilitation, hyperalgesia, chronic pain incidence, and quality-of-life parameters. At 24 hours, mean ± standard deviation pain values at rest (2.4 ± 1.7, 2.2 ± 1.2, and 4.2 ± 1.2, respectively, in EA, CSSA, and control groups, P <.001) and during coughing was lower in the EA and CSSA groups. Total morphine consumption was higher in the control group. Rehabilitation parameters improved sooner in the EA and CSSA groups. Median values of area of hyperalgesia differed at 48 hours between the EA group and the control group (36.4 cm) and (52 cm) (P = .01) and at 72 hours among the EA group, CSSA group, and the control group (40 cm, 39.5 cm, and 59 cm, respectively; P = .002). CSSA reduced the severity of pain and hyperalgesia at 1 month and optimized quality of life 3 months after surgery (role physical scores, P = .005). CSSA and EA significantly improve postoperative analgesia, reduce postoperative morphine consumption, area of wound hyperalgesia, and accelerate patient rehabilitation after open nephrectomy. CSSA significantly reduces the severity of residual pain 1 month after surgery and optimizes quality-of-life parameters 3 months after surgery.

Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury

PubMed Central

Daiutolo, Brittany V.; Tyburski, Ashley; Clark, Shannon W.

2016-01-01

Abstract The pain-signaling molecules, nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP), are implicated in the pathophysiology of post-traumatic headache (PTH) as they are for migraine. This study assessed the changes of inducible NOS (iNOS) and its cellular source in the trigeminal pain circuit, as well as the relationship between iNOS and CGRP after controlled cortical impact (CCI) injury in mice. The effects of a CGRP antagonist (MK8825) and sumatriptan on iNOS messenger RNA (mRNA) and protein were compared to vehicle at 2 weeks postinjury. Changes in CGRP levels in the trigeminal nucleus caudalis (TNC) in iNOS knockouts with CCI were compared to wild-type (WT) mice at 3 days and 2 weeks post injury. Trigeminal allodynia and photosensitivity were measured. MK8825 and sumatriptan increased allodynic thresholds in CCI groups compared to vehicle (p < 0.01), whereas iNOS knockouts were not different from WT. Photosensitivity was attenuated in MK8825 mice and iNOS knockouts compared to WT (p < 0.05). MK8825 and sumatriptan reduced levels of iNOS mRNA and iNOS immunoreactivity in the TNC and ganglia (p < 0.01). Differences in iNOS cellular localization were found between the trigeminal ganglia and TNC. Although the knockout of iNOS attenuated CGRP at 3 days (p < 0.05), it did not reduce CGRP at 2 weeks. CGRP immunoreactivity was found in the meningeal layers post-CCI, while negligible in controls. Findings support the importance of interactions between CGRP and iNOS in mediating allodynia, as well as the individual roles in photosensitivity. Mitigating prolonged increases in CGRP may be a promising intervention for treating acute PTH. PMID:26472135

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

Neutral endopeptidase knockout induces hyperalgesia in a model of visceral pain, an effect related to bradykinin and nitric oxide.

PubMed

Fischer, Hanspeter S; Zernig, Gerald; Hauser, Kurt F; Gerard, Craig; Hersh, Louis B; Saria, Alois

2002-01-01

Neutral endopeptidase (EC3.4.24.11, NEP, enkephalinase) is a zinc-metalloendopeptidase, cleaving a variety of substrates like enkephalins, substance P, and bradykinin. In the brain, NEP is a key enzyme in the degradation of enkephalins. Pharmacological inhibition of NEP-activity causes analgesia resulting from enhanced extracellular enkephalin concentrations. Recently, transgenic mice lacking the enzyme NEP have been developed (Lu, 1995). The present study was designed to investigate the nociceptive behavior of these NEP-knockout mice. Interestingly, NEP-deficient mice did not respond with decreased pain perception, but exhibited hyperalgesia in the hot-plate jump, warm-water tail-withdrawal, and mostnotablyin theacetic-acid writhing test. Inhibition of aminopeptidase N by bestatin reduced writhing in both strains, whereas NEP-inhibition by thiorphan reduced writhing selectively in wild-type mice. Naloxone increased writhing in wild-type but not in knockouts, whereas the bradykinin B2-receptor antagonist HOE140 reduced writhing selectively in NEP-knockouts. Similarly, the nitric oxide synthase inhibitor L-NAME reduced writhing in NEP-knockouts. These results indicate that genetic elimination of NEP, in contrast to pharmacological inhibition, leads to bradykinin-induced hyperalgesia instead of enkephalin-mediated analgesia. Nitric oxide (NO) is suggested to be involved in this process.

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.

Enhanced excitability of small dorsal root ganglion neurons in rats with bone cancer pain

PubMed Central

2012-01-01

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

IB4(+) nociceptors mediate persistent muscle pain induced by GDNF.

PubMed

Alvarez, Pedro; Chen, Xiaojie; Bogen, Oliver; Green, Paul G; Levine, Jon D

2012-11-01

Skeletal muscle is a well-known source of glial cell line-derived neurotrophic factor (GDNF), which can produce mechanical hyperalgesia. Since some neuromuscular diseases are associated with both increased release of GDNF and intense muscle pain, we explored the role of GDNF as an endogenous mediator in muscle pain. Intramuscularly injected GDNF induced a dose-dependent (0.1-10 ng/20 μl) persistent (up to 3 wk) mechanical hyperalgesia in the rat. Once hyperalgesia subsided, injection of prostaglandin E(2) at the site induced a prolonged mechanical hyperalgesia (>72 h) compared with naïve rats (<4 h; hyperalgesic priming). Selective neurotoxic destruction of IB4(+) nociceptors attenuated both GDNF hyperalgesia and hyperalgesic priming. Ergonomic muscular injury induced by eccentric exercise or mechanical vibration increased muscle GDNF levels at 24 h, a time point where rats also exhibited marked muscle hyperalgesia. Intrathecal antisense oligodeoxynucleotides to mRNA encoding GFRα1, the canonical binding receptor for GDNF, reversibly inhibited eccentric exercise- and mechanical vibration-induced muscle hyperalgesia. Finally, electrophysiological recordings from nociceptors innervating the gastrocnemius muscle in anesthetized rats, revealed significant increase in response to sustained mechanical stimulation after local GDNF injection. In conclusion, these data indicate that GDNF plays a role as an endogenous mediator in acute and induction of chronic muscle pain, an effect likely to be produced by GDNF action at GFRα1 receptors located in IB4(+) nociceptors.

Painful purinergic receptors.

PubMed

Donnelly-Roberts, Diana; McGaraughty, Steve; Shieh, Char-Chang; Honore, Prisca; Jarvis, Michael F

2008-02-01

Multiple P2 receptor-mediated mechanisms exist by which ATP can alter nociceptive sensitivity following tissue injury. Evidence from a variety of experimental strategies, including genetic disruption studies and the development of selective antagonists, has indicated that the activation of P2X receptor subtypes, including P2X(3), P2X(2/3), P2X(4) and P2X(7), and P2Y (e.g., P2Y(2)) receptors, can modulate pain. For example, administration of a selective P2X(3) antagonist, A-317491, has been shown to effectively block both hyperalgesia and allodynia in different animal models of pathological pain. Intrathecally delivered antisense oligonucleotides targeting P2X(4) receptors decrease tactile allodynia following nerve injury. Selective antagonists for the P2X(7) receptor also reduce sensitization in animal models of inflammatory and neuropathic pain, providing evidence that purinergic glial-neural interactions are important modulators of noxious sensory neurotransmission. Furthermore, activation of P2Y(2) receptors leads to sensitization of polymodal transient receptor potential-1 receptors. Thus, ATP acting at multiple purinergic receptors, either directly on neurons (e.g., P2X(3), P2X(2/3), and P2Y receptors) or indirectly through neural-glial cell interactions (P2X(4) and P2X(7) receptors), alters nociceptive sensitivity. The development of selective antagonists for some of these P2 receptors has greatly aided investigations into the nociceptive role of ATP. This perspective highlights some of the recent advances to identify selective P2 receptor ligands, which has enhanced the investigation of ATP-related modulation of pain sensitivity.

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.

Concurrent targeting of nitrosative stress-PARP pathway corrects functional, behavioral and biochemical deficits in experimental diabetic neuropathy

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

Negi, Geeta; Kumar, Ashutosh; Sharma, Shyam S., E-mail: sssharma@niper.ac.in

2010-01-01

Peroxynitrite mediated nitrosative stress, an indisputable initiator of DNA damage and overactivation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated after sensing DNA damage, are two crucial pathogenetic mechanisms in diabetic neuropathy. The intent of the present study was to investigate the effect of combination of a peroxynitrite decomposition catalyst (PDC), FeTMPyP and a PARP inhibitor, 4-ANI against diabetic peripheral neuropathy. The end points of evaluation of the study included motor nerve conduction velocity (MNCV) and nerve blood flow (NBF) for evaluating nerve functions; thermal hyperalgesia and mechanical allodynia for assessing nociceptive alterations, malondialdehyde and peroxynitrite levels to detect oxidativemore » stress-nitrosative stress; NAD concentration in sciatic nerve to assess overactivation of PARP. Additionally immunohistochemical studies for nitrotyrosine and Poly(ADP-ribose) (PAR) was also performed. Treatment with the combination of FeTMPyP and 4-ANI led to significant improvement in nerve functions and pain parameters and also attenuated the oxidative-nitrosative stress markers. Further, the combination also reduced the overactivation of PARP as evident from increased NAD levels and decreased PAR immunopositivity in sciatic nerve microsections. Thus, it can be concluded that treatment with the combination of a PDC and PARP inhibitor attenuates alteration in peripheral nerves in diabetic neuropathy (DN).« less

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.

Identification of subgroups of patients with tension type headache with higher widespread pressure pain hyperalgesia.

