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Sample records for acetic acid-induced nociception

  1. Computerized image analysis for acetic acid induced intraepithelial lesions

    NASA Astrophysics Data System (ADS)

    Li, Wenjing; Ferris, Daron G.; Lieberman, Rich W.

    2008-03-01

    Cervical Intraepithelial Neoplasia (CIN) exhibits certain morphologic features that can be identified during a visual inspection exam. Immature and dysphasic cervical squamous epithelium turns white after application of acetic acid during the exam. The whitening process occurs visually over several minutes and subjectively discriminates between dysphasic and normal tissue. Digital imaging technologies allow us to assist the physician analyzing the acetic acid induced lesions (acetowhite region) in a fully automatic way. This paper reports a study designed to measure multiple parameters of the acetowhitening process from two images captured with a digital colposcope. One image is captured before the acetic acid application, and the other is captured after the acetic acid application. The spatial change of the acetowhitening is extracted using color and texture information in the post acetic acid image; the temporal change is extracted from the intensity and color changes between the post acetic acid and pre acetic acid images with an automatic alignment. The imaging and data analysis system has been evaluated with a total of 99 human subjects and demonstrate its potential to screening underserved women where access to skilled colposcopists is limited.

  2. Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids

    PubMed Central

    Ringel, Amit; Majchrzak-Hong, Sharon F; Yang, Jun; Blanchard, Helene; Zamora, Daisy; Loewke, James D; Rapoport, Stanley I; Hibbeln, Joseph R; Davis, John M; Hammock, Bruce D; Taha, Ameer Y

    2016-01-01

    Background Chronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes. Results Increasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues. Conclusions The present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes. PMID:27030719

  3. Acetic acid induces a programmed cell death process in the food spoilage yeast Zygosaccharomyces bailii.

    PubMed

    Ludovico, Paula; Sansonetty, Filipe; Silva, Manuel T; Côrte-Real, Manuela

    2003-03-01

    Here we show that 320-800 mM acetic acid induces in Zygosaccharomyces bailii a programmed cell death (PCD) process that is inhibited by cycloheximide, is accompanied by structural and biochemical alterations typical of apoptosis, and occurs in cells with preserved mitochondrial and plasma membrane integrity (as revealed by rhodamine 123 (Rh123) and propidium iodide (PI) staining, respectively). Mitochondrial ultrastructural changes, namely decrease of the cristae number, formation of myelinic bodies and swelling were also seen. Exposure to acetic acid above 800 mM resulted in killing by necrosis. The occurrence of an acetic acid-induced active cell death process in Z. bailii reinforces the concept of a physiological role of the PCD in the normal yeast life cycle.

  4. Cell wall dynamics modulate acetic acid-induced apoptotic cell death of Saccharomyces cerevisiae

    PubMed Central

    Rego, António; Duarte, Ana M.; Azevedo, Flávio; Sousa, Maria J.; Côrte-Real, Manuela; Chaves, Susana R.

    2014-01-01

    Acetic acid triggers apoptotic cell death in Saccharomyces cerevisiae, similar to mammalian apoptosis. To uncover novel regulators of this process, we analyzed whether impairing MAPK signaling affected acetic acid-induced apoptosis and found the mating-pheromone response and, especially, the cell wall integrity pathways were the major mediators, especially the latter, which we characterized further. Screening downstream effectors of this pathway, namely targets of the transcription factor Rlm1p, highlighted decreased cell wall remodeling as particularly important for acetic acid resistance. Modulation of cell surface dynamics therefore emerges as a powerful strategy to increase acetic acid resistance, with potential application in industrial fermentations using yeast, and in biomedicine to exploit the higher sensitivity of colorectal carcinoma cells to apoptosis induced by acetate produced by intestinal propionibacteria. PMID:28357256

  5. Protective Effect of Ocimum basilicum Essential Oil Against Acetic Acid-Induced Colitis in Rats.

    PubMed

    Rashidian, Amir; Roohi, Parnia; Mehrzadi, Saeed; Ghannadi, Ali Reza; Minaiyan, Mohsen

    2016-10-01

    Ocimum basilicum L has been traditionally used for the treatment of inflammatory bowel disease in Iran. This study investigates the ameliorative effect of Ocimum basilicum essential oil on an acetic acid-induced colitis model in rats. Ocimum basilicum essential oil with 2 doses (200 and 400 μL/kg) significantly ameliorated wet weight/length ratio of colonic tissue compared to the control group. Higher doses of essential oil (200 and 400 μL/kg) significantly reduced ulcer severity, ulcer area, and ulcer index. On the other hand, histological examination revealed the diminution of total colitis index as a marker for inflammatory cell infiltration in the colonic segments of rats treated with Ocimum basilicum essential oil (200 and 400 μL/kg). The increased level of myeloperoxidase was significantly decreased after the treatment with the essential oil (200 and 400 μL/kg). These results suggest that Ocimum basilicum exhibits protective effect against acetic acid-induced colitis.

  6. Obestatin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Bonior, Joanna; Jaworek, Jolanta; Kuśnierz-Cabala, Beata; Konturek, Peter; Ambroży, Tadeusz; Dembiński, Artur

    2016-01-01

    Obestatin, a 23-amino acid peptide derived from the proghrelin, has been shown to exhibit some protective and therapeutic effects in the gut. The aim of present study was to determine the effect of obestatin administration on the course of acetic acid-induced colitis in rats. Materials and Methods. Studies have been performed on male Wistar rats. Colitis was induced by a rectal enema with 3.5% acetic acid solution. Obestatin was administered intraperitoneally twice a day at a dose of 8 nmol/kg, starting 24 h after the induction of colitis. Seven or 14 days after the induction of colitis, the healing rate of the colon was evaluated. Results. Treatment with obestatin after induction of colitis accelerated the healing of colonic wall damage and this effect was associated with a decrease in the colitis-evoked increase in mucosal activity of myeloperoxidase and content of interleukin-1β. Moreover, obestatin administration significantly reversed the colitis-evoked decrease in mucosal blood flow and DNA synthesis. Conclusion. Administration of exogenous obestatin exhibits therapeutic effects in the course of acetic acid-induced colitis and this effect is related, at least in part, to the obestatin-evoked anti-inflammatory effect, an improvement of local blood flow, and an increase in cell proliferation in colonic mucosa. PMID:26798415

  7. Obestatin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats.

    PubMed

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Bonior, Joanna; Jaworek, Jolanta; Kuśnierz-Cabala, Beata; Konturek, Peter; Ambroży, Tadeusz; Dembiński, Artur

    2016-01-01

    Obestatin, a 23-amino acid peptide derived from the proghrelin, has been shown to exhibit some protective and therapeutic effects in the gut. The aim of present study was to determine the effect of obestatin administration on the course of acetic acid-induced colitis in rats. Materials and Methods. Studies have been performed on male Wistar rats. Colitis was induced by a rectal enema with 3.5% acetic acid solution. Obestatin was administered intraperitoneally twice a day at a dose of 8 nmol/kg, starting 24 h after the induction of colitis. Seven or 14 days after the induction of colitis, the healing rate of the colon was evaluated. Results. Treatment with obestatin after induction of colitis accelerated the healing of colonic wall damage and this effect was associated with a decrease in the colitis-evoked increase in mucosal activity of myeloperoxidase and content of interleukin-1β. Moreover, obestatin administration significantly reversed the colitis-evoked decrease in mucosal blood flow and DNA synthesis. Conclusion. Administration of exogenous obestatin exhibits therapeutic effects in the course of acetic acid-induced colitis and this effect is related, at least in part, to the obestatin-evoked anti-inflammatory effect, an improvement of local blood flow, and an increase in cell proliferation in colonic mucosa.

  8. Exogenous Ghrelin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats.

    PubMed

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Ceranowicz, Dagmara; Gałązka, Krystyna; Bonior, Joanna; Jaworek, Jolanta; Bartuś, Krzysztof; Gil, Krzysztof; Olszanecki, Rafał; Dembiński, Artur

    2016-09-01

    Previous studies have shown that ghrelin reduces colonic inflammation induced by trinitrobenzene sulfonic acid and dextran sodium sulfate. In the present study we determined the effect of treatment with ghrelin on the course of acetic acid-induced colitis in rats. Rectal administration of 3% acetic acid solution led to induction of colitis in all animals. Damage of the colonic wall was accompanied by an increase in mucosal concentration of pro-inflammatory interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well mucosal activity of myeloperoxidase. Moreover, induction of colitis led to a reduction in colonic blood flow and DNA synthesis. Administration of ghrelin after induction of colitis led to faster regeneration of the colonic wall and reduction in colonic levels of IL-1β, TNF-α, and myeloperoxidase. In addition, treatment with ghrelin improved mucosal DNA synthesis and blood flow. Our study disclosed that ghrelin exhibits a strong anti-inflammatory and healing effect in acetic acid-induced colitis. Our current observation in association with previous findings that ghrelin exhibits curative effect in trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis suggest that therapeutic effect of ghrelin in the colon is universal and independent of the primary cause of colitis.

  9. Exogenous Ghrelin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Ceranowicz, Dagmara; Gałązka, Krystyna; Bonior, Joanna; Jaworek, Jolanta; Bartuś, Krzysztof; Gil, Krzysztof; Olszanecki, Rafał; Dembiński, Artur

    2016-01-01

    Previous studies have shown that ghrelin reduces colonic inflammation induced by trinitrobenzene sulfonic acid and dextran sodium sulfate. In the present study we determined the effect of treatment with ghrelin on the course of acetic acid-induced colitis in rats. Rectal administration of 3% acetic acid solution led to induction of colitis in all animals. Damage of the colonic wall was accompanied by an increase in mucosal concentration of pro-inflammatory interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well mucosal activity of myeloperoxidase. Moreover, induction of colitis led to a reduction in colonic blood flow and DNA synthesis. Administration of ghrelin after induction of colitis led to faster regeneration of the colonic wall and reduction in colonic levels of IL-1β, TNF-α, and myeloperoxidase. In addition, treatment with ghrelin improved mucosal DNA synthesis and blood flow. Our study disclosed that ghrelin exhibits a strong anti-inflammatory and healing effect in acetic acid-induced colitis. Our current observation in association with previous findings that ghrelin exhibits curative effect in trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis suggest that therapeutic effect of ghrelin in the colon is universal and independent of the primary cause of colitis. PMID:27598133

  10. The influence of pretreatment with ghrelin on the development of acetic-acid-induced colitis in rats.

    PubMed

    Maduzia, D; Matuszyk, A; Ceranowicz, D; Warzecha, Z; Ceranowicz, P; Fyderek, K; Galazka, K; Dembinski, A

    2015-12-01

    Ghrelin has been primarily shown to exhibit protective and therapeutic effect in the gut. Pretreatment with ghrelin inhibits the development of acute pancreatitis and accelerates pancreatic recovery in the course of this disease. In the stomach, ghrelin reduces gastric mucosal damage induced by ethanol, stress or alendronate, as well as accelerates the healing of acetic acid-induced gastric and duodenal ulcer. The aim of present studies was to investigate the effect of pretreatment with ghrelin on the development of acetic acid-induced colitis. Studies have been performed on male Wistar rats. Animals were treated intraperitoneally with saline (control) or ghrelin (4, 8 or 16 nmol/kg/dose). Saline or ghrelin was given twice: 8 and 1 h before induction of colitis. Colitis was induced by a rectal enema with 1 ml of 4% solution of acetic acid and the severity of colitis was assessed 1 or 24 hours after induction of inflammation. Rectal administration of acetic acid induced colitis in all animals. Damage of colonic wall was seen at the macroscopic and microscopic level. This effect was accompanied by a reduction in colonic blood flow and mucosal DNA synthesis. Moreover, induction of colitis significantly increased mucosal concentration of pro-inflammatory interleukin-1β (IL-1β), activity of myeloperoxidase and concentration of malondialdehyde (MDA). Mucosal activity of superoxide dismutase (SOD) was reduced. Pretreatment with ghrelin reduced the area and grade of mucosal damage. This effect was accompanied by an improvement of blood flow, DNA synthesis and SOD activity in colonic mucosa. Moreover, ghrelin administration reduced mucosal concentration of IL-1β and MDA, as well as decreased mucosal activity of myeloperoxidase. Administration of ghrelin protects the large bowel against the development of the acetic acid-induced colitis and this effect seems to be related to the ghrelin-evoked anti-inflammatory and anti-oxidative effects.