PubMed

Fernández-de-Las-Peñas, César; Benito-González, Elena; Palacios-Ceña, María; Wang, Kelun; Castaldo, Matteo; Arendt-Nielsen, Lars

2017-12-01

Identification of subgroups of patients with different levels of sensitization and clinical features can help to identify groups at risk and the development of better therapeutic strategies. The aim of this study was to identify subgroups of patients with tension type headache (TTH) with different levels of sensitization, clinical pain features, and psychological outcomes. A total of 197 individuals with TTH participated. Headache intensity, frequency, and duration and medication intake were collected with a 4-weeks diary. Pressure pain thresholds were assessed bilaterally over the temporalis muscle, C5-C6 joint, second metacarpal and tibialis anterior muscle to determine widespread pressure pain hyperalgesia. The Hospital Anxiety and Depression Scale assessed anxiety and depression. The State-Trait Anxiety Inventory evaluated the state and trait levels of anxiety. The Headache Disability Inventory evaluated the burden of headache. Health-related quality of life was determined with the SF-36 questionnaire. Groups were considered as positive (three or more criteria) or negative (less than three criteria) on a clinical prediction rule: headache duration <8.5 h/day; headache frequency <5.5 days/week; bodily pain <47 and vitality <47.5. The ANCOVA revealed that subjects in group 1 (positive rule, n = 89) exhibited longer headache history, shorter headache duration, lower headache frequency, higher widespread pressure hyperalgesia, higher anxiety trait levels, and lower quality of life (all, P < 0.01) than those subjects within group 2 (negative rule, n = 108). Differences were similar between men and women. This study identified a subgroup of patients with TTH with higher sensitization, higher chronicity of headaches and worse quality of life but lower frequency and duration of headache episodes. This subgroup of individuals with TTH may need particular attention and specific therapeutic programs for avoiding potential chronification.

Antihyperalgesic Properties of Honokiol in Inflammatory Pain Models by Targeting of NF-κB and Nrf2 Signaling.

PubMed

Khalid, Sidra; Ullah, Muhammad Z; Khan, Ashraf U; Afridi, Ruqayya; Rasheed, Hina; Khan, Adnan; Ali, Hussain; Kim, Yeong S; Khan, Salman

2018-01-01

The present study investigates the possible anti-nociceptive effect of intraperitoneal (i.p.) honokiol: a phenolic compound originally isolated from Magnolia officinalis , in acute and chronic inflammatory pain models. Doses of 0.1, 5, and 10 mg/kg honokiol were administered in carrageenan induced pain and the dose (honokiol 10 mg/kg i.p.) with most significant response among behavioral tests was selected for further experiments. The i.p. administration of honokiol inhibits mechanical hyperalgesia, mechanical allodynia, and thermal hyperalgesia, without causing any apparent toxicity. To elucidate the effect of honokiol on various cytokines and antioxidant enzymes, quantitative real-time-PCR was performed to determine the expression levels of pro-inflammatory cytokines and antioxidant enzymes. It is demonstrated that honokiol significantly reduced the expression levels of tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF). Similarly, honokiol was also found to potentiate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), and heme oxygenase-1 (HO-1) levels. Additionally, honokiol significantly reduced plasma nitrite levels as compared to complete Freund's adjuvant (CFA) induced group. X-ray analysis and hematoxylin and eosin (H&E) staining of inflamed and treated paws showed that honokiol reduced the inflammation with significantly less leukocyte infiltration and soft tissue inflammation. In order to explore the possible mechanism of action of honokiol, agonists [piroxicam (5 mg/kg), tramadol (50 mg/kg), and gabapentin (5 mg/kg) i.p.] as well as antagonists [naloxone (4 mg/kg), olanzapine (10 mg/kg), and flumazenil (0.2 mg/kg) i.p.] were used to study involvement of various receptors on the anti-nociceptive effect of honokiol. The potential side effects of honokiol on muscle activity were assessed. An adverse effect testing of honokiol by liver

Interactions of Notch1 and TLR4 signaling pathways in DRG neurons of in vivo and in vitro models of diabetic neuropathy.

PubMed

Chen, Tianhua; Li, Hao; Yin, Yiting; Zhang, Yuanpin; Liu, Zhen; Liu, Huaxiang

2017-11-02

Understanding the interactions between Notch1 and toll-like receptor 4 (TLR4) signaling pathways in the development of diabetic peripheral neuropathy may lead to interpretation of the mechanisms and novel approaches for preventing diabetic neuropathic pain. In the present study, the interactions between Notch1 and TLR4 signaling pathways were investigated by using dorsal root ganglion (DRG) from diabetic neuropathic pain rats and cultured DRG neurons under high glucose challenge. The results showed that high glucose induced not only Notch1 mRNA, HES1 mRNA, and TLR4 mRNA expression, but also Notch1 intracellular domain (NICD1) and TLR4 protein expression in DRG neurons. The proportion of NICD1-immunoreactive (IR) and TLR4-IR neurons in DRG cultures was also increased after high glucose challenge. The above alterations could be partially reversed by inhibition of either Notch1 or TLR4 signaling pathway. Inhibition of either Notch1 or TLR4 signaling pathway could improve mechanical allodynia and thermal hyperalgesia thresholds. Inhibition of Notch1 or TLR4 signaling also decreased tumor necrosis factor-α (TNF-α) levels in DRG from diabetic neuropathic rats. These data imply that the interaction between Notch1 and TLR4 signaling pathways is one of the important mechanisms in the development or progression of diabetic neuropathy.

Effect of resiniferatoxin on the noxious heat threshold temperature in the rat: a novel heat allodynia model sensitive to analgesics

PubMed Central

Almási, Róbert; Pethö, Gábor; Bölcskei, Kata; Szolcsányi, János

2003-01-01

An increasing-temperature hot plate (ITHP) was introduced to measure the noxious heat threshold (45.3±0.3°C) of unrestrained rats, which was reproducible upon repeated determinations at intervals of 5 or 30 min or 1 day. Morphine, diclofenac and paracetamol caused an elevation of the noxious heat threshold following i.p. pretreatment, the minimum effective doses being 3, 10 and 200 mg kg−1, respectively. Unilateral intraplantar injection of the VR1 receptor agonist resiniferatoxin (RTX, 0.048 nmol) induced a profound drop of heat threshold to the innocuous range with a maximal effect (8–10°C drop) 5 min after RTX administration. This heat allodynia was inhibited by pretreatment with morphine, diclofenac and paracetamol, the minimum effective doses being 1, 1 and 100 mg kg−1 i.p., respectively. The long-term sensory desensitizing effect of RTX was examined by bilateral intraplantar injection (0.048 nmol per paw) which produced, after an initial threshold drop, an elevation (up to 2.9±0.5°C) of heat threshold lasting for 5 days. The VR1 receptor antagonist iodo-resiniferatoxin (I-RTX, 0.05 nmol intraplantarly) inhibited by 51% the heat threshold-lowering effect of intraplantar RTX but not α,β-methylene-ATP (0.3 μmol per paw). I-RTX (0.1 or 1 nmol per paw) failed to alter the heat threshold either acutely (5–60 min) or on the long-term (5 days). The heat threshold of VR1 receptor knockout mice was not different from that of wild-type animals (45.6±0.5 vs 45.2±0.4°C). In conclusion, the RTX-induced drop of heat threshold measured by the ITHP is a novel heat allodynia model exhibiting a high sensitivity to analgesics. PMID:12746222

Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation.

PubMed

Vincent, Lucile; Vang, Derek; Nguyen, Julia; Benson, Barbara; Lei, Jianxun; Gupta, Kalpna

2016-05-01

Sickle cell anemia is a manifestation of a single point mutation in hemoglobin, but inflammation and pain are the insignia of this disease which can start in infancy and continue throughout life. Earlier studies showed that mast cell activation contributes to neurogenic inflammation and pain in sickle mice. Morphine is the common analgesic treatment but also remains a major challenge due to its side effects and ability to activate mast cells. We, therefore, examined cannabinoid receptor-specific mechanisms to mitigate mast cell activation, neurogenic inflammation and hyperalgesia, using HbSS-BERK sickle and cannabinoid receptor-2-deleted sickle mice. We show that cannabinoids mitigate mast cell activation, inflammation and neurogenic inflammation in sickle mice via both cannabinoid receptors 1 and 2. Thus, cannabinoids influence systemic and neural mechanisms, ameliorating the disease pathobiology and hyperalgesia in sickle mice. This study provides 'proof of principle' for the potential of cannabinoid/cannabinoid receptor-based therapeutics to treat several manifestations of sickle cell anemia. Copyright© Ferrata Storti Foundation.

The influence of ictal cutaneous allodynia on the response to occipital transcutaneous electrical stimulation in chronic migraine and chronic tension-type headache: a randomized, sham-controlled study.

PubMed

Bono, F; Salvino, D; Mazza, M R; Curcio, M; Trimboli, M; Vescio, B; Quattrone, A

2015-04-01

The objective of this article is to determine whether cutaneous allodynia (CA) influences the response to treatment with occipital transcutaneous electrical stimulation (OTES) in chronic migraine (CM) and chronic tension-type headache (CTTH). One hundred and sixty consecutive patients with CM or CTTH were randomized to be treated with real or sham OTES stimulation three times a day for two consecutive weeks. All patients completed the validated 12-item allodynia symptom checklist for assessing the presence and the severity of CA during headache attack. Primary end-point was change (≥50%) in number of monthly headache-free days. There was a significant difference in the percentage of responders in the real OTES compared with sham OTES group (p <0.001). Importantly, there was not a significant change of monthly headache-free days in the allodynic patients with CM and CTTH treated both with real and sham OTES, while the number of headache-free days per month was significantly reduced in the real (86%) but not in the sham group (7%) of non-allodynic patients with CTTH and CM. Severe CA is associated with decreased response to treatment with OTES in patients with CM and CTTH. © International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Utility of different outcome measures for the nitroglycerin model of migraine in mice.

PubMed

Farkas, Sándor; Bölcskei, Kata; Markovics, Adrienn; Varga, Anita; Kis-Varga, Ágnes; Kormos, Viktória; Gaszner, Balázs; Horváth, Csilla; Tuka, Bernadett; Tajti, János; Helyes, Zsuzsanna

2016-01-01

Majority of the work for establishing nitroglycerin (NTG)-induced migraine models in animals was done in rats, though recently some studies in mice were also reported. Different special formulations of NTG were investigated in various studies; however, NTG treated groups were often compared to simple saline treated control groups. The aim of the present studies was to critically assess the utility of a panel of potential outcome measures in mice by revisiting previous findings and investigating endpoints that have not been tested in mice yet. We investigated two NTG formulations, Nitrolingual and Nitro Pohl, at an intraperitoneal dose of 10mg/kg, in comparison with relevant vehicle controls, and evaluated the following outcome measures: light aversive behaviour, cranial blood perfusion by laser Doppler imaging, number of c-Fos- and neuronal nitrogen monoxide synthase (nNOS)-immunoreactive neurons in the trigeminal nucleus caudalis (TNC) and trigeminal ganglia, thermal hyperalgesia and tactile allodynia of the hind paw and orofacial pain hypersensitivity. We could not confirm previous reports of significant NTG-induced changes in light aversion and cranial blood perfusion of mice but we observed considerable effects elicited by the vehicle of Nitrolingual. In contrast, the vehicle of Nitro Pohl was apparently inert. Increased c-Fos expression in the TNC, thermal hyperalgesia, tactile allodynia and orofacial hypersensitivity were apparently good endpoints in mice that were increased by NTG-administration. The NTG-induced increase in c-Fos expression was prevented by topiramate but not by sumatriptan treatment. However, the NTG-induced orofacial hypersensitivity was dose dependently attenuated by sumatriptan. Our results pointed to utilisable NTG formulations and outcome measures for NTG-induced migraine models in mice. Pending further cross-validation with positive and negative control drugs in these mouse models and in the human NTG models of migraine, these tests

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.

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

Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia.

PubMed

Chen, Lucy; Sein, Michael; Vo, Trang; Amhmed, Shihab; Zhang, Yi; Hilaire, Kristin St; Houghton, Mary; Mao, Jianren

2014-01-01

Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

Bradykinin B1 and B2 receptors, tumour necrosis factor α and inflammatory hyperalgesia

PubMed Central

Poole, S; Lorenzetti, B B; Cunha, J M; Cunha, F Q; Ferreira, S H

1999-01-01

The effects of BK agonists and antagonists, and other hyperalgesic/antihyperalgesic drugs were measured (3 h after injection of hyperalgesic drugs) in a model of mechanical hyperalgesia (the end-point of which was indicated by a brief apnoea, the retraction of the head and forepaws, and muscular tremor). DALBK inhibited responses to carrageenin, bradykinin, DABK, and kallidin. Responses to kallidin and DABK were inhibited by indomethacin or atenolol and abolished by the combination of indomethacin+atenolol. DALBK or HOE 140, given 30 min before, but not 2 h after, carrageenin, BK, DABK and kallidin reduced hyperalgesic responses to these agents. A small dose of DABK+a small dose of BK evoked a response similar to the response to a much larger dose of DABK or BK, given alone. Responses to BK were antagonized by HOE 140 whereas DALBK antagonized only responses to larger doses of BK. The combination of a small dose of DALBK with a small dose of HOE 140 abolished the response to BK. The hyperalgesic response to LPS (1 μg) was inhibited by DALBK or HOE 140 and abolished by DALBK+HOE 140. The hyperalgesic response to LPS (5 μg) was not antagonized by DALBK+HOE 140. These data suggest: (a) a predominant role for B2 receptors in mediating hyperalgesic responses to BK and to drugs that stimulate BK release, and (b) activation of the hyperalgesic cytokine cascade independently of both B1 and B2 receptors if the hyperalgesic stimulus is of sufficient magnitude. PMID:10188975

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.

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.

Biochemistry and neurobiology of prosaposin: a potential therapeutic neuro-effector.

PubMed

Misasi, Roberta; Hozumi, Isao; Inuzuka, Takashi; Capozzi, Antonella; Mattei, Vincenzo; Kuramoto, Yukako; Shimeno, Hiroshi; Soeda, Shinji; Azuma, Norihiro; Yamauchi, Toyoaki; Hiraiwa, Masao

2009-06-01

Prosaposin, a 66 kDa glycoprotein, was identified initially as the precursor of the sphingolipid activator proteins, saposins A-D, which are required for the enzymatic hydrolysis of certain sphingolipids by lysosomal hydrolases. While mature saposins are distributed to lysosomes, prosaposin exists in secretory body fluids and plasma membranes. In addition to its role as the precursor, prosaposin shows a variety of neurotrophic and myelinotrophic activities through a receptor-mediated mechanism. In studies in vivo, prosaposin was demonstrated to exert a variety of neuro-efficacies capable of preventing neuro-degeneration following neuro-injury and promoting the amelioration of allodynia and hyperalgesia in pain models. Collective findings indicate that prosaposin is not a simple house-keeping precursor protein; instead, it is a protein essentially required for the development and maintenance of the central and peripheral nervous systems. Accumulating evidence over the last decade has attracted interests in exploring and developing new therapeutic approaches using prosaposin for human disorders associated with neuro-degeneration. In this review we detail the structure characteristics, cell biological feature, in vivo efficacy, and neuro-therapeutic potential of prosaposin, thereby providing future prospective in clinical application of this multifunctional protein.

Geraniol promotes functional recovery and attenuates neuropathic pain in rats with spinal cord injury.

PubMed

Lv, Yan; Zhang, Liang; Li, Na; Mai, Naiken; Zhang, Yu; Pan, Shuyi

2017-12-01

Geraniol, a plant-derived monoterpene, has been extensively studied and showed a wide variety of beneficial effects. The aim of this study was to investigate the therapeutic effect of geraniol on functional recovery and neuropathic pain in rats with spinal cord injury (SCI). Rats received a clip-compression SCI and were treated with geraniol 6 h following SCI. Treatment of SCI rats with geraniol markedly improved locomotor function, and reduced sensitivity to the mechanical allodynia and thermal hyperalgesia. Treatment of SCI rats with geraniol increased NeuN-positive cells, suppressed expression of glial fibrillary acidic protein, and reduced activity of caspase-3 in the injured region. Treatment of SCI rats with geraniol reduced levels of malondialdehyde and 3-nitrotyrosine, upregulated protein expression of nuclear factor-erythroid 2-related factor 2 and heme oxygenase 1, and suppressed expression of inducible nitric oxide synthase in the injured region. In addition, treatment of SCI rats with geraniol downregulated protein expression of N-methyl-d-aspartate receptor 1 and reduced the number of CD68-positive cells and protein levels of TNF-α in the injured region. In conclusion, geraniol significantly promoted the recovery of neuronal function and attenuated neuropathic pain after SCI.

Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome

PubMed Central

Meeus, Mira

2006-01-01

In addition to the debilitating fatigue, the majority of patients with chronic fatigue syndrome (CFS) experience chronic widespread pain. These pain complaints show the greatest overlap between CFS and fibromyalgia (FM). Although the literature provides evidence for central sensitization as cause for the musculoskeletal pain in FM, in CFS this evidence is currently lacking, despite the observed similarities in both diseases. The knowledge concerning the physiological mechanism of central sensitization, the pathophysiology and the pain processing in FM, and the knowledge on the pathophysiology of CFS lead to the hypothesis that central sensitization is also responsible for the sustaining pain complaints in CFS. This hypothesis is based on the hyperalgesia and allodynia reported in CFS, on the elevated concentrations of nitric oxide presented in the blood of CFS patients, on the typical personality styles seen in CFS and on the brain abnormalities shown on brain images. To examine the present hypothesis more research is required. Further investigations could use similar protocols to those already used in studies on pain in FM like, for example, studies on temporal summation, spatial summation, the role of psychosocial aspects in chronic pain, etc. PMID:17115100

Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion.

PubMed

Mitchell, Kendall; Lebovitz, Evan E; Keller, Jason M; Mannes, Andrew J; Nemenov, Michael I; Iadarola, Michael J

2014-04-01

TRPV1 is expressed in a subpopulation of myelinated Aδ and unmyelinated C-fibers. TRPV1+ fibers are essential for the transmission of nociceptive thermal stimuli and for the establishment and maintenance of inflammatory hyperalgesia. We have previously shown that high-power, short-duration pulses from an infrared diode laser are capable of predominantly activating cutaneous TRPV1+ Aδ-fibers. Here we show that stimulating either subtype of TRPV1+ fiber in the paw during carrageenan-induced inflammation or following hind-paw incision elicits pronounced hyperalgesic responses, including prolonged paw guarding. The ultrapotent TRPV1 agonist resiniferatoxin (RTX) dose-dependently deactivates TRPV1+ fibers and blocks thermal nociceptive responses in baseline or inflamed conditions. Injecting sufficient doses of RTX peripherally renders animals unresponsive to laser stimulation even at the point of acute thermal skin damage. In contrast, Trpv1-/- mice, which are generally unresponsive to noxious thermal stimuli at lower power settings, exhibit withdrawal responses and inflammation-induced sensitization using high-power, short duration Aδ stimuli. In rats, systemic morphine suppresses paw withdrawal, inflammatory guarding, and hyperalgesia in a dose-dependent fashion using the same Aδ stimuli. The qualitative intensity of Aδ responses, the leftward shift of the stimulus-response curve, the increased guarding behaviors during carrageenan inflammation or after incision, and the reduction of Aδ responses with morphine suggest multiple roles for TRPV1+ Aδ fibers in nociceptive processes and their modulation of pathological pain conditions. Copyright © 2014. Published by Elsevier B.V.

Neuropathic ocular pain: an important yet underevaluated feature of dry eye

PubMed Central

Galor, A; Levitt, R C; Felix, E R; Martin, E R; Sarantopoulos, C D

2015-01-01

Dry eye has gained recognition as a public health problem given its prevalence, morbidity, and cost implications. Dry eye can have a variety of symptoms including blurred vision, irritation, and ocular pain. Within dry eye-associated ocular pain, some patients report transient pain whereas others complain of chronic pain. In this review, we will summarize the evidence that chronicity is more likely to occur in patients with dysfunction in their ocular sensory apparatus (ie, neuropathic ocular pain). Clinical evidence of dysfunction includes the presence of spontaneous dysesthesias, allodynia, hyperalgesia, and corneal nerve morphologic and functional abnormalities. Both peripheral and central sensitizations likely play a role in generating the noted clinical characteristics. We will further discuss how evaluating for neuropathic ocular pain may affect the treatment of dry eye-associated chronic pain. PMID:25376119

Diagnostic criteria for CRPS I: differences between patient profiles using three different diagnostic sets.

PubMed

Perez, Roberto S G M; Collins, Susan; Marinus, Johan; Zuurmond, Wouter W A; de Lange, Jaap J

2007-11-01

Complex Regional Pain Syndrome type I (CRPS I) is an illness which usually occurs due to major or minor tissue injury to the extremities. Because a unique pathophysiological mechanism for CRPS I has not yet been established, the diagnosis is based on observation and measurement of clinical symptoms and signs. In this study, a comparison was made between three sets of diagnostic criteria (the IASP, Bruehl et al. and Veldman et al.) based on patient reports and physicians' assessments of signs and symptoms associated with CRPS I, in 372 outpatients suspected of having CRPS I. Agreement between CRPS I diagnosis among the three sets was poor (kappa-range: 0.29-0.42), leading to positive CRPS I diagnoses according to Veldman et al.'s criteria in 218 cases (59%), according to the IASP in 268 cases (72%), and according to Bruehl et al. in 129 cases (35%). Significant differences in patient profiles were found between the diagnostic sets for the number of patients reporting continuing disproportionate pain, larger area affected than the initial trauma (both p<0.001), increase of symptoms due to exercise (p=0.009), edema (p=0.015), temperature asymmetry (p=0.015), hyperesthesia, allodynia (both p<0.001) and hyperalgesia (p=0.036). Similarly, significant differences emerged for physicians' observations of hyperesthesia and allodynia (both p<0.001). Highest combined values of sensitivity (SE) and specificity (SP) for the strongest cases of presence (n=108) or absence (n=62) of CRPS I were found for reported hyperesthesia (SE+SP:165%), allodynia (160%), observed color asymmetry (162%), hyperesthesia (157%), temperature asymmetry (154%) and edema (152%). The lack of agreement between the different diagnostic sets for CRPS I and the different clinical profiles that result from it may lead to different therapeutic and study populations, hampering adequate treatment and scientific development for this illness. We propose explicit reference to diagnostic criteria used in studies

Brain potentials evoked by intraepidermal electrical stimuli reflect the central sensitization of nociceptive pathways

PubMed Central

Lee, M. C.; O'Neill, J.; Dickenson, A. H.; Iannetti, G. D.