  11. Effects of chlorpheniramine and ranitidine on the visceral nociception induced by acetic acid in rats: role of opioid system.

    PubMed

    Zanboori, A; Tamaddonfard, E; Mojtahedein, A

    2008-10-15

    In this study, effects of chlorpheniramine (H1-receptor blocker), ranitidine (H2-receptor blocker), morphine (an opioid agonist) and naloxone (an opioid antagonist) in separate and combined treatments were investigated on the visceral nociception in rats. Visceral nociception was induced by intraperitoneal injection of acetic acid (1 mL, 1%). The latency time to the beginning of the first abdominal wall contraction (first writhe) was measured and the numbers of writhes were counted for 1 h after acetic acid injection. Intraperitoneal injections of chlorpheniramine and ranitidine significantly (p < 0.05) increased the latency time to the beginning of the first writhe and also significantly (p < 0.05) decreased the numbers of writhes. The same results were obtained after subcutaneous injection of morphine. Subcutaneous injection of naloxone did not change the intensity of visceral nociception, but significantly (p < 0.05) prevented the morphine-induced antinociception. Intraperitoneal injection of chlorpheniramine significantly (p < 0.05) enhanced the morphine-induced analgesia, but did not reverse the effect of naloxone on nociceptive responses. Intraperitoneal injection of ranitidine, with no effect on the morphine-induced antinociception, significantly (p < 0.05) reversed the effect of naloxone on pain responses. These results suggest that both chlorpheniramine and ranitidine exert antinociceptive effect in the visceral nociception. In addition, morphine through a naloxone-dependent mechanism produces visceral antinociception. Moreover, the endogenous opioid system may participate in the chlorpheniramine- but not in the ranitidine-induced antinociception.

  12. Protective effect of Agave americana Linn. leaf extract in acetic acid-induced ulcerative colitis in rats

    PubMed Central

    Mannasaheb, Basheerahmed A.A.; Kulkarni, Preeti V.; Sangreskopp, Mashood Ahmed; Savant, Chetan; Mohan, Anjana

    2015-01-01

    Introduction: Natural plants always provide core compounds for new drug development. In the present life and food style, inflammatory bowel disease has become common and needs a lead compound for its drug development. Aim: To evaluate the effect of Agave americana Linn. leaf extract in acetic acid-induced ulcerative colitis in rats based on its traditional anti-inflammatory use. Materials and Methods: Male Wistar rats were pretreated with A. americana leaf extract in the dose of 200 and 400 mg/kg p.o. daily for 7 days. On 8th day, 2 ml of 4% v/v acetic acid in saline was instilled into rats’ rectum. Prednisolone was used as standard drug and it was administered on the day of acetic acid instillation and continued for 3 days. Extract treatment was continued till 11th day. Body weight, ulcer score, colonic muscle contraction, antioxidant activity and histopathology were studied. Statistical analysis was performed using Parametric one-way analysis of variance followed by Tukey's posttest. Results: A. americana have retained total body weight significantly (P < 0.01) and decreased colon weight/length ratio. Extract have shown a significant decrease (P < 0.001) in ulcer scores, myeloperoxidase, lipid peroxidase activity. Further, extract have shown significant improvement in colonic muscle contraction, histopathology of colon etc., which is comparable with standard drug. Conclusion: A. americana possess protective effect against acetic acid-induced colitis in rats. PMID:26730148

  13. Evaluation of Prevalent Phytocannabinoids in the Acetic Acid Model of Visceral Nociception

    PubMed Central

    Booker, Lamont; Naidu, Pattipati S.; Razdan, Raj K.; Mahadevan, Anu; Lichtman, Aron H.

    2009-01-01

    Considerable preclinical research has demonstrated the efficacy of Δ9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent of Cannabis sativa, in a wide variety of animal models of pain, but few studies have examined other phytocannabinoids. Indeed, other plant-derived cannabinoids, including cannabidiol (CBD), cannabinol (CBN), and cannabichromene (CBC) elicit antinociceptive effects in some assays. In contrast, tetrahydrocannabivarin (THCV), another component of cannabis, antagonizes the pharmacological effects of Δ9-THC. These results suggest that various constituents of this plant may interact in a complex manner to modulate pain. The primary purpose of the present study was to assess the antinociceptive effects of these other prevalent phytocannabinoids in the acetic acid stretching test, a rodent visceral pain model. Of the cannabinoid compounds tested, Δ9-THC and CBN bound to the CB1 receptor and produced antinociceptive effects. The CB1 receptor antagonist, rimonabant, but not the CB2 receptor antagonist, SR144528, blocked the antinociceptive effects of both compounds. Although THCV bound to the CB1 receptor with similar affinity as Δ9-THC, it had no effects when administered alone, but antagonized the antinociceptive effects of Δ9-THC when both drugs were given in combination. Importantly, the antinociceptive effects of Δ9-THC and CBN occurred at lower doses than those necessary to produce locomotor suppression, suggesting motor dysfunction did not account for the decreases in acetic acid-induced abdominal stretching. These data raise the intriguing possibility that other constituents of cannabis can be used to modify the pharmacological effects of Δ9-THC by either eliciting antinociceptive effects (i.e., CBN) or antagonizing (i.e., THCV) the actions of Δ9-THC. PMID:19679411

  14. Effect of capsaicin and cimetidine on the healing of acetic acid induced gastric ulceration in the rat.

    PubMed Central

    Kang, J Y; Teng, C H; Chen, F C

    1996-01-01

    BACKGROUND: Capsaicin protects the gastric mucosa against experimental injury while capsaicin desensitisation reduces the rate of gastric ulcer healing. The effect of exogenous capsaicin on gastric ulcer healing has not to date been reported. AIM/METHOD: To investigate the effect of capsaicin, cimetidine, and in combination, given intragastrically in the healing of acetic acid induced chronic gastric ulcer in the rat. Treatment started immediately after ulcer induction. RESULTS: At the end of one week, capsaicin, cimetidine, and in combination increased ulcer healing but the effect of combined treatment was less than that of capsaicin alone. In an in vivo gastric chamber preparation, capsaicin increased, while cimetidine decreased, gastric mucosal blood flow measured by laser Doppler flowmetry. A dose response effect in reduction of gastric mucosal blood flow could be demonstrated for cimetidine. The gastric hyperaemic effect of capsaicin was blunted by prior administration of cimetidine. In contrast, capsaicin had no effect on gastric acid secretion and its addition to cimetidine did not affect the acid suppressant effect of the latter. CONCLUSIONS: Capsaicin promotes the healing of acetic acid induced gastric ulcer, probably by its gastric hyperaemic effect. Although cimetidine also promotes ulcer healing due to its inhibitory effect on acid secretion it may have an antagonistic effect on the gastric ulcer healing effect of capsaicin by virtue of inhibition of gastric hyperaemia. PMID:8984019

  15. Acetic acid induces pH-independent cellular energy depletion in Salmonella enterica.

    PubMed

    Tan, Sin Mei; Lee, Sui Mae; Dykes, Gary A

    2015-03-01

    Weak organic acids are widely used as preservatives and disinfectants in the food industry. Despite their widespread use, the antimicrobial mode of action of organic acids is still not fully understood. This study investigated the effect of acetic acid on the cell membranes and cellular energy generation of four Salmonella strains. Using a nucleic acid/protein assay, it was established that acetic acid did not cause leakage of intracellular components from the strains. A scanning electron microscopy study further confirmed that membrane disruption was not the antimicrobial mode of action of acetic acid. Some elongated Salmonella cells observed in the micrographs indicated a possibility that acetic acid may inhibit DNA synthesis in the bacterial cells. Using an ATP assay, it was found that at a neutral pH, acetic acid caused cellular energy depletion with an ADP/ATP ratio in the range between 0.48 and 2.63 (p<0.05) that was apparent for the four Salmonella strains. We suggest that this effect was probably due solely to the action of undissociated acid molecules. The antimicrobial effect of acetic acid was better under acidic conditions (ADP/ATP ratio of 5.56 ± 1.27; p<0.05), where the role of both pH and undissociated acid molecules can act together. We concluded that the inhibitory effect of acetic acid is not solely attributable to acidic pH but also to undissociated acid molecules. This finding has implication for the use of acetic acid as an antimicrobial against Salmonella on food products, such as chicken meat, which can buffer its pH.

  16. Protective Effect of the Methanolic Extract of Malva parviflora L. leaves on Acetic Acid-induced Ulcerative Colitis in Rats

    PubMed Central

    Dugani, Aisha; Dakhil, Bushra; Treesh, Soad

    2016-01-01

    Background/Aims: Inflammatory bowel disease (IBD) is a general term describing chronic, idiopathic relapsing, inflammatory conditions of the gastrointestinal tract of unknown etiology. Previous studies have indicated that Malva parviflora leaf extract possesses anti-inflammatory, antioxidant, and antiulcerogenic activity. activity. This work aimed to investigatee the anti-inflammatory effect of the methanolic (MEMP) and aqueous (AEMP) extracts of M. parviflora leaves on acetic acid-induced colitis in rats. Materials and Methods: 42 male Wistar albino rats were divided into seven groups (n = 6). Group I: Normal saline control group with no colitis; Group II: Acetic acid colitis group; Group III: 100 mg/kg/5 d MEMP; Group IV: 200 mg/kg/5 d.MEMP; Group V: 100 mg/kg/5 d AEMP; Group VI: 200 mg/kg/5 d AEMP; Group VII: Prednisolone group (2 mg/kg/5 d). Treatments were followed by induction of colitis using intrarectal instillation of 2 mL of 4% acetic acid. Colon damage was evaluated macroscopically (spleen weight/body weight, colon weight/length ratio) and the histological changes were also recorded. Results: The results of this study showed that acetic acid caused severe inflammation of the colon and a significant increase in spleen weight/body weight, and an increase in colon weight/length ratio compared with normal control group. Pretreatment with MEMP and AEMP for 5 days followed by induction of colitis resulted in a significant attenuation of spleen weight and colon weight/length ratio compared with acetic acid control group. Methanolic extract provided better anticolitic effect than aqueous extract; the effect was prominent at the dose of 200 mg/kg. Histopathological findings confirmed the protective effect of the MEMP. Conclusion: In conclusion, MEMP could ameliorate mucosal damage in experimentally induced colitis when given orally. PMID:27184642

  17. Acetic acid-induced programmed cell death and release of volatile organic compounds in Chlamydomonas reinhardtii.

    PubMed

    Zuo, Zhaojiang; Zhu, Yerong; Bai, Yanling; Wang, Yong

    2012-02-01

    Acetic acid widely spreads in atmosphere, aquatic ecosystems containing residues and anoxic soil. It can inhibit aquatic plant germination and growth, and even cause programmed cell death (PCD) of yeast. In the present study, biochemical and physiological responses of the model unicellular green algae Chlamydomonas reinhardtii were examined after acetic acid stress. H(2)O(2) burst was found in C. reinhardtii after acetic acid stress at pH 5.0 for 10 min. The photosynthetic pigments were degraded, gross photosynthesis and respiration were disappeared gradually, and DNA fragmentation was also detected. Those results indicated that C. reinhardtii cells underwent a PCD but not a necrotic, accidental cell death event. It was noticed that C. reinhardtii cells in PCD released abundant volatile organic compounds (VOCs) upon acetic acid stress. Therefore, we analyzed the VOCs and tested their effects on other normal cells. The treatment of C. reinhardtii cultures with VOCs reduced the cell density and increased antioxidant enzyme activity. Therefore, a function of VOCs as infochemicals involved in cell-to-cell communication at the conditions of applied stress is suggested.

  18. Yeast acetic acid-induced programmed cell death can occur without cytochrome c release which requires metacaspase YCA1.

    PubMed

    Guaragnella, Nicoletta; Bobba, Antonella; Passarella, Salvatore; Marra, Ersilia; Giannattasio, Sergio

    2010-01-04

    To investigate the role of cytochrome c (cyt c) release in yeast acetic acid-induced programmed cell death (AA-PCD), wild type (wt) and cells lacking metacaspase (Deltayca1), cytochrome c (Deltacyc1,7) and both (Deltacyc1,7Deltayca1) were compared for AA-PCD occurrence, hydrogen peroxide (H(2)O(2)) production and caspase activity. AA-PCD occurs in Deltacyc1,7 and Deltacyc1,7Deltayca1 cells slower than in wt, but similar to that in Deltayca1 cells, in which no cytochrome c release occurs. Both H(2)O(2) production and caspase activation occur in these cells with early and extra-activation in Deltacyc1,7 cells. We conclude that alternative death pathways can be activated in yeast AA-PCD, one dependent on cyt c release, which requires YCA1, and the other(s) independent on it.