2016-01-01

Central sensitization (CS), the increased sensitivity of the central nervous system to somatosensory inputs, accounts for secondary hyperalgesia, a typical sign of several painful clinical conditions. Brain potentials elicited by mechanical punctate stimulation using flat-tip probes can provide neural correlates of CS, but their signal-to-noise ratio is limited by poor synchronization of the afferent nociceptive input. Additionally, mechanical punctate stimulation does not activate nociceptors exclusively. In contrast, low-intensity intraepidermal electrical stimulation (IES) allows selective activation of type II Aδ-mechano-heat nociceptors (II-AMHs) and elicits reproducible brain potentials. However, it is unclear whether hyperalgesia from IES occurs and coexists with secondary mechanical punctate hyperalgesia, and whether the magnitude of the electroencephalographic (EEG) responses evoked by IES within the hyperalgesic area is increased. To address these questions, we explored the modulation of the psychophysical and EEG responses to IES by intraepidermal injection of capsaicin in healthy human subjects. We obtained three main results. First, the intensity of the sensation elicited by IES was significantly increased in participants who developed robust mechanical punctate hyperalgesia after capsaicin injection (i.e., responders), indicating that hyperalgesia from IES coexists with punctate mechanical hyperalgesia. Second, the N2 peak magnitude of the EEG responses elicited by IES was significantly increased after the intraepidermal injection of capsaicin in responders only. Third, a receiver-operator characteristics analysis showed that the N2 peak amplitude is clearly predictive of the presence of CS. These findings suggest that the EEG responses elicited by IES reflect secondary hyperalgesia and therefore represent an objective correlate of CS. PMID:27098022

Non-steroidal Anti-inflammatory Drugs Attenuate Hyperalgesia and Block Upregulation of Trigeminal Ganglionic Sodium Channel 1.7 after Induction of Temporomandibular Joint Inflammation in Rats.

PubMed

Bi, Rui Yun; Ding, Yun; Gan, Ye Hua

2016-03-01

To investigate the association between the analgesic effect of non-steroidal antiinflammatory drugs (NSAIDs) and sodium channel 1.7 (Nav1.7) expression in the trigeminal ganglion (TG). Temporomandibular joint (TMJ) inflammation was induced by complete Freund's adjuvant (CFA) in female rats. Ibuprofen, diclofenac sodium and meloxicam were given intragastrically before induction of TMJ inflammation. Histopathological evaluation and scoring of TMJ inflammation was used to evaluate the level of inflammation. The head withdrawal threshold and food intake were measured to evaluate TMJ nociceptive responses. The mRNA and protein expression of trigeminal ganglionic Nav1.7 was examined using real-time polymerase chain reaction and western blot. Twenty-four hours after the injection of CFA into the TMJs, NSAIDs attenuated hyperalgesia of inflamed TMJ and simultaneously blocked inflammation-induced upregulation of Nav1.7 mRNA and protein expression in the TG. However, ibuprofen and diclofenac sodium slightly attenuated TMJ inflammation and meloxicam did not affect TMJ inflammation. Attenuation of hyperalgesia of inflamed TMJ by NSAIDs might be associated with their role in blocking upregulation of trigeminal ganglionic Nav1.7.

Joint nociceptor nerve activity and pain in an animal model of acute gout and its modulation by intra-articular hyaluronan

PubMed Central

Marcotti, Aida; Miralles, Ana; Dominguez, Eduardo; Pascual, Eliseo; Gomis, Ana; Belmonte, Carlos; de la Peña, Elvira

2018-01-01

Abstract The mechanisms whereby deposition of monosodium urate (MSU) crystals in gout activates nociceptors to induce joint pain are incompletely understood. We tried to reproduce the signs of painful gouty arthritis, injecting into the knee joint of rats suspensions containing amorphous or triclinic, needle MSU crystals. The magnitude of MSU-induced inflammation and pain behavior signs were correlated with the changes in firing frequency of spontaneous and movement-evoked nerve impulse activity recorded in single knee joint nociceptor saphenous nerve fibers. Joint swelling, mechanical and cold allodynia, and hyperalgesia appeared 3 hours after joint injection of MSU crystals. In parallel, spontaneous and movement-evoked joint nociceptor impulse activity raised significantly. Solutions containing amorphous or needle-shaped MSU crystals had similar inflammatory and electrophysiological effects. Intra-articular injection of hyaluronan (HA, Synvisc), a high-MW glycosaminoglycan present in the synovial fluid with analgesic effects in osteoarthritis, significantly reduced MSU-induced behavioral signs of pain and decreased the enhanced joint nociceptor activity. Our results support the interpretation that pain and nociceptor activation are not triggered by direct mechanical stimulation of nociceptors by MSU crystals, but are primarily caused by the release of excitatory mediators by inflammatory cells activated by MSU crystals. Intra-articular HA decreased behavioral and electrophysiological signs of pain, possibly through its viscoelastic filtering effect on the mechanical forces acting over sensitized joint sensory endings and probably also by a direct interaction of HA molecules with the transducing channels expressed in joint nociceptor terminals. PMID:29319609

Slick (Kcnt2) Sodium-Activated Potassium Channels Limit Peptidergic Nociceptor Excitability and Hyperalgesia.

PubMed

Tomasello, Danielle L; Hurley, Edward; Wrabetz, Lawrence; Bhattacharjee, Arin

2017-01-01

The Slick (Kcnt2) sodium-activated potassium (K Na ) channel is a rapidly gating and weakly voltage-dependent and sodium-dependent potassium channel with no clearly defined physiological function. Within the dorsal root ganglia (DRGs), we show Slick channels are exclusively expressed in small-sized and medium-sized calcitonin gene-related peptide (CGRP)-containing DRG neurons, and a pool of channels are localized to large dense-core vesicles (LDCV)-containing CGRP. We stimulated DRG neurons for CGRP release and found Slick channels contained within CGRP-positive LDCV translocated to the neuronal membrane. Behavioral studies in Slick knockout (KO) mice indicated increased basal heat detection and exacerbated thermal hyperalgesia compared with wild-type littermate controls during neuropathic and chronic inflammatory pain. Electrophysiologic recordings of DRG neurons from Slick KO mice revealed that Slick channels contribute to outward current, propensity to fire action potentials (APs), and to AP properties. Our data suggest that Slick channels restrain the excitability of CGRP-containing neurons, diminishing pain behavior after inflammation and injury.

The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating β-endorphin release from spinal microglia

PubMed Central

Fan, Hui; Gong, Nian; Li, Teng-Fei; Ma, Ai-Niu; Wu, Xiao-Yan; Wang, Ming-Wei; Wang, Yong-Xiang

2015-01-01

BACKGROUND AND PURPOSE Two peptide agonists of the glucagon-like peptide-1 (GLP-1) receptor, exenatide and GLP-1 itself, exert anti-hypersensitive effects in neuropathic, cancer and diabetic pain. In this study, we have assessed the anti-allodynic and anti-hyperalgesic effects of the non-peptide agonist WB4-24 in inflammatory nociception and the possible involvement of microglial β-endorphin and pro-inflammatory cytokines. EXPERIMENTAL APPROACH We used rat models of inflammatory nociception induced by formalin, carrageenan or complete Freund's adjuvant (CFA), to test mechanical allodynia and thermal hyperalgesia. Expression of β-endorphin and pro-inflammatory cytokines was measured using real-time quantitative PCR and fluorescent immunoassays. KEY RESULTS WB4-24 displaced the specific binding of exendin (9–39) in microglia. Single intrathecal injection of WB4-24 (0.3, 1, 3, 10, 30 and 100 μg) exerted dose-dependent, specific, anti-hypersensitive effects in acute and chronic inflammatory nociception induced by formalin, carrageenan and CFA, with a maximal inhibition of 60–80%. Spinal WB4-24 was not effective in altering nociceptive pain. Subcutaneous injection of WB4-24 was also antinociceptive in CFA-treated rats. WB4-24 evoked β-endorphin release but did not inhibit expression of pro-inflammatory cytokines in either the spinal cord of CFA-treated rats or cultured microglia stimulated by LPS. WB4-24 anti-allodynia was prevented by a microglial inhibitor, β-endorphin antiserum and a μ-opioid receptor antagonist. CONCLUSIONS AND IMPLICATIONS Our results suggest that WB4-24 inhibits inflammatory nociception by releasing analgesic β-endorphin rather than inhibiting the expression of proalgesic pro-inflammatory cytokines in spinal microglia, and that the spinal GLP-1 receptor is a potential target molecule for the treatment of pain hypersensitivity including inflammatory nociception. PMID:25176008

Complex Regional Pain Syndrome following an Episode of Herpes Zoster: A Case Report.

PubMed

Marrero, Christopher E; Mclean, Neuyen; Varnado, Keyana

2017-01-01

Complex regional pain syndrome (CRPS) is characterized by searing pain, hyperalgesia, edema, allodynia, and skin changes. CRPS may be difficult to diagnose and to treat given poorly understood mechanisms as well as its presentation of symptoms that may mimic common conditions such as joint stiffness in this condition as well as rheumatoid arthritis. A 71-year-old female presented to our clinic post shingles of the right upper extremity. We diagnosed her with CRPS based on the Budapest diagnostic criteria and the clinical findings of pain and decreased the range of motion along with edema, hypersensitivity, discoloration and allodynia of the right thumb and index finger. She was treated with vitamin C as well as gabapentin and physical therapy. The patient was unable to go consistently to physical therapy due to insurance limitations, and we found no clinical benefit of vitamin C in reducing her symptoms. She was lost to follow-up during her treatment but re-emerged at 21 months. At that time she reported, she was largely unchanged in regards to her right-hand symptoms but did believe the gabapentin was helpful and still continued to take 300 mg daily. This case report highlights the usefulness of the Budapest diagnostic criteria to make the diagnosis of CRPS when associated with shingles, which can cause long-term pain and mimic some findings. Prompt diagnosis is important, as recovery typically extends beyond 6 months; our patient still reported continued symptoms at 21 months post initial presentation. Our primary treatment plan was physical therapy, which she discontinued due to insurance limitations. We recommend that patients, physicians, and third-party payers work together to extend access to physical therapy. More investigation is warranted regarding symptomatic treatment, as we found limited clinical benefit of gabapentin and vitamin C.

Complex Regional Pain Syndrome following an Episode of Herpes Zoster: A Case Report

PubMed Central

Marrero, Christopher E; Mclean, Neuyen; Varnado, Keyana

2017-01-01

Introduction: Complex regional pain syndrome (CRPS) is characterized by searing pain, hyperalgesia, edema, allodynia, and skin changes. CRPS may be difficult to diagnose and to treat given poorly understood mechanisms as well as its presentation of symptoms that may mimic common conditions such as joint stiffness in this condition as well as rheumatoid arthritis. Case Report: A 71-year-old female presented to our clinic post shingles of the right upper extremity. We diagnosed her with CRPS based on the Budapest diagnostic criteria and the clinical findings of pain and decreased the range of motion along with edema, hypersensitivity, discoloration and allodynia of the right thumb and index finger. She was treated with vitamin C as well as gabapentin and physical therapy. The patient was unable to go consistently to physical therapy due to insurance limitations, and we found no clinical benefit of vitamin C in reducing her symptoms. She was lost to follow-up during her treatment but re-emerged at 21 months. At that time she reported, she was largely unchanged in regards to her right-hand symptoms but did believe the gabapentin was helpful and still continued to take 300 mg daily. Conclusion: This case report highlights the usefulness of the Budapest diagnostic criteria to make the diagnosis of CRPS when associated with shingles, which can cause long-term pain and mimic some findings. Prompt diagnosis is important, as recovery typically extends beyond 6 months; our patient still reported continued symptoms at 21 months post initial presentation. Our primary treatment plan was physical therapy, which she discontinued due to insurance limitations. We recommend that patients, physicians, and third-party payers work together to extend access to physical therapy. More investigation is warranted regarding symptomatic treatment, as we found limited clinical benefit of gabapentin and vitamin C. PMID:28819596

Brain potentials evoked by intraepidermal electrical stimuli reflect the central sensitization of nociceptive pathways.

PubMed

Liang, M; Lee, M C; O'Neill, J; Dickenson, A H; Iannetti, G D

2016-08-01

Central sensitization (CS), the increased sensitivity of the central nervous system to somatosensory inputs, accounts for secondary hyperalgesia, a typical sign of several painful clinical conditions. Brain potentials elicited by mechanical punctate stimulation using flat-tip probes can provide neural correlates of CS, but their signal-to-noise ratio is limited by poor synchronization of the afferent nociceptive input. Additionally, mechanical punctate stimulation does not activate nociceptors exclusively. In contrast, low-intensity intraepidermal electrical stimulation (IES) allows selective activation of type II Aδ-mechano-heat nociceptors (II-AMHs) and elicits reproducible brain potentials. However, it is unclear whether hyperalgesia from IES occurs and coexists with secondary mechanical punctate hyperalgesia, and whether the magnitude of the electroencephalographic (EEG) responses evoked by IES within the hyperalgesic area is increased. To address these questions, we explored the modulation of the psychophysical and EEG responses to IES by intraepidermal injection of capsaicin in healthy human subjects. We obtained three main results. First, the intensity of the sensation elicited by IES was significantly increased in participants who developed robust mechanical punctate hyperalgesia after capsaicin injection (i.e., responders), indicating that hyperalgesia from IES coexists with punctate mechanical hyperalgesia. Second, the N2 peak magnitude of the EEG responses elicited by IES was significantly increased after the intraepidermal injection of capsaicin in responders only. Third, a receiver-operator characteristics analysis showed that the N2 peak amplitude is clearly predictive of the presence of CS. These findings suggest that the EEG responses elicited by IES reflect secondary hyperalgesia and therefore represent an objective correlate of CS. Copyright © 2016 the American Physiological Society.

Osthole ameliorates neurogenic and inflammatory hyperalgesia by modulation of iNOS, COX-2, and inflammatory cytokines in mice.

PubMed

Singh, Gurjit; Bhatti, Rajbir; Mannan, Rahul; Singh, Drishtant; Kesavan, Anup; Singh, Palwinder

2018-05-07

Osthole is a bioactive component reported in medicinal plants such as Angelica pubescens and Cnidium monnieri, known for analgesic activity. However, the toxicity, median effective dose (ED 50 ), and dual modulation of nitric oxide and cyclooxygenase pathways along with inflammatory cytokines of osthole are yet to be determined. The animals (mice) were assessed for general behaviour and mortality in varying doses (50, 300, and 2000 mg kg -1 ) of osthole for acute toxicity over 14 days. The analgesic activity was investigated using acetic acid and formalin-induced hyperalgesia, and anti-inflammatory activity was explored in carrageenan-induced paw oedema. ED 50 of osthole was calculated using Design Expert software. Involvement of nitric oxide and cyclooxygenase pathways was investigated by agonist challenges with L-arginine and substance P, respectively. The expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was determined in spinal sections by immunohistochemical analysis. Lipopolysaccharide (LPS) challenge was used to assess in vivo effect on inflammatory cytokines (TNFα and IL-6). Acute toxicity studies revealed no behavioural abnormality or mortality on osthole treatment and unremarkable histological findings. Osthole was found to significantly decrease acetic acid and formalin-induced hyperalgesia (ED 50  = 5.43 mg kg -1 ) and carrageenan-induced paw oedema with no toxicity symptoms. Osthole produced a marked decrease in iNOS and COX-2 expression as well as TNFα and IL-6. The findings corroborate to modulation of iNOS and COX-2 and inflammatory cytokines by osthole. This study provides promising insights and prospects for application of osthole in pain management.

Diabetes-induced microvascular complications at the level of the spinal cord; a contributing factor in diabetic neuropathic pain.

PubMed

Ved, N; Da Vitoria Lobo, M E; Bestall, S M; L Vidueira, C; Beazley-Long, N; Ballmer-Hofer, K; Hirashima, M; Bates, D O; Donaldson, L F; Hulse, R P

2018-05-17

Abnormalities of neurovascular interactions within the central nervous system of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investigated despite neuropathic pain being common in diabetes. We hypothesised that hyperglycaemia-induced endothelial degeneration in the spinal cord, due to suppression of VEGF-A/VEGFR2 signalling, induces diabetic neuropathic pain. Nociceptive pain behaviour was investigated in a chemically induced model of type 1 diabetes (streptozotocin induced, insulin supplemented; either vehicle or VEGF-A 165 b treated) and an inducible endothelial knockdown of VEGFR2 (tamoxifen induced). Diabetic animals developed mechanical allodynia and heat hyperalgesia. This was associated with a reduction in the number of blood vessels and reduction in Evans blue extravasation in the lumbar spinal cord of diabetic animals versus age-matched controls. Endothelial markers occludin, CD31 and VE-cadherin were downregulated in the spinal cord of the diabetic group versus controls, as well as a concurrent reduction of VEGF-A 165 b expression. In diabetic animals, VEGF-A 165 b treatment (biweekly intraperitoneal, 20 ng g -1 ) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes-induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreER T2 -vegfr2 flfl mice) led to a reduction in blood vessel network volume in the lumbar spinal cord and development of heat hyperalgesia. These findings indicate that hyperglycaemia leads to a reduction in the VEGF-A/VEGFR2 signalling cascade resulting in endothelial dysfunction in the spinal cord, which could be an undiscovered contributing factor to diabetic neuropathic pain. This article is protected by copyright. All rights reserved. This article is protected by copyright. All

Reduced laser-evoked potential habituation detects abnormal central pain processing in painful radiculopathy patients.

PubMed

Hüllemann, P; von der Brelie, C; Manthey, G; Düsterhöft, J; Helmers, A K; Synowitz, M; Baron, R

2017-05-01

Repetitive painful laser stimuli lead to physiological laser-evoked potential (LEP) habituation, measurable by a decrement of the N2/P2 amplitude. The time course of LEP-habituation is reduced in the capsaicin model for peripheral and central sensitization and in patients with migraine and fibromyalgia. In the present investigation, we aimed to assess the time course of LEP-habituation in a neuropathic pain syndrome, i.e. painful radiculopathy. At the side of radiating pain, four blocks of 25 painful laser stimuli each were applied to the ventral thigh at the L3 dermatome in 27 patients with painful radiculopathy. Inclusion criteria were (1) at least one neurological finding of radiculopathy, (2) low back pain with radiation into the foot and (3) a positive one-sided compression of the L5 and/or S1 root in the MRI. The time course of LEP-habituation was compared to 20 healthy height and age matched controls. Signs of peripheral (heat hyperalgesia) and central sensitization (dynamic mechanical allodynia and hyperalgesia) at the affected L5 or S1 dermatome were assessed with quantitative sensory testing. Painful radiculopathy patients showed decreased LEP-habituation compared to controls. Patients with signs of central sensitization showed a more prominent LEP-habituation decrease within the radiculopathy patient group. Laser-evoked potential habituation is reduced in painful radiculopathy patients, which indicates an abnormal central pain processing. Central sensitization seems to be a major contributor to abnormal LEP habituation. The LEP habituation paradigm might be useful as a clinical tool to assess central pain processing alterations in nociceptive and neuropathic pain conditions. Abnormal central pain processing in neuropathic pain conditions may be revealed with the laser-evoked potential habituation paradigm. In painful radiculopathy patients, LEP-habituation is reduced compared to healthy controls. © 2017 European Pain Federation - EFIC®.

Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats.

PubMed

Rahn, Elizabeth J; Zvonok, Alexander M; Thakur, Ganesh A; Khanolkar, Atmaram D; Makriyannis, Alexandros; Hohmann, Andrea G

2008-11-01

Activation of cannabinoid CB(2) receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB(2) receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the antitumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p./day) on 4 alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the Cremophor EL/ethanol/saline vehicle at the same times. Two structurally distinct cannabinoid CB(2) agonists, the aminoalkylindole (R,S)-AM1241 [(R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone] and the cannabilactone AM1714 (1,9-dihydroxy-3-(1',1'-dimethylheptyl)-6H-benzo[c]chromene-6-one), produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia after systemic administration. Pretreatment with the CB(2) antagonist SR144528 [5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide], but not the CB(1) antagonist SR141716 [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide], blocked the antiallodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or preinjection thresholds, consistent with mediation by CB(2). Administration of either the CB(1) or CB(2) antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the Cremophor EL vehicle in lieu of paclitaxel, whereas AM

Anti-nociceptive and anti-inflammatory actions of sulforaphane in chronic constriction injury-induced neuropathic pain mice.