  19. Mitochondrial proteomics of the acetic acid - induced programmed cell death response in a highly tolerant Zygosaccharomyces bailii - derived hybrid strain

    PubMed Central

    Guerreiro, Joana F.; Sampaio-Marques, Belém; Soares, Renata; Coelho, Ana V.; Leão, Cecília; Ludovico, Paula; Sá-Correia, Isabel

    2016-01-01

    Very high concentrations of acetic acid at low pH induce programmed cell death (PCD) in both the experimental model Saccharomyces cerevisiae and in Zygosaccharomyces bailii, the latter being considered the most problematic acidic food spoilage yeast due to its remarkable intrinsic resistance to this food preservative. However, while the mechanisms underlying S. cerevisiae PCD induced by acetic acid have been previously examined, the corresponding molecular players remain largely unknown in Z. bailii. Also, the reason why acetic acid concentrations known to be necrotic for S. cerevisiae induce PCD with an apoptotic phenotype in Z. bailii remains to be elucidated. In this study, a 2-DE-based expression mitochondrial proteomic analysis was explored to obtain new insights into the mechanisms involved in PCD in the Z. bailii derived hybrid strain ISA1307. This allowed the quantitative assessment of expression of protein species derived from each of the parental strains, with special emphasis on the processes taking place in the mitochondria known to play a key role in acetic acid - induced PCD. A marked decrease in the content of proteins involved in mitochondrial metabolism, in particular, in respiratory metabolism (Cor1, Rip1, Lpd1, Lat1 and Pdb1), with a concomitant increase in the abundance of proteins involved in fermentation (Pdc1, Ald4, Dld3) was registered. Other differentially expressed identified proteins also suggest the involvement of the oxidative stress response, protein translation, amino acid and nucleotide metabolism, among other processes, in the PCD response. Overall, the results strengthen the emerging concept of the importance of metabolic regulation of yeast PCD. PMID:28357336

  20. Stability of the Acetic Acid-Induced Bladder Irritation Model in Alpha Chloralose-Anesthetized Female Cats

    PubMed Central

    Kullmann, F. Aura; Wells, Grace I.; Langdale, Christopher L.; Zheng, Jihong; Thor, Karl B.

    2013-01-01

    Time- and vehicle-related variability of bladder and urethral rhabdosphincter (URS) activity as well as cardiorespiratory and blood chemistry values were examined in the acetic acid-induced bladder irritation model in α-chloralose-anesthetized female cats. Additionally, bladder and urethra were evaluated histologically using Mason trichrome and toluidine blue staining. Urodynamic, cardiovascular and respiratory parameters were collected during intravesical saline infusion followed by acetic acid (0.5%) to irritate the bladder. One hour after starting acetic acid infusion, a protocol consisting of a cystometrogram, continuous infusion-induced rhythmic voiding contractions, and a 5 min “quiet period” (bladder emptied without infusion) was precisely repeated every 30 minutes. Administration of vehicle (saline i.v.) occurred 15 minutes after starting each of the first 7 cystometrograms and duloxetine (1mg/kg i.v.) after the 8th. Acetic acid infusion into the bladder increased URS-EMG activity, bladder contraction frequency, and decreased contraction amplitude and capacity, compared to saline. Bladder activity and URS activity stabilized within 1 and 2 hours, respectively. Duloxetine administration significantly decreased bladder contraction frequency and increased URS-EMG activity to levels similar to previous reports. Cardiorespiratory parameters and blood gas levels remained consistent throughout the experiment. The epithelium of the bladder and urethra were greatly damaged and edema and infiltration of neutrophils in the lamina propria of urethra were observed. These data provide an ample evaluation of the health of the animals, stability of voiding function and appropriateness of the model for testing drugs designed to evaluate lower urinary tract as well as cardiovascular and respiratory systems function. PMID:24040064

  1. Stability of the acetic acid-induced bladder irritation model in alpha chloralose-anesthetized female cats.

    PubMed

    Kullmann, F Aura; Wells, Grace I; Langdale, Christopher L; Zheng, Jihong; Thor, Karl B

    2013-01-01

    Time- and vehicle-related variability of bladder and urethral rhabdosphincter (URS) activity as well as cardiorespiratory and blood chemistry values were examined in the acetic acid-induced bladder irritation model in α-chloralose-anesthetized female cats. Additionally, bladder and urethra were evaluated histologically using Mason trichrome and toluidine blue staining. Urodynamic, cardiovascular and respiratory parameters were collected during intravesical saline infusion followed by acetic acid (0.5%) to irritate the bladder. One hour after starting acetic acid infusion, a protocol consisting of a cystometrogram, continuous infusion-induced rhythmic voiding contractions, and a 5 min "quiet period" (bladder emptied without infusion) was precisely repeated every 30 minutes. Administration of vehicle (saline i.v.) occurred 15 minutes after starting each of the first 7 cystometrograms and duloxetine (1mg/kg i.v.) after the 8(th). Acetic acid infusion into the bladder increased URS-EMG activity, bladder contraction frequency, and decreased contraction amplitude and capacity, compared to saline. Bladder activity and URS activity stabilized within 1 and 2 hours, respectively. Duloxetine administration significantly decreased bladder contraction frequency and increased URS-EMG activity to levels similar to previous reports. Cardiorespiratory parameters and blood gas levels remained consistent throughout the experiment. The epithelium of the bladder and urethra were greatly damaged and edema and infiltration of neutrophils in the lamina propria of urethra were observed. These data provide an ample evaluation of the health of the animals, stability of voiding function and appropriateness of the model for testing drugs designed to evaluate lower urinary tract as well as cardiovascular and respiratory systems function.

  2. Protective Effect of Cod (Gadus macrocephalus) Skin Collagen Peptides on Acetic Acid-Induced Gastric Ulcer in Rats.

    PubMed

    Niu, Huina; Wang, Zhicong; Hou, Hu; Zhang, Zhaohui; Li, Bafang

    2016-07-01

    This research was performed to explore the protective effect of cod skin collagen peptides (CCP) on gastric ulcer induced by acetic acid. The CCP were fractionated into low molecular CCP (LMCCP, Mw < 3 kDa) and high molecular CCP (HMCCP, Mw > 3 kDa). In HMCCP and LMCCP, glycine of accounted for about one-third of the total amino acids without cysteine and tryptophan, and hydrophobic amino acids accounted for about 50%. After 21 d CCP treatment (60 or 300 mg/kg, p.o./daily), the healing effects on acetic acid-induced gastric ulcers were evaluated by macroscopic measure, microscopic measure, and immune histochemistry. Moreover, the expression levels of the growth factors, such as vascular endothelial growth factor, epidermal growth factor, transforming growth factor β1 (TGFβ1), and the heat shock protein 70 (HSP70) was detected. The results showed that both LMCCP and HMCCP could significantly decrease the ulcer areas and promote the healing of the lesions. They also could improve the levels of hexosamine, glutathione, superoxide dismutase, and glutathione peroxidase, and reduce the content of malondialdehyde and inducible nitric oxide synthase. In addition, the expression level of TGFβ1 gene and HSP70 mRNA was significantly improved by the treatment. It suggested that CCP could be able to improve symptoms of gastric ulcer and probably be used in the treatment of gastric ulcer.

  3. The Healing Effect of Teucrium polium in Acetic Acid-Induced Ulcerative Colitis in the Dog as an Animal Model

    PubMed Central

    Mehrabani, Davood; Bahrami, Faranak; Hosseini, Seyed Vahid; Ashraf, Mohammad Javad; Tanideh, Nader; Rezaianzadeh, Abbas; Amini, Masoud; Amini, Afshin

    2012-01-01

    BACKGROUND Inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn’s disease (CD), are debilitating and chronic disorders with unpredictable courses and complicated treatment measures. Therefore, an efficient treatment protocol seems necessary as therapeutic prophylaxis for these disorders. This study aims to determine the healing effect of Teucrium polium (T. polium) in acetic acid-induced UC in an experimental dog model. METHODS From September to December 2010, eight male (20-25 kg) crossbred dogs were used for induction of UC by 6% acetic acid, transrectally. After one week, three biopsies (10, 20 and 30 cm proximal to the anal verge) were taken from the colon of each animal for histological studies. In the presence of UC, 400 mg/kg/day of T. polium extract was administered orally and transrectally (via enema) for 30 days in six of the dogs. The remaining two dogs were used as controls and did not receive T. polium. Multiple biopsies were taken 7, 14, and 30 days after discontinuation of T. polium in the same manner as before treatment. RESULTS After administration of acetic acid, we noted the presence of multiple ulcers, diffuse inflammation, PMN infiltration in the lamina propria, glandular destruction and goblet cell depletion. Treatment with T. polium restored the colonic architecture with an increased number of healthy cells and a reduction in inflammatory cells. Damage of the surface epithelial cells and mucosal layer of the lumen were reversed, which lead to faster ulcer healing. CONCLUSION T. polium may be a treatment choice for UC and can broaden the current therapy options for UC. PMID:24829634

  4. Somatic pain sensitivity during formation and healing of acetic acid-induced gastric ulcers in conscious rats.

    PubMed

    Yarushkina, Natalya; Bogdanov, Anatoly; Filaretova, Ludmila

    2006-06-30

    A classical feature of visceral pain is its referring to somatic locations. Gastric ulcer is a source of visceral pain. In the present study we investigated whether gastric ulcers may trigger the changes in somatic nociception. For this aim somatic pain sensitivity was estimated under conditions of gastric ulcer development and healing. Gastric ulcers were induced by luminal application of 60% acetic acid under surgical conditions. Control rats were subjected to the same surgical procedure, but with the application of saline instead of the acid. Somatic pain sensitivity (tail flick latency), plasma corticosterone level, adrenal and thymus weight were investigated under conditions of the formation and the healing of gastric ulcers. The application of the acid resulted in the formation of kissing gastric ulcers, the increase of somatic pain sensitivity (the decrease of tail flick latency) as well as the appearance of typical signs of chronic stress: long-lasting increase of plasma corticosterone level, adrenal gland hypertrophy and thymus gland involution. Natural healing of gastric ulcers was accompanied by restoration of pain sensitivity as well as attenuation of the signs of chronic stress. Delay of ulcer healing by the daily indomethacin administration (2 mg/kg, s.c.) prevented the restoration of somatic pain sensitivity. The results suggest that chronic gastric ulcers may trigger somatic hypersensitivity.

  5. Nadroparin sodium activates Nrf2/HO-1 pathway in acetic acid-induced colitis in rats.

    PubMed

    Yalniz, Mehmet; Demirel, Ulvi; Orhan, Cemal; Bahcecioglu, Ibrahim Halil; Ozercan, Ibrahim Hanefi; Aygun, Cem; Tuzcu, Mehmet; Sahin, Kazim

    2012-06-01

    Effects of nadroparin sodium, a low molecular weight heparin, in colitis was investigated by analyzing proteins implicated in nuclear factor E2-related factor-2/heme oxygenase-1 (Nrf2/HO-1) and nuclear factor kappa B (NF-κB) pathways. Twenty-eight rats were used. Colitis was induced by acetic acid (AA). Nadroparin sodium was given to prevention and treatment groups in addition to AA. Colitis was assessed histologically and levels of proteins were analyzed with Western blot. Nadroparin not only prevented and ameliorated the AA-induced colitis histopathologically but also decreased expression of colon NF-κB, activator protein-1, cyclooxygenase-2, tumor necrosis factor-alpha, and IL-6, which were significantly increased in group AA compared to control. The accumulation of Nrf2 in nuclear fraction and HO-1 found low in group AA was increased with nadroparin (p < 0.05). The mean malondialdehyde level increased with AA and was decreased significantly with nadroparin prevention and treatment (p < 0.001). Nadroparin sodium has both protective and therapeutic effects against colonic inflammation via exerting anti-oxidative and anti-inflammatory effects by modulating Nrf2/HO-1 and NF-κB pathways.

  6. Effects of dexpanthenol on acetic acid-induced colitis in rats

    PubMed Central

    Cagin, Yasir Furkan; Parlakpinar, Hakan; Vardi, Nigar; Polat, Alaadin; Atayan, Yahya; Erdogan, Mehmet Ali; Tanbek, Kevser

    2016-01-01

    While the pathogenesis of acetic acid (AA)-induced colitis is unclear, reactive oxygen species are considered to have a significant effect. The aim of the present study was to elucidate the therapeutic potential of dexpanthenol (Dxp) on the amelioration of colitis in rats. Group I (n=8; control group) was intrarectally administered 1 ml saline solution (0.9%); group II [n=8; AA] was administered 4% AA into the colon via the rectum as a single dose for three consecutive days; group III (n=8; AA + Dxp) was administered AA at the same dosage as group II from day 4, and a single dose of Dxp was administered intraperitoneally; and group IV (n=8; Dxp) was administered Dxp similarly to Group III. Oxidative stress and colonic damage were assessed via biochemical and histologic examination methods. AA treatment led to an increase in oxidative parameters and a decrease in antioxidant systems. Histopathological examination showed that AA treatment caused tissue injury and increased caspase-3 activity in the distal colon and triggered apoptosis. Dxp treatment caused biochemical and histopathological improvements, indicating that Dxp may have an anti-oxidant effect in colitis; therefore, Dxp may be a potential therapeutic agent for the amelioration of IBD. PMID:27882101

  7. Effects of dexpanthenol on acetic acid-induced colitis in rats.

    PubMed

    Cagin, Yasir Furkan; Parlakpinar, Hakan; Vardi, Nigar; Polat, Alaadin; Atayan, Yahya; Erdogan, Mehmet Ali; Tanbek, Kevser

    2016-11-01

    While the pathogenesis of acetic acid (AA)-induced colitis is unclear, reactive oxygen species are considered to have a significant effect. The aim of the present study was to elucidate the therapeutic potential of dexpanthenol (Dxp) on the amelioration of colitis in rats. Group I (n=8; control group) was intrarectally administered 1 ml saline solution (0.9%); group II [n=8; AA] was administered 4% AA into the colon via the rectum as a single dose for three consecutive days; group III (n=8; AA + Dxp) was administered AA at the same dosage as group II from day 4, and a single dose of Dxp was administered intraperitoneally; and group IV (n=8; Dxp) was administered Dxp similarly to Group III. Oxidative stress and colonic damage were assessed via biochemical and histologic examination methods. AA treatment led to an increase in oxidative parameters and a decrease in antioxidant systems. Histopathological examination showed that AA treatment caused tissue injury and increased caspase-3 activity in the distal colon and triggered apoptosis. Dxp treatment caused biochemical and histopathological improvements, indicating that Dxp may have an anti-oxidant effect in colitis; therefore, Dxp may be a potential therapeutic agent for the amelioration of IBD.

  8. Anti-nociceptive Effect of 7-methoxy Coumarin from Eupatorium Triplinerve vahl (Asteraceae)

    PubMed Central

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

    2017-01-01

    Aim: To evaluate the anti-nociceptive activity of 7-methoxy coumarin isolated from ethyl acetate fraction of the alcoholic extract of Eupatorium triplinerve Vahl. Materials and Methods: The shade dried leaves of E. triplinerve were extracted with ethyl alcohol and the extract was condensed. This extract was fractionated with n-hexane, ethyl acetate, and n-butanol. The ethyl acetate fraction was subjected to column chromatography which yielded a crystalline compound-A, which was investigated for spectral characteristics. Pharmacological studies: The isolated compound-A was subjected to behavioral studies and anti-nociceptive evaluation in mice by acetic acid induced writhing and formalin induced nociception. Results: The spectral studies indicated that the structure of compound-A complies with 7- methoxy coumarin. Pre-treatment with 7-methoxy coumarin reduced the number of abdominal constrictions in mice and decreased the time spent in paw licking and biting response in formalin assay. There were no significant behavioral changes. Conclusion: A dose dependent anti-nociceptive action of 7- methoxy coumarin was revealed by the present experiments which support the traditional use of E. triplinerve in pain and inflammatory disorders. SUMMARY Bio-guided fractionation of alcoholic extract of E. triplinerve yielded 7-methoxy coumarin.7-methoxy coumarin was evaluated for its anti-nociceptive potential by acetic acid induced writhing and formalin induced nociception assays.7-methoxy coumarin exhibited significant inhibition of acetic acid induced writhing response and the second phase of formalin nociception.The anti-nociceptive action of 7-methoxy coumarin revealed by the present experiments supports the traditional use of E. triplinerve in pain and inflammatory disorders. Abbreviation used: TLC-Thin layer chromatography, Kg-kilogram, g-gram, TXB2-Thromboxane B2, UV-Ultraviolet, IgE-Immunoglobulin E, s.c-subcutaneous, p.o-oral route PMID:28216887

  9. Myrrh attenuates oxidative and inflammatory processes in acetic acid-induced ulcerative colitis

    PubMed Central

    Fatani, Amal Jamil; Alrojayee, Fatima Salih; Parmar, Mihir Yogeshkumar; Abuohashish, Hatem Mustafa; Ahmed, Mohammed Mahboobuddin; Al-Rejaie, Salim Salih

    2016-01-01

    The pathogenesis of ulcerative colitis (UC) has been associated with a weakened antioxidant capacity and increased inflammatory processes. Myrrh is traditionally used for the treatment of inflammatory diseases due to its antioxidant and anti-inflammatory properties. The present study aimed to evaluate the effects of myrrh on an experimental rat model of UC. UC was induced in rats using acetic acid (AA) after pre-treatment with myrrh (125, 250 or 500 mg/kg/day) or mesalazine (MES; 300 mg/kg/day) for 7 days. The levels of various inflammatory cytokines, prostaglandin E2 (PGE2) and nitric oxide (NO) in the rat colon tissues were assessed. In addition, the colonic levels of thiobarbituric acid reactive substances (TBARS) and non-protein sulfhydryl groups (NP-SH), as well as the activities of superoxide dismutase (SOD) and catalase (CAT), were estimated. Furthermore, total protein (TP) contents and the levels of DNA and RNA were measured, and histopathological changes in colonic tissues were analyzed. The results indicated that the levels of pro-inflammatory cytokines, PGE2, NO and TBARS were markedly increased. By contrast, the levels of interleukin-10, NP-SH, TP and nucleic acids, and the enzymatic activities of SOD and CAT were significantly decreased in the AA model group. In addition, pretreatment with myrrh and MES was able to attenuate the impaired oxidative stress response and upregulation of inflammatory biomarkers. Furthermore, the enzymatic activities of SOD and CAT were near to normal in the myrrh and MES pretreated groups. The ability of myrrh to protect against UC was further confirmed by histopathological analysis, and the high dose of myrrh exerted an effect comparable to MES. In conclusion, the results of the present study suggested that myrrh has potent therapeutic value in the amelioration of experimental colitis in laboratory animals by downregulating the expression of proinflammatory mediators and improving endogenous antioxidative activities. PMID

  10. Healing Acceleration of Acetic Acid-induced Colitis by Marigold (Calendula officinalis) in Male Rats

    PubMed Central

    Tanideh, Nader; Jamshidzadeh, Akram; Sepehrimanesh, Masood; Hosseinzadeh, Masood; Koohi-Hosseinabadi, Omid; Najibi, Asma; Raam, Mozhdeh; Daneshi, Sajad; Asadi-Yousefabad, Seyedeh-Leili

    2016-01-01

    Background/Aim: Ulcerative colitis (UC) is a type of chronic inflammatory bowel disease with unknown etiology. Several therapeutic strategies such as consumption of medicinal plants have been used for its treatment. The aim of this study was to evaluate healing effects of Calendula officinalis hydroalcoholic extract in experimentally induced UC in rat. Materials and Methods: Ninety-six rats, weighing 200 ± 20 g, were randomly divided into eight equal groups. UC induced by 3% acetic acid and oral doses of C. officinalis extract, 1500 and 3000 mg/kg, and enema (gel 10% and 20%) were given. Two groups as positive controls were given asacol (enema) and oral mesalamine. Negative control groups were given normal saline and base gel. On days 3 and 7, intestinal histopathology and weight changes, plus oxidative stress indices including malondialdehyde (MDA) level and myeloperoxidase (MPO) activity were assayed. Results: A significant increase in the body weight of rats was seen in the group given C. officinalis extract 3000 mg/kg orally, oral mesalamine, and 20% intracolonic gel form of marigold extract compared with negative control and base gel groups during the experimental period. Acute inflammation and granular atrophy after UC induction were resolved completely completely by both 20% intracolonic gel and 3000 mg/kg orally. An increase in MPO activity and a decrease in MDA level in response to oral and intracolonic gel form of C. officinalis were observed 3 and and 7 days after treatment (P < 0.05). Conclusion: Our results indicate that oral and enema forms of hydroalcoholic extract of C. officinalis can be offered as are potential therapeutic agents for UC induced in rats. PMID:26831607

  11. Healing Effect of Pistacia Atlantica Fruit Oil Extract in Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Tanideh, Nader; Masoumi, Samira; Hosseinzadeh, Massood; Safarpour, Ali Reza; Erjaee, Hoda; Koohi-Hosseinabadi, Omid; Rahimikazerooni, Salar

    2014-01-01

    Background: Considering the anti-oxidant properties of Pistacia atlantica and lack of data regarding its efficacy in the treatment of ulcerative colitis, this study aims at investigating the effect of the Pistacia atlantica fruit extract in treating experimentally induced colitis in a rat model. Methods: Seventy male Sprague-Dawley rats (weighing 220±20 g) were used. All rats fasted 24 hours before the experimental procedure. The rats were randomly divided into 7 groups, each containing 10 induced colitis with 2ml acetic acid (3%). Group 1 (Asacol), group 2 (base gel) and group 7 (without treatment) were assigned as control groups. Group 3 (300 mg/ml) and group 4 (600 mg/ml) received Pistacia atlantica fruit orally. Group 5 (10% gel) and group 6 (20% gel) received Pistacia atlantica in the form of gel as enema. Macroscopic, histopathological examination and MDA measurement were carried out. Results: All groups revealed significant macroscopic healing in comparison with group 7 (P<0.001). Regarding microscopic findings in the treatment groups compared with group 7, the latter group differed significantly with groups 1, 2, 4 and 6 (P<0.001). There was a significant statistical difference in MDA scores of the seven treatment groups (F(5,54)=76.61, P<0.001). Post-hoc comparisons indicated that the mean±SD score of Asacol treated group (1.57±0.045) was not significantly different from groups 4 (1.62±0.024) and 6 (1.58±0.028). Conclusion: Our study showed that a high dose of Pistacia atlantica fruit oil extract, administered orally and rectally can improve colitis physiologically and pathologically in a rat model, and may be efficient for ulcerative colitis. PMID:25429174

  12. Pretreatment of Gymnema sylvestre revealed the protection against acetic acid-induced ulcerative colitis in rats

    PubMed Central

    2014-01-01

    Background Overproduction of free radicals and decreased antioxidant capacity are well-known risk factors for inflammatory bowel diseases. Gymnema sylvestre (GS) leaves extract is distinguished for its anti-diabetic, antioxidant and anti-inflammatory properties. Present study is designed to evaluate the preventative activities of GS against acetic acid (AA)-induced ulcerative colitis in Wistar rats. Methods Experimentally ulcerative colitis (UC) was induced by AA in animals pretreated with three different doses of GS leaves extract (50, 100, 200 mg/kg/day) and a single dose of mesalazine (MES, 300 mg/kg/day) for seven days. Twenty four hours later, animals were sacrificed and the colonic tissues were collected. Colonic mucus content was determined using Alcian blue dye binding technique. Levels of thiobarbituric acid reactive substances (TBARS), total glutathione sulfhydryl group (T-GSH) and non-protein sulfhydryl group (NPSH) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were estimated in colon tissues. Colonic nucleic acids (DNA and RNA) and total protein (TP) concentrations were also determined. Levels of pro-inflammatory cytokines including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) as well as prostaglandin E2 (PGE2) and nitric oxide (NO) were estimated in colonic tissues. The histopathological changes of the colonic tissues were also observed. Results In AA administered group TBARS levels were increased, while colonic mucus content, T-GSH and NP-SH, SOD and CAT were reduced in colon. Pretreatment with GS inhibited TBARS elevation as well as mucus content, T-GSH and NP-SH reduction. Enzymatic activities of SOD and CAT were brought back to their normal levels in GS pretreated group. A significant reduction in DNA, RNA and TP levels was seen following AA administration and this inhibition was significantly eliminated by GS treatment. GS pretreatment also inhibited

  13. Hydroalcoholic extract of Brazilian red propolis exerts protective effects on acetic acid-induced ulcerative colitis in a rodent model.