PubMed

Wang, Cheng; Wang, Congpin

2017-02-01

Neuropathic pain is still considered as incurable disease as current therapies are not ideal in terms of efficacy and tolerability. It is imperative to search for novel drugs to obtain better treatments. Sulforaphane (SFN), a derivative of glucoraphanin present in cruciferous vegetables, exhibits therapeutic effects on inflammation-related diseases. Since inflammation plays an important role in regulating chronic pain, in the present study, we investigated anti-nociceptive effects of SFN and its underlying mechanisms in a neuropathic pain mouse model, sciatic nerve chronic constriction injury (CCI). SFN (0.1-100 mg/kg) was injected intraperitoneally for 7 days when pain behaviors, including mechanical allodynia and thermal hyperalgesia, reached to the maximum in CCI mice. We observed that SFN dose-dependently attenuated CCI-induced pain behavioral hypersensitivity, accompanied by reduction in pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and upregulation of an anti-inflammatory cytokine (IL-10). Moreover, SFN counteracted CCI enhancement of COX2 and iNOS in injured nerves, two key enzymes implicated in inflammation and neuropathic pain. Furthermore, pretreatment of naloxone, an antagonist of opioid receptors, significantly blocked SFN attenuation of behavioral hypersensitivity without affecting SFN modulation of inflammatory cytokines in CCI mice. Interestingly, CCI-induced increase in µ-opioid receptors in injured sciatic nerves was further increased by SFN treatment. Taken together, SFN has both anti-nociceptive and anti-inflammatory actions.

Berberine Ameliorates Diabetic Neuropathy: TRPV1 Modulation by PKC Pathway.

PubMed

Zan, Yan; Kuai, Cui-Xing; Qiu, Zhi-Xia; Huang, Fang

2017-01-01

In recent years, berberine has increasingly become a topic of research as a treatment for diabetes due to its repair function, which recovers damaged pancreatic β cells. However, it is the complications of diabetes that seriously affect patients' life quality and longevity, among which diabetic neuropathy and the consequent acute pain are the most common. In this study, we established STZ-induced diabetic models to observe whether berberine, a main constitute of Coptis chinensis Franch which has shown good hypoglycemic effects, could relieve diabetes-induced pain and explored its possible mechanism in rats and mice. Behavior assays showed increasing mechanical allodynia and thermal hyperalgesia thresholds by the Von Frey test and tail flick test during the treatment of berberine. It was found that the administration of berberine (20, 60 mg/kg; 30, 90 mg/kg) suppressed the expression of PKCε and TRPV1 which could be activated by hyperglycemia-induced inflammatory reaction. Our results also presented its capability to reduce the over expression of TNF-[Formula: see text] in diabetic rats and mice. TNF-[Formula: see text] is an inflammatory cytokine, which is closely related to diabetic peripheral neuropathy (DPN). Consequently, we supposed that berberine exerts its therapeutic effects in part by suppressing the inflammatory process and blocking the PKC pathway to inhibit TRPV1 activation, which damages neurons and causes diabetic pain.

Massaging over the greater occipital nerve reduces the intensity of migraine attacks: evidence for inhibitory trigemino-cervical convergence mechanisms.

PubMed

Piovesan, Elcio Juliato; Di Stani, Fabrizio; Kowacs, Pedro André; Mulinari, Rogério Andrade; Radunz, Victor Hugo; Utiumi, Marco; Muranka, Eder B; Giublin, Mario Luiz; Werneck, Lineu César

2007-09-01

Activation of the trigemino-cervical system constitutes one of the first steps in the genesis of migraine. The objective of this study was to confirm the presence of trigemino-cervical convergence mechanisms and to establish whether such mechanisms may also be of inhibitory origin. We describe a case of a 39-years-old woman suffering from episodic migraine who showed a significant improvement in her frontal headache during migraine attacks if the greater occipital nerve territory was massaged after the appearance of static mechanical allodynia (cortical sensitization). We review trigemino-cervical convergence and diffuse nociceptive inhibitory control (DNIC) mechanisms and suggest that the convergence mechanisms are not only excitatory but also inhibitory.

MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain

PubMed Central

Sakai, Atsushi; Saitow, Fumihito; Maruyama, Motoyo; Miyake, Noriko; Miyake, Koichi; Shimada, Takashi; Okada, Takashi; Suzuki, Hidenori

2017-01-01

miR-17-92 is a microRNA cluster with six distinct members. Here, we show that the miR-17-92 cluster and its individual members modulate chronic neuropathic pain. All cluster members are persistently upregulated in primary sensory neurons after nerve injury. Overexpression of miR-18a, miR-19a, miR-19b and miR-92a cluster members elicits mechanical allodynia in rats, while their blockade alleviates mechanical allodynia in a rat model of neuropathic pain. Plausible targets for the miR-17-92 cluster include genes encoding numerous voltage-gated potassium channels and their modulatory subunits. Single-cell analysis reveals extensive co-expression of miR-17-92 cluster and its predicted targets in primary sensory neurons. miR-17-92 downregulates the expression of potassium channels, and reduced outward potassium currents, in particular A-type currents. Combined application of potassium channel modulators synergistically alleviates mechanical allodynia induced by nerve injury or miR-17-92 overexpression. miR-17-92 cluster appears to cooperatively regulate the function of multiple voltage-gated potassium channel subunits, perpetuating mechanical allodynia. PMID:28677679

Involvement of transient receptor potential vanilloid 2 in intra-oral incisional pain.

PubMed

Urata, K; Shinoda, M; Ikutame, D; Iinuma, T; Iwata, K

2018-03-05

To examine whether transient receptor potential vanilloid 2 (TRPV2) contributes to the changes in intra-oral thermal and mechanical sensitivity following the incision of buccal mucosa. Buccal mucosal pain threshold was measured after the incision. Changes in the number of TRPV2-immunoreactive (IR) trigeminal ganglion (TG) neurons which innervate the whisker pad skin and buccal mucosa, changes in the number of isolectin B4-negative/isolectin B4-positive TRPV2-IR TG neurons which innervate the whisker pad skin and the buccal mucosa, and the effect of peripheral TRPV2 antagonism on the pain threshold of incisional whisker pad skin and buccal mucosa were examined after these injuries. Buccal mucosal pain hypersensitivities were induced on day 3 following the incision. The total number of TRPV2-IR TG neurons and the number of isolectin B4-negative TRPV2-IR TG neurons which innervate the whisker pad skin and buccal mucosa were increased. Buccal mucosal TRPV2 antagonism completely suppressed the heat and mechanical hypersensitivities, but not cold hypersensitivity. TRPV2 antagonist administration to the incisional whisker pad skin only partially suppressed pain hypersensitivities. The increased expression of TRPV2 in peptidergic TG neurons innervating the incisional buccal mucosa is predominantly involved in buccal mucosal heat hyperalgesia and mechanical allodynia following buccal mucosal incision. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.

Carbonic Anhydrase-8 Regulates Inflammatory Pain by Inhibiting the ITPR1-Cytosolic Free Calcium Pathway

PubMed Central

Zhuang, Gerald Z.; Keeler, Benjamin; Grant, Jeff; Bianchi, Laura; Fu, Eugene S.; Zhang, Yan Ping; Erasso, Diana M.; Cui, Jian-Guo; Wiltshire, Tim; Li, Qiongzhen; Hao, Shuanglin; Sarantopoulos, Konstantinos D.; Candiotti, Keith; Wishnek, Sarah M.; Smith, Shad B.; Maixner, William; Diatchenko, Luda; Martin, Eden R.; Levitt, Roy C.

2015-01-01

Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntington’s disease, Alzheimer’s, spinal cerebellar ataxia (SCA) and chronic pain. Carbonic anhydrase-8 (Car8) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release, mitochondrial energy production and cell fate. In this report we test the hypothesis that Car8 regulation of ITPR1 and cytoplasmic free calcium release is critical to nociception and pain behaviors. We show Car8 null mutant mice (MT) exhibit mechanical allodynia and thermal hyperalgesia. Dorsal root ganglia (DRG) from MT also demonstrate increased steady-state ITPR1 phosphorylation (pITPR1) and cytoplasmic free calcium release. Overexpression of Car8 wildtype protein in MT nociceptors complements Car8 deficiency, down regulates pITPR1 and abolishes thermal and mechanical hypersensitivity. We also show that Car8 nociceptor overexpression alleviates chronic inflammatory pain. Finally, inflammation results in downregulation of DRG Car8 that is associated with increased pITPR1 expression relative to ITPR1, suggesting a possible mechanism of acute hypersensitivity. Our findings indicate Car8 regulates the ITPR1-cytosolic free calcium pathway that is critical to nociception, inflammatory pain and possibly other neuropathological states. Car8 and ITPR1 represent new therapeutic targets for chronic pain. PMID:25734498

Fibromyalgia: Prevalence, epidemiologic profiles and economic costs.

PubMed

Cabo-Meseguer, Asensi; Cerdá-Olmedo, Germán; Trillo-Mata, José Luis

2017-11-22

Fibromyalgia is an idiopathic chronic condition that causes widespread musculoskeletal pain, hyperalgesia and allodynia. This review aims to approach the general epidemiology of fibromyalgia according to the most recent published studies, identifying the general worldwide prevalence of the disease, its basic epidemiological profiles and its economic costs, with specific interest in the Spanish and Comunidad Valenciana cases. Fibromyalgia affects, on average, 2.10% of the world's population; 2.31% of the European population; 2.40% of the Spanish population; and 3.69% of the population in the Comunidad Valenciana. It supposes a painful loss of the quality of life of the people who suffer it and the economic costs are enormous: in Spain is has been estimated at more than 12,993 million euros annually. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

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.

Effect of agmatine on acute and mononeuropathic pain.

PubMed

Aricioglu, Feyza; Korcegez, Eylem; Bozkurt, Ayhan; Ozyalcin, Suleyman

2003-12-01

Agmatine is a polycationic amine synthesized from L-arginine by arginine decarboxylase in brain and several tissues. It binds to N-methyl-D-aspartate (NMDA) subtype of glutamatergic, alpha(2)-adrenergic and imidazoline (I) receptors. The present study was designed to investigate effect of agmatine on acute and mononeuropathic pain after chronic constriction injury (CCI). CCI was created by four loose ligations around the right sciatic nerve. The analgesic threshold in rats was evaluated by using thermal hyperalgesia/allodynia (THA) at 4 degrees C. The evaluations were made preoperatively, on postoperative day 15, and after drug administration. Agmatine (10, 20, 40, 80, and 100 mg/kg) was administered intraperitoneally for 5 days beginning on postoperative day 15. Agmatine significantly reduced the hyperalgesia in all doses applied. When agmatine was injected intraperitoneally (10, 20, 40, 80, and 100 mg/kg), it increased the nociceptive threshold in the tail-immersion test in a dose-dependent manner, but it had no effect in the hot-plate test. This effect of agmatine in the tail-immersion test was blocked by both yohimbine (1 mg/kg) and idazoxan (0.5 mg/kg). When agmatine was administered intracerebroventricularly (25-200 microg/10 microL), it increased the nociceptive threshold in the hot-plate but not in the tail-immersion test. We conclude that agmatine, an endogenous substance derived from arginine, can modulate both acute and chronic pain.