    PubMed

    Barbosa Bezerra, Gislaine; de Menezes de Souza, Luana; Dos Santos, Adailma Santana; de Almeida, Grace Kelly Melo; Souza, Marília Trindade Santana; Santos, Sandra Lauton; Aparecido Camargo, Enilton; Dos Santos Lima, Bruno; de Souza Araújo, Adriano Antunes; Cardoso, Juliana Cordeiro; Gomes, Silvana Vieira Floresta; Gomes, Margarete Zanardo; de Albuquerque, Ricardo Luiz Cavalcanti

    2017-01-01

    Ulcerative colitis (UC) is a common intestinal inflammatory disease with an etiology that is not well understood. Although the anti-inflammatory and anti-oxidant effects of the hydroalcoholic extract of Brazilian red propolis (HERP) have been reported in various experimental models, its protective effect in models of UC have not been evaluated. The purpose of this study was to investigate the chemopreventive effect of hydroalcoholic extract of Brazilian red propolis (HERP) in acetic acid-induced colitis (AAIC) using a rodent model. The HERP was chemically characterised by HPLC/DAD analyses. Male rats were randomly assigned into four groups: sham, vehicle (with AAIC, treated with vehicle), P10 (with AAIC, treated with 10mg/kg HERP), and P100 (with AAIC, treated with 100mg/kg HERP). Treatments were performed for 7days, and colitis was induced on day seven. Animals were euthanized 24h after colitis induction and body weight, colon length, gross and histological scores, malondialdehyde (MDA) and myeloperoxidase (MPO) concentrations in colon tissue, and the immunohistochemical expression of inducible nitric oxide synthase (iNOS) were assessed. The major compounds found in HERP were liquiritigenin (68.8mg/g), formononetin (54.29mg/g), biochanin A (30.97mg/g), and daidzein (19.90mg/g). Rats treated with 10mg/kg HERP demonstrated significant decreases in MPO concentrations, gross and histological scores of tissue damage, and iNOS expression (p<0.05). Similarly, rats treated with 100mg/kg HERP demonstrated significant decreases in MPO levels (p<0.05) and histological scores of tissue damage (p<0.05). The results of this study indicate that oral administration of HERP attenuates AAIC in rats, which may be due to anti-inflammatory effects related to iNOS inhibition.

  14. Synergic Interaction of Rifaximin and Mutaflor (Escherichia coli Nissle 1917) in the Treatment of Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Warzecha, Zygmunt; Ceranowicz, Piotr; Dembiński, Marcin; Cieszkowski, Jakub; Bulanda, Małgorzata; Kuśnierz-Cabala, Beata; Gałązka, Krystyna; Konturek, Peter Christopher

    2016-01-01

    Background. Inflammatory bowel disease results from the dysregulation of immune response to environmental and microbial agents in genetically susceptible individuals. The aim of the present study was to examine the effect of rifaximin and/or Mutaflor (Escherichia coli Nissle 1917, EcN) administration on the healing of acetic acid-induced colitis. Methods. Colitis was induced in male Wistar rats by rectal enema with 3.5% acetic acid solution. Rifaximin (50 mg/kg/dose) and/or Mutaflor (109 CFU/dose) were given intragastrically once a day. The severity of colitis was assessed at the 8th day after induction of inflammation. Results. Treatment with rifaximin significantly accelerated the healing of colonic damage. This effect was associated with significant reversion of the acetic acid-evoked decrease in mucosal blood flow and DNA synthesis. Moreover, administration of rifaximin significantly reduced concentration of proinflammatory TNF-α and activity of myeloperoxidase in colonic mucosa. Mutaflor given alone was without significant effect on activity of colitis. In contrast, Mutaflor given in combination with rifaximin significantly enhanced therapeutic effect of rifaximin. Moreover, Mutaflor led to settle of the colon by EcN and this effect was augmented by pretreatment with rifaximin. Conclusion. Rifaximin and Mutaflor exhibit synergic anti-inflammatory and therapeutic effect in acetic acid-induced colitis in rats. PMID:27433160

  15. Synergic Interaction of Rifaximin and Mutaflor (Escherichia coli Nissle 1917) in the Treatment of Acetic Acid-Induced Colitis in Rats.

    PubMed

    Dembiński, Artur; Warzecha, Zygmunt; Ceranowicz, Piotr; Dembiński, Marcin; Cieszkowski, Jakub; Gosiewski, Tomasz; Bulanda, Małgorzata; Kuśnierz-Cabala, Beata; Gałązka, Krystyna; Konturek, Peter Christopher

    2016-01-01

    Background. Inflammatory bowel disease results from the dysregulation of immune response to environmental and microbial agents in genetically susceptible individuals. The aim of the present study was to examine the effect of rifaximin and/or Mutaflor (Escherichia coli Nissle 1917, EcN) administration on the healing of acetic acid-induced colitis. Methods. Colitis was induced in male Wistar rats by rectal enema with 3.5% acetic acid solution. Rifaximin (50 mg/kg/dose) and/or Mutaflor (10(9) CFU/dose) were given intragastrically once a day. The severity of colitis was assessed at the 8th day after induction of inflammation. Results. Treatment with rifaximin significantly accelerated the healing of colonic damage. This effect was associated with significant reversion of the acetic acid-evoked decrease in mucosal blood flow and DNA synthesis. Moreover, administration of rifaximin significantly reduced concentration of proinflammatory TNF-α and activity of myeloperoxidase in colonic mucosa. Mutaflor given alone was without significant effect on activity of colitis. In contrast, Mutaflor given in combination with rifaximin significantly enhanced therapeutic effect of rifaximin. Moreover, Mutaflor led to settle of the colon by EcN and this effect was augmented by pretreatment with rifaximin. Conclusion. Rifaximin and Mutaflor exhibit synergic anti-inflammatory and therapeutic effect in acetic acid-induced colitis in rats.

  16. Role of extracellular signal-regulated kinase in synaptic transmission and plasticity of a nociceptive input on capsular central amygdaloid neurons in normal and acid-induced muscle pain mice.

    PubMed

    Cheng, Sin-Jhong; Chen, Chien-Chang; Yang, Hsiu-Wen; Chang, Ya-Ting; Bai, Shin-Wen; Chen, Chih-Cheng; Yen, Chen-Tung; Min, Ming-Yuan

    2011-02-09

    Application of phorbol 12,13-diacetate (PDA) caused marked enhancement of synaptic transmission of nociceptive parabrachio-amygdaloid (PBA) input onto neurons of the capsular central amygdaloid (CeAC) nucleus. The potentiation of PBA-CeAC EPSCs by PDA involved a presynaptic protein kinase C (PKC)-dependent component and a postsynaptic PKC-extracellular-regulated kinase (ERK)-dependent component. NMDA glutamatergic receptor (NMDAR)-dependent long-term potentiation (LTP) of PBA-CeAC EPSCs, which was also dependent on the PKC-ERK signaling pathway, was induced by tetanus stimulation at 100 Hz. In slices from mice subjected to acid-induced muscle pain (AIMP), phosphorylated ERK levels in the CeAC increased, and PBA-CeAC synaptic transmission was postsynaptically enhanced. The enhanced PBA-CeAC synaptic transmission in AIMP mice shared common mechanisms with the postsynaptic potentiation effect of PDA and induction of NMDAR-dependent LTP by high-frequency stimulation in normal slices, both of which required ERK activation. Since the CeAC plays an important role in the emotionality of pain, enhanced synaptic function of nociceptive (PBA) inputs onto CeAC neurons might partially account for the supraspinal mechanisms underlying central sensitization.

  17. Yogurt containing Lactobacillus gasseri OLL 2716 (LG21 yogurt) accelerated the healing of acetic acid-induced gastric ulcer in rats.

    PubMed

    Uchida, Masayuki; Shimizu, Kimiko; Kurakazu, Keiko

    2010-01-01

    We have reported that LG21 yogurt containing Lactobacillus gasseri OLL 2716 (LG21 yogurt) inhibits the formation of HCl-induced acute gastric lesions through the generation of prostaglandin E₂. This study aimed to determine the role of viable Lactobacillus in the healing of acetic acid-induced chronic gastric ulcer. LG21 yogurt or γ-ray radiated LG21 yogurt was administered orally twice a day for 10 d at a dose of 5 ml/kg. LG21 yogurt significantly accelerated the healing of the ulcer, but γ-ray radiated LG21 yogurt did not. However, both yogurts significantly inhibited HCl-induced gastric erosive lesions and enhanced the generation of gastric mucosal prostaglandin E₂. From the above results, it was found that viable bacteria are needed to accelerate the healing of chronic gastric ulcer, but not to inhibit gastric lesions.

  18. Analgesic and Anti-Inflammatory Properties of Gelsolin in Acetic Acid Induced Writhing, Tail Immersion and Carrageenan Induced Paw Edema in Mice

    PubMed Central

    Gupta, Ashok Kumar; Parasar, Devraj; Sagar, Amin; Choudhary, Vikas; Chopra, Bhupinder Singh; Garg, Renu; Ashish; Khatri, Neeraj

    2015-01-01

    Plasma gelsolin levels significantly decline in several disease conditions, since gelsolin gets scavenged when it depolymerizes and caps filamentous actin released in the circulation following tissue injury. It is well established that our body require/implement inflammatory and analgesic responses to protect against cell damage and injury to the tissue. This study was envisaged to examine analgesic and anti-inflammatory activity of exogenous gelsolin (8 mg/mouse) in mice models of pain and acute inflammation. Administration of gelsolin in acetic acid-induced writhing and tail immersion tests not only demonstrated a significant reduction in the number of acetic acid-induced writhing effects, but also exhibited an analgesic activity in tail immersion test in mice as compared to placebo treated mice. Additionally, anti-inflammatory function of gelsolin (8 mg/mouse) compared with anti-inflammatory drug diclofenac sodium (10 mg/kg)] was confirmed in the carrageenan injection induced paw edema where latter was measured by vernier caliper and fluorescent tomography imaging. Interestingly, results showed that plasma gelsolin was capable of reducing severity of inflammation in mice comparable to diclofenac sodium. Analysis of cytokines and histo-pathological examinations of tissue revealed administration of gelsolin and diclofenac sodium significantly reduced production of pro-inflammatory cytokines, TNF-α and IL-6. Additionally, carrageenan groups pretreated with diclofenac sodium or gelsolin showed a marked decrease in edema and infiltration of inflammatory cells in paw tissue. Our study provides evidence that administration of gelsolin can effectively reduce the pain and inflammation in mice model. PMID:26426535

  19. Accelerated Ulcer Healing and Resistance to Ulcer Recurrence with Gastroprotectants in Rat Model of Acetic Acid-induced Gastric Ulcer

    PubMed Central

    Young Oh, Tae; Ok Ahn, Byung; Jung Jang, Eun; Sang Park, Joo; Jong Park, Sang; Wook Baik, Hyun; Hahm, Ki-Baik

    2008-01-01

    Quality of ulcer healing (QOUH) is defined as ideal ulcer healing featuring with the fine granular ulcer scar, high functional restoration and the resistance to recurrence. This study was designed to compare the rates of QOUH achievement in rat gastric ulcer model between acid suppressant treated group and gastroprotectant treated group accompanied with elucidations of molecular mechanisms. Serosal injection of acetic acids for generating gastric ulcer and intraperitoneal (ip) injection of recombinant interleukin 1-beta (IL-1β) for recurring healed ulcer was done in SD rats. The 72 rats were divided into three groups according to treatment as follows; Group I, no further treatment, Group II, 8 weeks treatment of omeprazole, and Group III, 8 weeks of gastroprotectant treatment. IL-1β was administered for ulcer recurrence after 28 weeks of acetic acid injection. At four weeks after gastric ulcerogenesis, 58.3% (7/12) of active gastric ulcer were converted to healing stage in Group III, but 16.7% (2/12) in Group II and none in Group I, for which significant levels of epidermal growth factor, mucin, and pS2/trefoil peptide1 were contributive to these accelerated healings of Group III. ip injections of rIL-1β (200 µg/kg) at 28 weeks after acetic acid injection led to 100% of ulcer recurrence in Group I and 75.0% in Group II, but only 16.7% of Group III rats showed ulcer recurrence. Significantly attenuated levels of inflammatory cytokines including IL-2, transforming growth factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), nitrotyrosine were responsible for the resistance to ulcer recurrence in Group III. Conclusively, gastroprotectant might be prerequisite in order to achieve ideal QOUH through significant inductions of remodeling. PMID:18545642

  20. [Influence of KU-1257 on the recurrence and relapse of acetic acid-induced chronic gastric ulcers in rats].

    PubMed

    Sekiguchi, H; Ohsawa, A; Kobayashi, F; Ohkubo, H; Taga, F

    1996-02-01

    The influence of KU-1257 on the recurrence and relapse of acetic acid ulcers in rats was investigated grossly and histologically in comparison with that of cimetidine. The ulcer was induced by topical application of glacial acetic acid at the junction of the corpus and antrum on the anterior wall of the stomach. The drug was administered from the 5th to the 153rd day after the ulcer induction and then discontinued to the 238th day. The healing rates of the control groups (control) rose until the 119th day after the ulcer induction, followed by ups and downs. The quality of healing in the regenerated mucosa and the granulation tissue of the healed ulcer was poor, resulting in the recurrence and relapse of ulcers. The recurrence and relapse of ulcers also occurred in the cimetidine groups (CIM). On the other hand, the KU-1257 groups (KU-1257) showed much lower recurrence and relapse rates of ulcers than the control and CIM groups. Moreover, KU-1257, unlike CIM, improved the quality of ulcer healing throughout the period of its administration and even after it was discontinued. These results suggest that KU-1257 improves the quality of ulcer healing, and this may contribute to the low recurrence and relapse rates of ulcers.

  1. Kaempferol, a dietary flavonoid, ameliorates acute inflammatory and nociceptive symptoms in gastritis, pancreatitis, and abdominal pain.

    PubMed

    Kim, Shi Hyoung; Park, Jae Gwang; Sung, Gi-Ho; Yang, Sungjae; Yang, Woo Seok; Kim, Eunji; Kim, Jun Ho; Ha, Van Thai; Kim, Han Gyung; Yi, Young-Su; Kim, Ji Hye; Baek, Kwang-Soo; Sung, Nak Yoon; Lee, Mi-nam; Kim, Jong-Hoon; Cho, Jae Youl

    2015-07-01

    Kaempferol (KF) is the most abundant polyphenol in tea, fruits, vegetables, and beans. However, little is known about its in vivo anti-inflammatory efficacy and mechanisms of action. To study these, several acute mouse inflammatory and nociceptive models, including gastritis, pancreatitis, and abdominal pain were employed. Kaempferol was shown to attenuate the expansion of inflammatory lesions seen in ethanol (EtOH)/HCl- and aspirin-induced gastritis, LPS/caerulein (CA) triggered pancreatitis, and acetic acid-induced writhing.

  2. Effect of Coriandrum sativum hydroalcoholic extract and its essential oil on acetic acid- induced acute colitis in rats

    PubMed Central

    Heidari, Bahareh; Sajjadi, Seyed Ebrahim; Minaiyan, Mohsen

    2016-01-01

    Objective: The aim of this study was to determine the protective effects of Coriandrum sativum on acetic acid-inducedcolitis in rats. C. sativum (Coriander) has long been used in Iranian traditional medicine and its use as an anti-inflammatory agent is still common in some herbal formulations. Materials and Methods: Colitis was induced by intra-rectal administration of 2ml acetic acid 4% in fasted male Wistar rats. Treatment was carried out using three increasing doses of extract (250, 500, 1000 mg/kg) and essential oil (0.25, 0.5, 1 ml/kg) of coriander started 2 h before colitis induction and continued for a five-day period. Colon biopsies were taken for weighting, macroscopic scoring of injured tissue, histopathological examination and measuring myeloperoxidase (MPO) activity. Results: Colon weight was decreased in the groups treated with extract (500 and 1000 mg/kg) and essential oil (0.5 ml/kg) compared to the control group. Regarding MPO levels, ulcer severity and area as well as the total colitis index, same results indicating meaningful alleviation of colitis was achieved after treatment with oral extract and essential oil. Conclusion: Since the present experiment was made by oral fractions of coriander thus the resulting effects could be due to both the absorption of the active ingredients and/or the effect of non-absorbable materials on colitis after reaching the colon. In this regard, we propose more toxicological and clinical experiments to warranty its beneficial application in human inflammatory bowel diseases. PMID:27222834

  3. Naringin ameliorates acetic acid induced colitis through modulation of endogenous oxido-nitrosative balance and DNA damage in rats

    PubMed Central

    Kumar, Venkatashivam Shiva; Rajmane, Anuchandra Ramchandra; Adil, Mohammad; Kandhare, Amit Dattatraya; Ghosh, Pinaki; Bodhankar, Subhash Laxman

    2014-01-01

    The aim of this study was to evaluate the effect of naringin on experimentally induced inflammatory bowel disease in rats. Naringin (20, 40 and 80 mg/kg) was given orally for 7 days to Wistar rats before induction of colitis by intrarectal instillation of 2 mL of 4% (v/v) acetic acid solution. The degree of colonic mucosal damage was analyzed by examining mucosal damage, ulcer area, ulcer index and stool consistency. Intrarectal administration of 4% acetic acid resulted in significant modulation of serum alkaline phosphatase, lactate dehydrogenase, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO) content along with colonic nitric oxide (NO), xanthine oxidase (XO) level and protein carbonyl content in the colonic tissue as well as in blood. Naringin (40 and 80 mg/kg) exerted a dose dependent (P < 0.05) ameliorative effect, as it significantly increased hematological parameter as well as colonic SOD and GSH. There was a significant (P < 0.05) and dose dependant inhibition of macroscopical score, ulcer area along with colonic MDA, MPO activity by the 7 days of pretreatment of naringin (40 and 80 mg/kg). Biochemical studies revealed a significant (P < 0.05) dose dependant inhibition in serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels by pretreatment of naringin. Increased levels of colonic NO, XO, protein carbonyl content and DNA damage were also significantly decreased by naringin pretreatment. The findings of the present investigation propose that naringin has an anti-inflammatory, anti-oxidant and anti-apoptotic potential effect at colorectal sites as it modulates the production and expression of oxidative mediators such as MDA, MPO, NO and XO, thus reducing DNA damage. PMID:24683411

  4. Indole-3-acetic acid-induced oxidative burst and an increase in cytosolic calcium ion concentration in rice suspension culture.

    PubMed

    Nguyen, Hieu T H; Umemura, Kenji; Kawano, Tomonori

    2016-08-01

    Indole-3-acetic acid (IAA) is the major natural auxin involved in the regulation of a variety of growth and developmental processes such as division, elongation, and polarity determination in growing plant cells. It has been shown that dividing and/or elongating plant cells accompanies the generation of reactive oxygen species (ROS) and a number of reports have suggested that hormonal actions can be mediated by ROS through ROS-mediated opening of ion channels. Here, we surveyed the link between the action of IAA, oxidative burst, and calcium channel activation in a transgenic cells of rice expressing aequorin in the cytosol. Application of IAA to the cells induced a rapid and transient generation of superoxide which was followed by a transient increase in cytosolic Ca(2+) concentration ([Ca(2+)]c). The IAA-induced [Ca(2+)]c elevation was inhibited by Ca(2+) channel blockers and a Ca(2+) chelator. Furthermore, ROS scavengers effectively blocked the action of IAA on [Ca(2+)]c elevation.

  5. Assessment of the antinociceptive effects of pregabalin alone or in combination with morphine during acetic acid-induced writhing in mice.

    PubMed

    Shamsi Meymandi, Manzumeh; Keyhanfar, Fariborz

    2013-09-01

    Visceral pain currently represents one of the most important pain treatment challenges in clinical practice, and investigators across the world are continuously designing and conducting numerous studies in search of new analgesics and new combination therapies. The current study assessed the analgesic effects of saline, pregabalin (2, 5, 17, 50, 100, and 200 mg/kg, i.p.) and morphine (0.25, 0.5, 1, 3 and 5 mg/kg) alone or in combination on acetic-acid induced abdominal contractions in mice. The number of writhes and the inhibitory effects (as percentages, %E) were calculated as antinociception indexes. These indexes indicated that both pregabalin (Prg) and morphine (Mrp) produced dose-dependent antinociception. Pregabalin at 5 mg/kg (%E=32.5±4.0) or 2 mg/kg (%E=20.8±4.5) and morphine at 0.25 mg/kg (%E=20.2±7.8) and 0.5 mg/kg (%E=43.6±4.5) exhibited antinociceptive effects, and the combination of pregabalin and morphine produced significantly greater antinociceptive effects (%E=62.4±5.8 for Prg5+Mrp0.25; %E=71.7±4.8 for Prg5+Mrp0.5; and %E=54.1±4.0 for Prg2+Mrp0.25), although this enhancement was not observed when morphine was combined with 17 mg/kg pregabalin. Pre-treatment with 2 mg/kg (i.p.) naloxone did not affect increased analgesia when combined with these drugs. A dose-response curve was established for pregabalin at a fixed morphine dose and revealed that, at low doses, pregabalin dose-dependently enhanced the antinociceptive effects, while the opposite was true at high doses (17 and 25 mg/kg). In conclusion, pregabalin can produce levels of antinociception that are similar to those of morphine in acetic acid-induced viscero-somatic pain. The enhancement of antinociception produced by the co-administration of morphine and pregabalin is termed a supra-additive interaction and occurred at low doses but not at high doses. These findings militate for increased attention and caution in clinical settings.

  6. Observing Anti-inflammatory and Anti-nociceptive Activities of Glycyrrhizin Through Regulating COX-2 and Pro-inflammatory Cytokines Expressions in Mice.

    PubMed

    Wang, Hong-Ling; Li, Yu-Xiang; Niu, Ya-Ting; Zheng, Jie; Wu, Jing; Shi, Guang-Jiang; Ma, Lin; Niu, Yang; Sun, Tao; Yu, Jian-Qiang

    2015-12-01

    The present study aimed to investigate the potential anti-inflammatory and anti-nociceptive activities of glycyrrhizin (GL) in mice and to explore the possible related mechanisms. Xylene-induced ear edema, carrageenan-induced paw edema and acetic acid-induced vascular permeability test were used to investigate the anti-inflammatory activities of GL in mice. Anti-nociceptive effects of GL were assessed by using acetic acid-induced writhing, hot plate test and formalin test, as well as evaluation of spontaneous locomotor activity and motor performance. The mRNA expression of pro-inflammatory cytokines (such as TNF-α, IL-6 and iNOS) and the protein expression of cyclooxygenase-2 (COX-2) were explored by using real-time fluorogenic PCR and Western blot, respectively. The results showed that GL significantly reduced xylene-induced ear edema, carrageenan-induced paw edema, and acetic acid-induced vascular permeation. Additionally, GL significantly inhibited the nociceptions induced by acetic acid and formalin. However, the nociceptions could not be decreased by GL in the hot plate test, and GL did not affect spontaneous locomotor activity and motor performance. The expression levels of TNF-α, IL-6, iNOS and COX-2 were significantly downregulated by GL. In conclusion, GL exerts significant anti-inflammatory and analgesic activities by attenuating the expression levels of TNF-α, IL-6, iNOS and COX-2.

  7. Manuka Honey Exerts Antioxidant and Anti-Inflammatory Activities That Promote Healing of Acetic Acid-Induced Gastric Ulcer in Rats

    PubMed Central

    Almasaudi, Saad B.; Al-Hindi, Rashad R.; Abdel-dayem, Umama A.; Ali, Soad S.; Saleh, Rasha M.; Al Jaouni, Soad K.

    2017-01-01

    Gastric ulcers are a major problem worldwide with no effective treatment. The objective of this study was to evaluate the use of manuka honey in the treatment of acetic acid-induced chronic gastric ulcers in rats. Different groups of rats were treated with three different concentrations of honey. Stomachs were checked macroscopically for ulcerative lesions in the glandular mucosa and microscopically for histopathological alterations. Treatment with manuka honey significantly reduced the ulcer index and maintained the glycoprotein content. It also reduced the mucosal myeloperoxidase activity, lipid peroxidation (MDA), and the inflammatory cytokines (TNF-α, IL-1β, and IL-6) as compared to untreated control group. In addition, honey-treated groups showed significant increase in enzymatic (GPx and SOD) and nonenzymatic (GSH) antioxidants besides levels of the anti-inflammatory cytokine IL-10. Flow cytometry studies showed that treatment of animals with manuka honey has normalized cell cycle distribution and significantly lowered apoptosis in gastric mucosa. In conclusion, the results indicated that manuka honey is effective in the treatment of chronic ulcer and preservation of mucosal glycoproteins. Its effects are due to its antioxidant and anti-inflammatory properties that resulted in a significant reduction of the gastric mucosal MDA, TNF-α, IL-1β, and IL-6 and caused an elevation in IL-10 levels. PMID:28250794

  8. Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade.