[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.

Involvement of MrgprC in Electroacupuncture Analgesia for Attenuating CFA-Induced Thermal Hyperalgesia by Suppressing the TRPV1 Pathway.

PubMed

Liu, Ying-Jun; Lin, Xiao-Xi; Fang, Jian-Qiao; Fang, Fang

2018-01-01

Mas-related G-protein-coupled receptor C (MrgprC) plays an important role in modulating chronic inflammatory pain. Electroacupuncture (EA) has a satisfactory analgesic effect on chronic pain. This study aimed to investigate the involvement of MrgprC and its transient receptor potential vanilloid 1 (TRPV1) pathway in EA analgesia in chronic inflammatory pain. Chronic inflammatory pain was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the left hind paw. EA (2/100 Hz) stimulation was administered. MrgprC siRNAs were intrathecally administered to inhibit MrgprC expression, and bovine adrenal medulla 8-22 (BAM8-22) was used to activate MrgprC. The mechanical allodynia was decreased by EA significantly since day 3. The piled analgesic effect of EA was partially blocked by 6 intrathecal administrations of MrgprC siRNA. Both EA and BAM8-22 could downregulate the expression of TRPV1 and PKC in both the DRG and the SCDH. Both EA and BAM8-22 could also decrease the TRPV1 translocation and p-TRPV1 level in both the DRG and the SCDH. The effects of EA on PKC ε , TRPV1 translocation, and p-TRPV1 in both the DRG and the SCDH were reversed by MrgprC siRNA. The results indicated that MrgprC played crucial roles in chronic pain modulation and was involved in EA analgesia partially through the regulation of TRPV1 function at the DRG and SCDH levels.

Multimodal pain stimulation of the gastrointestinal tract

PubMed Central

Drewes, Asbjørn Mohr; Gregersen, Hans

2006-01-01

Understanding and characterization of pain and other sensory symptoms are among the most important issues in the diagnosis and assessment of patient with gastrointestinal disorders. Methods to evoke and assess experimental pain have recently developed into a new area with the possibility for multimodal stimulation (e.g., electrical, mechanical, thermal and chemical stimulation) of different nerves and pain pathways in the human gut. Such methods mimic to a high degree the pain experienced in the clinic. Multimodal pain methods have increased our basic understanding of different peripheral receptors in the gut in health and disease. Together with advanced muscle analysis, the methods have increased our understanding of receptors sensitive to mechanical, chemical and temperature stimuli in diseases, such as systemic sclerosis and diabetes. The methods can also be used to unravel central pain mechanisms, such as those involved in allodynia, hyperalgesia and referred pain. Abnormalities in central pain mechanisms are often seen in patients with chronic gut pain and hence methods relying on multimodal pain stimulation may help to understand the symptoms in these patients. Sex differences have been observed in several diseases of the gut, and differences in central pain processing between males and females have been hypothesized using multimodal pain stimulations. Finally, multimodal methods have recently been used to gain more insight into the effect of drugs against pain in the GI tract. Hence, the multimodal methods undoubtedly represents a major step forward in the future characterization and treatment of patients with various diseases of the gut. PMID:16688791

Peripheral substance P and neurokinin-1 receptors have a role in inflammatory and neuropathic orofacial pain models.

PubMed

Teodoro, Fernanda C; Tronco Júnior, Marcos F; Zampronio, Aleksander R; Martini, Alessandra C; Rae, Giles A; Chichorro, Juliana G

2013-06-01

There is accumulating evidence that substance P released from peripheral sensory neurons participates in inflammatory and neuropathic pain. In this study it was investigated the ability of substance P to induce orofacial nociception and thermal and mechanical hyperalgesia, as well as the role of NK1 receptors on models of orofacial inflammatory and neuropathic pain. Substance P injected into the upper lip at 1, 10 and 100 μg/50 μL failed to induce nociceptive behavior. Also, substance P (0.1-10 μg/50 μL) injected into the upper lip did not evoke orofacial cold hyperalgesia and when injected at 1 μg/50 μL did not induce mechanical hyperalgesia. However, substance P at this latter dose induced orofacial heat hyperalgesia, which was reduced by the pre-treatment of rats with a non-peptide NK1 receptor antagonist (SR140333B, 3mg/kg). Systemic treatment with SR140333B (3 mg/kg) also reduced carrageenan-induced heat hyperalgesia, but did not exert any influence on carrageenan-induced cold hyperalgesia. Blockade of NK1 receptors with SR140333B also reduced by about 50% both phases of the formalin response evaluated in the orofacial region. Moreover, heat, but not cold or mechanical, hyperalgesia induced by constriction of the infraorbital nerve, a model of trigeminal neuropathic pain, was abolished by pretreatment with SR140333B. Considering that substance P was peripherally injected (i.e. upper lip) and the NK1 antagonist used lacks the ability to cross the blood-brain-barrier, our results demonstrate that the peripheral SP/NK1 system participates in the heat hyperalgesia associated with inflammation or nerve injury and in the persistent pain evoked by formalin in the orofacial region. Copyright © 2012 Elsevier Ltd. All rights reserved.

FK1706, a novel non-immunosuppressive immunophilin ligand, modifies gene expression in the dorsal root ganglia during painful diabetic neuropathy.

PubMed

Yamazaki, Shunji; Yamaji, Takayuki; Murai, Nobuhito; Yamamoto, Hiroko; Matsuda, Takashi; Price, Raymond Daniel; Matsuoka, Nobuya

2012-06-01

FK1706, a non-immunosuppressive immunophilin ligand, potentiated nerve growth factor-induced neurite outgrowth, putatively mediated via FKBP-52 and the Ras/Raf/MAPK signaling pathway. It also improved mechanical allodynia accompanied by the recovery of intraepidermal nerve fiber density in a painful diabetic neuropathy in rats. The aim of this study was to demonstrate the gene expression profiling in dorsal root ganglion in streptozotocin-induced diabetic rats related to pain and anti-allodynia effects of FK1706 administration to elucidate the putative mechanisms of its neurotrophic activity in vivo. Here, we analyzed gene expression of the dorsal root ganglia using microarray together with behavioral measurement of mechanical allodynia in diabetic rats to try to capture the global fingerprint of changes in gene expression associated with FK1706 administration. The withdrawal threshold of streptozotocin-induced diabetic rats was measured by an electronic von Frey system. The gene expression of the ganglia from L4 to L6 obtained from streptozotocin-treated rats with or without chronic administration of FK1706 was analyzed using an Affymetrix GeneChip to extract interesting genes in the development of mechanical allodynia in diabetes and anti-allodynia effect of FK1706. Daily oral administration of FK1706 improved mechanical allodynia without decreasing plasma glucose levels. From gene expression analysis, the expression of thioredoxin interacting protein gene was sustained to increased change, whereas those of collagen I alpha1, II alpha1 and IX alpha1 genes were decreased from 2 to 4 weeks after streptozotocin injection. While no changes occurred after 1 week of commencing of FK1706 administration (2 weeks after streptozotocin injection), changes in expression more than 1.5-fold were observed for genes such as Ckm, Actn3, Atp2a1, Bglap, Acta1, Myl1, Tnnc2, and Mylpf at 2 weeks of FK1706 administration (3 weeks after streptozotocin injection). The genes RGD1564519

Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause Toll-like receptor 4 activation and enhanced pain

PubMed Central

Lewis, Susannah S.; Hutchinson, Mark R.; Zhang, Yingning; Hund, Dana K.; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R.

2013-01-01

We have previously observed that the non-opioid morphine metabolite, morphine-3-glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3-glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects. PMID:23348028

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

Ameliorative potential of Vernonia cinerea on chronic constriction injury of sciatic nerve induced neuropathic pain in rats.

PubMed

Thiagarajan, Venkata R K; Shanmugam, Palanichamy; Krishnan, Uma M; Muthuraman, Arunachalam

2014-08-29

The aim of the present study is to investigate the ameliorative potential of ethanolic extract of whole plant of Vernonia cinerea in the chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Behavioral parameters such as a hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal, chemical and mechanical hyperalgesia and allodynia. Biochemical changes in sciatic nerve tissue were ruled out by estimating thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total calcium levels. Ethanolic extract of Vernonia cinerea and pregabalin were administered for 14 consecutive days starting from the day of surgery. CCI of sciatic nerve has been shown to induce significant changes in behavioral, biochemical and histopathological assessments when compared to the sham control group. Vernonia cinerea attenuated in a dose dependent manner the above pathological changes induced by CCI of the sciatic nerve, which is similar to attenuation of the pregabalin pretreated group. The ameliorating effect of ethanolic extract of Vernonia cinerea against CCI of sciatic nerve induced neuropathic pain may be due to the presence of flavonoids and this effect is attributed to anti-oxidative, neuroprotective and calcium channel modulator actions of these compounds.

Ameliorative potential of Vernonia cinerea on chronic constriction injury of sciatic nerve induced neuropathic pain in rats.

PubMed

Thiagarajan, Venkata R K; Shanmugam, Palanichamy; Krishnan, Uma M; Muthuraman, Arunachalam

2014-09-01

The aim of the present study is to investigate the ameliorative potential of ethanolic extract of whole plant of Vernonia cinerea in the chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Behavioral parameters such as a hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal, chemical and mechanical hyperalgesia and allodynia. Biochemical changes in sciatic nerve tissue were ruled out by estimating thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total calcium levels. Ethanolic extract of Vernonia cinerea and pregabalin were administered for 14 consecutive days starting from the day of surgery. CCI of sciatic nerve has been shown to induce significant changes in behavioral, biochemical and histopathological assessments when compared to the sham control group. Vernonia cinerea attenuated in a dose dependent manner the above pathological changes induced by CCI of the sciatic nerve, which is similar to attenuation of the pregabalin pretreated group. The ameliorating effect of ethanolic extract of Vernonia cinerea against CCI of sciatic nerve induced neuropathic pain may be due to the presence of flavonoids and this effect is attributed to anti-oxidative, neuroprotective and calcium channel modulator actions of these compounds.

Loss of central inhibition: implications for behavioral hypersensitivity after contusive spinal cord injury in rats.