    PubMed

    El-Gowelli, Hanan M; Saad, Evan I; Abdel-Galil, Abdel-Galil A; Ibrahim, Einas R

    2015-11-01

    In this work, α-lipoic acid and cyclosporine demonstrated significant protection against acetic acid-induced ulcerative colitis in rats. We proposed that α-lipoic acid and cyclosporine co-administration might modulate their individual effects. Induction of ulcerative colitis in rats was performed by intra-rectal acetic acid (5% v/v) administration for 3 consecutive days. Effects of individual or combined used of α-lipoic acid (35 mg/kg ip) or cyclosporine (5mg/kg sc) for 6 days starting 2 days prior to acetic acid were assessed. Acetic acid caused colon ulceration, bloody diarrhea and weight loss. Histologically, there was mucosal atrophy and inflammatory cells infiltration in submucosa, associated with depletion of colon reduced glutathione, superoxide dismutase and catalase activities and elevated colon malondialdehyde, serum C-reactive protein (C-RP) and tumor necrosis factor-α (TNF-α). Colon gene expression of cyclooxygenase-2 and miR-210 was also elevated. These devastating effects of acetic acid were abolished upon concurrent administration of α-lipoic acid. Alternatively, cyclosporine caused partial protection against acetic acid-induced ulcerative colitis. Cyclosporine did not restore colon reduced glutathione, catalase activity, serum C-RP or TNF-α. Unexpectedly, co-administration of α-lipoic acid and cyclosporine aggravated colon ulceration. Concomitant use of α-lipoic acid and cyclosporine significantly increased nitric oxide production, cyclooxygenase-2 and miR-210 gene expression compared to all other studied groups. The current findings suggest that facilitation of nitric oxide/cyclooxygenase-2/miR-210 cascade constitutes, at least partially, the cellular mechanism by which concurrent use of α-lipoic acid and cyclosporine aggravates colon damage. Collectively, the present work highlights the probable risk of using α-lipoic acid/cyclosporine combination in ulcerative colitis patients.

  9. Anti-Inflammatory and Anti-Nociceptive Activities of Methanol Extract from Aerial Part of Phlomis younghusbandii Mukerjee

    PubMed Central

    Wang, Qiu-Shi; Yang, Li; Cui, Wen-Yao; Chen, Lei; Jiang, Yan-Hua

    2014-01-01

    This study was designed to investigate the anti-inflammatory and anti-nociceptive activity of the methanol extract from the aerial part of Phlomis younghusbandii (MEAP) and to explore the possible related mechanisms. Anti-inflammatory effects of MEAP were evaluated by using the ear edema test induced by dimethylbenzene and vascular permeability test induced by acetic acid. Anti-nociceptive activities of MEAP were evaluated by the chemical nociception in models of acetic acid-induced writhing and formalin-induced hind paw licking, and by the thermal nociception in hot plate tests. Mechanisms of MEAP activities also were explored by evaluating expression levels of TNF-α, IL-6 and iNOS induced by LPS using real-time fluorogenic PCR and expression of COX-2 using Western blotting and an open-field test. The results indicated that the MEAP administered orally could significantly decrease ear edema induced by dimethylbenzene and increase vascular permeability induced by acetic acid. Additionally, the nociceptions induced by acetic acid and formalin were significantly inhibited. The anti-nociceptive effect could not be decreased by naloxone in the formalin test, and MEAP did not affect the normal autonomic activities of mice. Expression levels of pro-inflammatory cytokines (TNF-α, IL-6, iNOS) induced by LPS were decreased obviously by treatment with MEAP. Furthermore, COX-2 expression in the spinal dorsal horns of the pain model mice induced by formalin was significantly down-regulated by MEAP. In conclusion, MEAP has significant anti-inflammatory and antinociceptive activities, and the mechanisms may be related to the down-regulated expression of TNF-α, IL-6, iNOS and COX-2. PMID:24598860

  10. Protective Role of Curcumin and Flunixin Against Acetic Acid-Induced Inflammatory Bowel Disease via Modulating Inflammatory Mediators and Cytokine Profile in Rats.

    PubMed

    Gopu, Boobalan; Dileep, Rasakatla; Rani, Matukumalli Usha; Kumar, C S V Satish; Kumar, Matham Vijay; Reddy, Alla Gopala

    2015-01-01

    Ulcerative colitis is a chronically recurrent inflammatory bowel disease of unknown origin. The present study is to evaluate the effect of flunixin and curcumin in experimentally induced ulcerative colitis in rats. Animals were randomly divided into four groups, each consisting of 12 animals: normal control group, acetic acid group, curcumin-treated group, and flunixin-treated group. Induction of colitis by intracolonic administration of 4% acetic acid produced severe macroscopic inflammation in the colon, 14 days after acetic acid administration as assessed by the colonic damage score. Microscopically, colonic tissues showed ulceration, edema, and inflammatory cells infiltration. Biochemical studies revealed increased serum levels of lactate dehydrogenase (LDH), colonic alkaline phosphatase (ALP), and myeloperoxidase (MPO). Oxidative stress was indicated by elevated lipid peroxide formation and depleted reduced glutathione concentrations in colonic tissues. After induction of colitis, treatment with curcumin (50 mg/kg daily, p.o.) and flunixin (2.5 mg/kg daily, s.c.) decreased serum LDH, ALP, interleukin (IL)-1β, and tumor necrosis factor-α levels, as well as colonic MPO and lipid peroxide levels, whereas increased colonic prostaglandin E2 and IL-10 concentrations were observed. Moreover, effective doses of curcumin and flunixin were effective in restoring the histopathological changes induced by acetic acid administration. The findings of the present study provide evidence that flunixin may be beneficial in patients with inflammatory bowel disease.

  11. Knock-out of metacaspase and/or cytochrome c results in the activation of a ROS-independent acetic acid-induced programmed cell death pathway in yeast.

    PubMed

    Guaragnella, Nicoletta; Passarella, Salvatore; Marra, Ersilia; Giannattasio, Sergio

    2010-08-20

    To gain further insight into yeast acetic acid-induced programmed cell death (AA-PCD) we analyzed the effects of the antioxidant N-acetyl-L-cysteine (NAC) on cell viability, hydrogen peroxide (H(2)O(2)) production, DNA fragmentation, cytochrome c (cyt c) release and caspase-like activation in wild type (wt) and metacaspase and/or cyt c-lacking cells. We found that NAC prevents AA-PCD in wt cells, by scavenging H(2)O(2) and by inhibiting both cyt c release and caspase-like activation. This shows the occurrence of a reactive oxygen species (ROS)-dependent AA-PCD. Contrarily no NAC dependent change in AA-PCD of mutant cells was detectable, showing that a ROS-independent AA-PCD can also occur.

  12. L-arginine and aminoguanidine reduce colonic damage of acetic acid-induced colitis in rats: potential modulation of nuclear factor-κB/p65.

    PubMed

    Farghaly, Hanan S M; Thabit, Romany H

    2014-10-01

    The transcription factor, nuclear factor-κB (NF-κB) is a key inducer of inducible nitric oxide synthase (iNOS) gene expression. The aim of the present study was to investigate the potential protective effect of l-arginine (Arg; nitric oxide precursor) and aminoguanidine (inducible nitric oxide synthase inhibitor) against acetic acid (AA)-induced colitis in rats, and the potential role of NF-κB. Colitis was induced by intrarectal inoculation of rats with 4% acetic acid for three consecutive days. The effect of Arg and aminoguanidine on nitric oxide levels was assessed by Greiss assay and protein expression of NF-κB/p65, and inducible nitric oxide synthase was also investigated by immunohistochemistry. Slides were examined using ImageJ, and results reported as the percent area positive for each marker. Intrarectal AA caused a significant increase in bodyweight loss and colon weights. Arg at 100 mg/day for 7 days before induction of colitis diminished the changes in both bodyweight loss and colon weights. Furthermore, Arg attenuated the colonic tissues macroscopic and microscopic damage induced by acetic acid. In addition, i.p. AG 100 mg/kg given during and after induction of colitis recovered the colonic ulcerative lesion induced by AA. Arg can protect against colonic inflammation; an effect that probably be attributed to its nitric oxide-donating property, resulting in modulatory effects on the expression of NF-κB/p65 in the colon tissues. The results suggested that Arg might reduce the inflammation associated with colitis as confirmed by histopathological investigations. Arg might inhibit AA-induced colitis through the NF-κB/nitric oxide pathway.

  13. The transcription factors ADR1 or CAT8 are required for RTG pathway activation and evasion from yeast acetic acid-induced programmed cell death in raffinose

    PubMed Central

    Laera, Luna; Guaragnella, Nicoletta; Ždralević, Maša; Marzulli, Domenico; Liu, Zhengchang; Giannattasio, Sergio

    2016-01-01

    Yeast Saccharomyces cerevisiae grown on glucose undergoes programmed cell death (PCD) induced by acetic acid (AA-PCD), but evades PCD when grown in raffinose. This is due to concomitant relief of carbon catabolite repression (CCR) and activation of mitochondrial retrograde signaling, a mitochondria-to-nucleus communication pathway causing up-regulation of various nuclear target genes, such as CIT2, encoding peroxisomal citrate synthase, dependent on the positive regulator RTG2 in response to mitochondrial dysfunction. CCR down-regulates genes mainly involved in mitochondrial respiratory metabolism. In this work, we investigated the relationships between the RTG and CCR pathways in the modulation of AA-PCD sensitivity under glucose repression or de-repression conditions. Yeast single and double mutants lacking RTG2 and/or certain factors regulating carbon source utilization, including MIG1, HXK2, ADR1, CAT8, and HAP4, have been analyzed for their survival and CIT2 expression after acetic acid treatment. ADR1 and CAT8 were identified as positive regulators of RTG-dependent gene transcription. ADR1 and CAT8 interact with RTG2 and with each other in inducing cell resistance to AA-PCD in raffinose and controlling the nature of cell death. In the absence of ADR1 and CAT8, AA-PCD evasion is acquired through activation of an alternative factor/pathway repressed by RTG2, suggesting that RTG2 may play a function in promoting necrotic cell death in repressing conditions when RTG pathway is inactive. Moreover, our data show that simultaneous mitochondrial retrograde pathway activation and SNF1-dependent relief of CCR have a key role in central carbon metabolism reprogramming which modulates the yeast acetic acid-stress response. PMID:28357334

  14. Anti-inflammatory effect of volatile oil and hydroalcoholic extract of Rosa damascena Mill. on acetic acid-induced colitis in rats.

    PubMed

    Latifi, Ghazal; Ghannadi, Alireza; Minaiyan, Mohsen

    2015-01-01

    Rosa damascena is a small plant belonging to Rosaceae family which has been used for the treatment of some inflammatory diseases and digestive disorders in the Iranian folk medicine. This study was performed to investigate the effect of R. damascena hydroalcoholic extract (RDHE) and R. damascena volatile oil (RDVO) on ulcerative colitis induced by acetic acid in rats. Different doses of RDHE (250, 500, 1000 mg/kg) and RDVO (100, 200, 400 µl/kg) were given orally (p.o.) and doses of RDHE (125, 250, 500 mg/kg) were administrated intraperitoneally (i.p.) to the male Wistar rats (n=6) 2 h before induction of colitis which continued daily for 4 successive days. Prednisolone (4 mg/kg p.o.) and dexamethasone (1 mg/kg i.p.) were used in the reference groups. Weight/length ratios of wet colon were measured and the tissues were assessed macroscopically, histopathologically, and biochemically via measuring the myeloperoxidase (MPO) activity. Oral RDHE at all doses examined, and the lowest dose of RDVO given p.o. or RDHE administered i.p. reduced all indices of colitis measured in different assays as well as the MPO activity. These results provide encouraging support for the use of hydroalcoholic extract of R. damascena in relieving alimentary inflammatory conditions and reinforce the use of this plant to develop new agents for treating ulcerative colitis.