PubMed

Berrocal, Yerko A; Almeida, Vania W; Puentes, Rocio; Knott, Eric P; Hechtman, Jaclyn F; Garland, Mary; Pearse, Damien D

2014-01-01

Behavioral hypersensitivity is common following spinal cord injury (SCI), producing significant discomfort and often developing into chronic pain syndromes. While the mechanisms underlying the development of behavioral hypersensitivity after SCI are poorly understood, previous studies of SCI contusion have shown an increase in amino acids, namely, aspartate and glutamate, along with a decrease in GABA and glycine, particularly below the injury. The current study sought to identify alterations in key enzymes and receptors involved in mediating central inhibition via GABA and glycine after a clinically-relevant contusion SCI model. Following thoracic (T8) 25.0 mm NYU contusion SCI in rodents, significant and persistent behavioral hypersensitivity developed as evidenced by cutaneous allodynia and thermal hyperalgesia. Biochemical analyses confirmed upregulation of glutamate receptor GluR3 with downregulation of the GABA synthesizing enzyme (GAD65/67) and the glycine receptor α3 (GLRA3), notably below the injury. Combined, these changes result in the disinhibition of excitatory impulses and contribute to behavioral hyperexcitability. This study demonstrates a loss of central inhibition and the development of behavioral hypersensitivity in a contusive SCI paradigm. Future use of this model will permit the evaluation of different antinociceptive strategies and help in the elucidation of new targets for the treatment of neuropathic pain.

Loss of Central Inhibition: Implications for Behavioral Hypersensitivity after Contusive Spinal Cord Injury in Rats

PubMed Central

Berrocal, Yerko A.; Almeida, Vania W.; Puentes, Rocio; Knott, Eric P.; Hechtman, Jaclyn F.; Pearse, Damien D.

2014-01-01

Behavioral hypersensitivity is common following spinal cord injury (SCI), producing significant discomfort and often developing into chronic pain syndromes. While the mechanisms underlying the development of behavioral hypersensitivity after SCI are poorly understood, previous studies of SCI contusion have shown an increase in amino acids, namely, aspartate and glutamate, along with a decrease in GABA and glycine, particularly below the injury. The current study sought to identify alterations in key enzymes and receptors involved in mediating central inhibition via GABA and glycine after a clinically-relevant contusion SCI model. Following thoracic (T8) 25.0 mm NYU contusion SCI in rodents, significant and persistent behavioral hypersensitivity developed as evidenced by cutaneous allodynia and thermal hyperalgesia. Biochemical analyses confirmed upregulation of glutamate receptor GluR3 with downregulation of the GABA synthesizing enzyme (GAD65/67) and the glycine receptor α3 (GLRA3), notably below the injury. Combined, these changes result in the disinhibition of excitatory impulses and contribute to behavioral hyperexcitability. This study demonstrates a loss of central inhibition and the development of behavioral hypersensitivity in a contusive SCI paradigm. Future use of this model will permit the evaluation of different antinociceptive strategies and help in the elucidation of new targets for the treatment of neuropathic pain. PMID:25180088

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.

Effects of Listening to Music versus Environmental Sounds in Passive and Active Situations on Levels of Pain and Fatigue in Fibromyalgia.

PubMed

Mercadíe, Lolita; Mick, Gérard; Guétin, Stéphane; Bigand, Emmanuel

2015-10-01

In fibromyalgia, pain symptoms such as hyperalgesia and allodynia are associated with fatigue. Mechanisms underlying such symptoms can be modulated by listening to pleasant music. We expected that listening to music, because of its emotional impact, would have a greater modulating effect on the perception of pain and fatigue in patients with fibromyalgia than listening to nonmusical sounds. To investigate this hypothesis, we carried out a 4-week study in which patients with fibromyalgia listened to either preselected musical pieces or environmental sounds when they experienced pain in active (while carrying out a physical activity) or passive (at rest) situations. Concomitant changes of pain and fatigue levels were evaluated. When patients listened to music or environmental sounds at rest, pain and fatigue levels were significantly reduced after 20 minutes of listening, with no difference of effect magnitude between the two stimuli. This improvement persisted 10 minutes after the end of the listening session. In active situations, pain did not increase in presence of the two stimuli. Contrary to our expectations, music and environmental sounds produced a similar relieving effect on pain and fatigue, with no benefit gained by listening to pleasant music over environmental sounds. Copyright © 2015 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Selective Activation of Cannabinoid CB2 Receptors Suppresses Neuropathic Nociception Induced by Treatment with the Chemotherapeutic Agent Paclitaxel in Rats

PubMed Central

Rahn, Elizabeth J.; Zvonok, Alexander M.; Thakur, Ganesh A.; Khanolkar, Atmaram D.; Makriyannis, Alexandros; Hohmann, Andrea G.

2009-01-01

Activation of cannabinoid CB2 receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB2 receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the anti-tumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p. per day) on four alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the cremophor: ethanol: saline vehicle at the same times. Two structurally distinct cannabinoid CB2 agonists—the aminoalkylindole (R,S)-AM1241 ((R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone) and the cannabilactone AM1714 (1,9-dihydroxy-3-(1′,1′-dimethylheptyl)-6H-benzo[c]chromene-6-one)—produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia following systemic administration. Pretreatment with the CB2 antagonist SR144528 (5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide), but not the CB1 antagonist SR141716 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide), blocked the anti-allodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or pre-injection thresholds, consistent with mediation by CB2. Administration of either the CB1 or CB2 antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the cremophor vehicle in lieu of paclitaxel whereas AM1714

Female Adults with Patellofemoral Pain Are Characterized by Widespread Hyperalgesia, Which Is Not Affected Immediately by Patellofemoral Joint Loading.

PubMed

Pazzinatto, Marcella Ferraz; de Oliveira Silva, Danilo; Barton, Christian; Rathleff, Michael Skovdal; Briani, Ronaldo Valdir; de Azevedo, Fábio Mícolis

2016-10-01

Compare pressure pain thresholds (PPTs) at the knee and a site remote to the knee in female adults with patellofemoral pain (PFP) to pain-free controls before and after a patellofemoral joint (PFJ) loading protocol designed to aggravate symptoms. Cross-sectional study SETTING: Participants were recruited via advertisements in fitness centers, public places for physical activity and universities. Thirty-eight females with patellofemoral pain, and 33 female pain-free controls. All participant performed a novel PFJ loading protocol involving stair negotiation with an extra load equivalent 35% of body mass. PPTs and current knee pain (measured on a visual analogue scale) was assessed before and after the loading protocol. PPTs were measured at four sites around the knee and one remote site on the upper contralateral limb. Females with PFP demonstrated significantly lower PPTs locally and remote to the knee, both before and after the PFJ loading protocol when compared to control group. Following the loading protocol, PPTs at knee were significantly reduced by 0.54 kgf (95%CI = 0.33; 0.74) for quadriceps tendon, 0.38 kgf (95%CI = 0.14; 0.63) for medial patella, and 0.44 kgf (95%CI = 0.18; 0.69) for lateral patella. No significant change in PPT remote to the knee was observed - 0.10 kgf (95%CI = -0.04; 0.24). Female adults with PFP have local and widespread hyperalgesia compared to pain free controls. A novel loading protocol designed to aggravate symptoms, lowers the PPTs locally at the knee but has no effect on PPT on the upper contralateral limb. This suggests widespread hyperalgesia is not affected by acute symptom aggravation. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Chronic cervical radiculopathic pain is associated with increased excitability and hyperpolarization-activated current ( Ih) in large-diameter dorsal root ganglion neurons.

PubMed

Liu, Da-Lu; Wang, Xu; Chu, Wen-Guang; Lu, Na; Han, Wen-Juan; Du, Yi-Kang; Hu, San-Jue; Bai, Zhan-Tao; Wu, Sheng-Xi; Xie, Rou-Gang; Luo, Ceng

2017-01-01

Cervical radiculopathic pain is a very common symptom that may occur with cervical spondylosis. Mechanical allodynia is often associated with cervical radiculopathic pain and is inadequately treated with current therapies. However, the precise mechanisms underlying cervical radiculopathic pain-associated mechanical allodynia have remained elusive. Compelling evidence from animal models suggests a role of large-diameter dorsal root ganglion neurons and plasticity of spinal circuitry attached with Aβ fibers in mediating neuropathic pain. Whether cervical radiculopathic pain condition induces plastic changes of large-diameter dorsal root ganglion neurons and what mechanisms underlie these changes are yet to be known. With combination of patch-clamp recording, immunohistochemical staining, as well as behavioral surveys, we demonstrated that upon chronic compression of C7/8 dorsal root ganglions, large-diameter cervical dorsal root ganglion neurons exhibited frequent spontaneous firing together with hyperexcitability. Quantitative analysis of hyperpolarization-activated cation current ( I h ) revealed that I h was greatly upregulated in large dorsal root ganglion neurons from cervical radiculopathic pain rats. This increased I h was supported by the enhanced expression of hyperpolarization-activated, cyclic nucleotide-modulated channels subunit 3 in large dorsal root ganglion neurons. Blockade of I h with selective antagonist, ZD7288 was able to eliminate the mechanical allodynia associated with cervical radiculopathic pain. This study sheds new light on the functional plasticity of a specific subset of large-diameter dorsal root ganglion neurons and reveals a novel mechanism that could underlie the mechanical allodynia associated with cervical radiculopathy.

Negative modultors of excitatory amino acids in episodic and chronic migraine: preventing and reverting chronic migraine. Special lecture 7th INWIN Congress.

PubMed

Nicolodi, M; Sicuteri, F

1998-01-01

The mechanism capable of transforming episodic migraine into chronic migraine is attributed by the authors to hyperalgesia and related neuroplastic changes, chiefly long-term potentiation, due to the action of excitatory amino acids, chiefly the ones acting at N-methyl D-aspartate (NMDA) receptor. A preeminent role has been attributed to 'third hyperalgesia', a newly observed type of hyperalgesia which is inheritable and can act as a ground for the above-mentioned mechanism of 'chronicization' of migraine. The role of primary and secondary hyperalgesia in giving redundance to neuraxial abnormalities is also discussed. The fact that NMDA noncompetitive antagonist ketamine and gabapentin, inhibitor of the neuronal synthesis of L-glutamate, can cure chronic migraine, so far considered refractory to prophylactic therapies, gives indirect but evident support to the mechanism suggested above. The antinociceptive role of the above-mentioned negative modulators of excitatory amino acids and the possible interplay between ionotropic and metabotropic receptors are also taken into consideration.

Prolonged amelioration of experimental postoperative pain by bupivacaine released from microsphere-coated hernia mesh.

PubMed