  15. Anti-inflammatory effect of volatile oil and hydroalcoholic extract of Rosa damascena Mill. on acetic acid-induced colitis in rats

    PubMed Central

    Latifi, Ghazal; Ghannadi, Alireza; Minaiyan, Mohsen

    2015-01-01

    Rosa damascena is a small plant belonging to Rosaceae family which has been used for the treatment of some inflammatory diseases and digestive disorders in the Iranian folk medicine. This study was performed to investigate the effect of R. damascena hydroalcoholic extract (RDHE) and R. damascena volatile oil (RDVO) on ulcerative colitis induced by acetic acid in rats. Different doses of RDHE (250, 500, 1000 mg/kg) and RDVO (100, 200, 400 µl/kg) were given orally (p.o.) and doses of RDHE (125, 250, 500 mg/kg) were administrated intraperitoneally (i.p.) to the male Wistar rats (n=6) 2 h before induction of colitis which continued daily for 4 successive days. Prednisolone (4 mg/kg p.o.) and dexamethasone (1 mg/kg i.p.) were used in the reference groups. Weight/length ratios of wet colon were measured and the tissues were assessed macroscopically, histopathologically, and biochemically via measuring the myeloperoxidase (MPO) activity. Oral RDHE at all doses examined, and the lowest dose of RDVO given p.o. or RDHE administered i.p. reduced all indices of colitis measured in different assays as well as the MPO activity. These results provide encouraging support for the use of hydroalcoholic extract of R. damascena in relieving alimentary inflammatory conditions and reinforce the use of this plant to develop new agents for treating ulcerative colitis. PMID:26779271

  16. Ethanolic extract of roots from Arctium lappa L. accelerates the healing of acetic acid-induced gastric ulcer in rats: Involvement of the antioxidant system.

    PubMed

    da Silva, Luisa Mota; Allemand, Alexandra; Mendes, Daniel Augusto G B; Dos Santos, Ana Cristina; André, Eunice; de Souza, Lauro Mera; Cipriani, Thales Ricardo; Dartora, Nessana; Marques, Maria Consuelo Andrade; Baggio, Cristiane Hatsuko; Werner, Maria Fernanda

    2013-01-01

    We evaluate the curative efficacy of the ethanolic extract (EET) of roots from Arctium lappa (bardana) in healing of chronic gastric ulcers induced by 80% acetic acid in rats and additionally studies the possible mechanisms underlying this action. Oral administration of EET (1, 3, 10 and 30mg/kg) reduced the gastric lesion area in 29.2%, 41.4%, 59.3% and 38.5%, respectively, and at 10mg/kg promoted significant regeneration of the gastric mucosa, which was confirmed by proliferating cell nuclear antigen immunohistochemistry. EET (10mg/kg) treatment did not increase the gastric mucus content but restored the superoxide dismutase activity, prevented the reduction of glutathione levels, reduced lipid hydroperoxides levels, inhibited the myeloperoxidase activity and reduced the microvascular permeability. In addition, EET reduced the free radical generation and increased scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals in vitro. Furthermore, intraduodenal EET (10 and 30mg/kg) decreased volume and acidity of gastric secretion. Total phenolic compounds were high in EET (Folin-Ciocalteau assay) and the analysis by liquid chromatography-mass spectrometry revealed that the main compounds present in EET were a serie of hydroxycinnamoylquinic acid isomers. In conclusion, these data reveal that EET promotes regeneration of damaged gastric mucosa, probably through its antisecretory and antioxidative mechanisms.

  17. Changes in saccharin preference behavior as a primary outcome to evaluate pain and analgesia in acetic acid-induced visceral pain in mice

    PubMed Central

    de la Puente, Beatriz; Romero-Alejo, Elizabeth; Vela, José Miguel; Merlos, Manuel; Zamanillo, Daniel; Portillo-Salido, Enrique

    2015-01-01

    Reflex-based procedures are important measures in preclinical pain studies that evaluate stimulated behaviors. These procedures, however, are insufficient to capture the complexity of the pain experience, which is often associated with the depression of several innate behaviors. While recent studies have made efforts to evidence the suppression of some positively motivated behaviors in certain pain models, they are still far from being routinely used as readouts for analgesic screening. Here, we characterized and compared the effect of the analgesic ibuprofen (Ibu) and the stimulant, caffeine, in assays of acute pain-stimulated and pain-depressed behavior. Intraperitoneal injection of acetic acid (AA) served as a noxious stimulus to stimulate a writhing response or depress saccharin preference and locomotor activity (LMA) in mice. AA injection caused the maximum number of writhes between 5 and 20 minutes after administration, and writhing almost disappeared 1 hour later. AA-treated mice showed signs of depression-like behaviors after writhing resolution, as evidenced by reduced locomotion and saccharin preference for at least 4 and 6 hours, respectively. Depression-like behaviors resolved within 24 hours after AA administration. A dose of Ibu (40 mg/kg) – inactive to reduce AA-induced abdominal writhing – administered before or after AA injection significantly reverted pain-induced saccharin preference deficit. The same dose of Ibu also significantly reverted the AA-depressed LMA, but only when it was administered after AA injection. Caffeine restored locomotion – but not saccharin preference – in AA-treated mice, thus suggesting that the reduction in saccharin preference – but not in locomotion – was specifically sensitive to analgesics. In conclusion, AA-induced acute pain attenuated saccharin preference and LMA beyond the resolution of writhing behavior, and the changes in the expression of hedonic behavior, such as sweet taste preference, can be

  18. Yeast growth in raffinose results in resistance to acetic-acid induced programmed cell death mostly due to the activation of the mitochondrial retrograde pathway.

    PubMed

    Guaragnella, Nicoletta; Zdralević, Maša; Lattanzio, Paolo; Marzulli, Domenico; Pracheil, Tammy; Liu, Zhengchang; Passarella, Salvatore; Marra, Ersilia; Giannattasio, Sergio

    2013-12-01

    In order to investigate whether and how a modification of mitochondrial metabolism can affect yeast sensitivity to programmed cell death (PCD) induced by acetic acid (AA-PCD), yeast cells were grown on raffinose, as a sole carbon source, which, differently from glucose, favours mitochondrial respiration. We found that, differently from glucose-grown cells, raffinose-grown cells were mostly resistant to AA-PCD and that this was due to the activation of mitochondrial retrograde (RTG) response, which increased with time, as revealed by the up-regulation of the peroxisomal isoform of citrate synthase and isocitrate dehydrogenase isoform 1, RTG pathway target genes. Accordingly, the deletion of RTG2 and RTG3, a positive regulator and a transcription factor of the RTG pathway, resulted in AA-PCD, as shown by TUNEL assay. Neither deletion in raffinose-grown cells of HAP4, encoding the positive regulatory subunit of the Hap2,3,4,5 complex nor constitutive activation of the RTG pathway in glucose-grown cells due to deletion of MKS1, a negative regulator of RTG pathway, had effect on yeast AA-PCD. The RTG pathway was found to be activated in yeast cells containing mitochondria, in which membrane potential was measured, capable to consume oxygen in a manner stimulated by the uncoupler CCCP and inhibited by the respiratory chain inhibitor antimycin A. AA-PCD resistance in raffinose-grown cells occurs with a decrease in both ROS production and cytochrome c release as compared to glucose-grown cells en route to AA-PCD.

  19. Changes in saccharin preference behavior as a primary outcome to evaluate pain and analgesia in acetic acid-induced visceral pain in mice.

    PubMed

    de la Puente, Beatriz; Romero-Alejo, Elizabeth; Vela, José Miguel; Merlos, Manuel; Zamanillo, Daniel; Portillo-Salido, Enrique

    2015-01-01

    Reflex-based procedures are important measures in preclinical pain studies that evaluate stimulated behaviors. These procedures, however, are insufficient to capture the complexity of the pain experience, which is often associated with the depression of several innate behaviors. While recent studies have made efforts to evidence the suppression of some positively motivated behaviors in certain pain models, they are still far from being routinely used as readouts for analgesic screening. Here, we characterized and compared the effect of the analgesic ibuprofen (Ibu) and the stimulant, caffeine, in assays of acute pain-stimulated and pain-depressed behavior. Intraperitoneal injection of acetic acid (AA) served as a noxious stimulus to stimulate a writhing response or depress saccharin preference and locomotor activity (LMA) in mice. AA injection caused the maximum number of writhes between 5 and 20 minutes after administration, and writhing almost disappeared 1 hour later. AA-treated mice showed signs of depression-like behaviors after writhing resolution, as evidenced by reduced locomotion and saccharin preference for at least 4 and 6 hours, respectively. Depression-like behaviors resolved within 24 hours after AA administration. A dose of Ibu (40 mg/kg) - inactive to reduce AA-induced abdominal writhing - administered before or after AA injection significantly reverted pain-induced saccharin preference deficit. The same dose of Ibu also significantly reverted the AA-depressed LMA, but only when it was administered after AA injection. Caffeine restored locomotion - but not saccharin preference - in AA-treated mice, thus suggesting that the reduction in saccharin preference - but not in locomotion - was specifically sensitive to analgesics. In conclusion, AA-induced acute pain attenuated saccharin preference and LMA beyond the resolution of writhing behavior, and the changes in the expression of hedonic behavior, such as sweet taste preference, can be used as a more

  20. Netupitant, a Potent and Highly Selective NK1 Receptor Antagonist, Alleviates Acetic Acid-Induced Bladder Overactivity in Anesthetized Guinea-Pigs.

    PubMed

    Palea, Stefano; Guilloteau, Véronique; Rekik, Moéz; Lovati, Emanuela; Guerard, Marc; Guardia, Maria-Alba; Lluel, Philippe; Pietra, Claudio; Yoshiyama, Mitsuharu

    2016-01-01

    Introduction. Tachykinins potently contract the isolated urinary bladder from a number of animal species and play an important role in the regulation of the micturition reflex. On the guinea-pig isolated urinary bladder we examined the effects of a new potent and selective NK1 receptor antagonist (netupitant) on the contractions induced by a selective NK1 receptor agonist, SP-methylester (SP-OMe). Moreover, the effects of netupitant and another selective NK1 antagonist (L-733,060) were studied in anesthetized guinea-pigs using two experimental models, the isovolumetric bladder contractions and a model of bladder overactivity induced by intravesical administration of acetic acid (AA). Methods and Results. Detrusor muscle strips were mounted in 5 mL organ baths and isometric contractions to cumulative concentrations of SP-OME were recorded before and after incubation with increasing concentrations of netupitant. In anesthetized female guinea-pigs, reflex bladder activity was examined under isovolumetric conditions with the bladder distended with saline or during cystometry using intravesical infusion of AA. After a 30 min stabilization period, netupitant (0.1-3 mg/kg, i.v.) or L-733,060 (3-10 mg/kg, i.v.) were administered. In the detrusor muscle, netupitant produced a concentration-dependent inhibition (mean pKB = 9.24) of the responses to SP-OMe. Under isovolumetric conditions, netupitant or L-733,060 reduced bladder contraction frequency in a dose-dependent manner, but neither drug changed bladder contraction amplitude. In the AA model, netupitant dose-dependently increased intercontraction interval (ICI) but had no effect on the amplitude of micturition (AM). L-733,060 dose-dependently increased ICI also but this effect was paralleled by a significant reduction of AM. Conclusion. Netupitant decreases the frequency of reflex bladder contractions without altering their amplitude, suggesting that this drug targets the afferent limb of the micturition reflex circuit

  1. Netupitant, a Potent and Highly Selective NK1 Receptor Antagonist, Alleviates Acetic Acid-Induced Bladder Overactivity in Anesthetized Guinea-Pigs

    PubMed Central

    Palea, Stefano; Guilloteau, Véronique; Rekik, Moéz; Lovati, Emanuela; Guerard, Marc; Guardia, Maria-Alba; Lluel, Philippe; Pietra, Claudio; Yoshiyama, Mitsuharu

    2016-01-01

    Introduction. Tachykinins potently contract the isolated urinary bladder from a number of animal species and play an important role in the regulation of the micturition reflex. On the guinea-pig isolated urinary bladder we examined the effects of a new potent and selective NK1 receptor antagonist (netupitant) on the contractions induced by a selective NK1 receptor agonist, SP-methylester (SP-OMe). Moreover, the effects of netupitant and another selective NK1 antagonist (L-733,060) were studied in anesthetized guinea-pigs using two experimental models, the isovolumetric bladder contractions and a model of bladder overactivity induced by intravesical administration of acetic acid (AA). Methods and Results. Detrusor muscle strips were mounted in 5 mL organ baths and isometric contractions to cumulative concentrations of SP-OME were recorded before and after incubation with increasing concentrations of netupitant. In anesthetized female guinea-pigs, reflex bladder activity was examined under isovolumetric conditions with the bladder distended with saline or during cystometry using intravesical infusion of AA. After a 30 min stabilization period, netupitant (0.1–3 mg/kg, i.v.) or L-733,060 (3–10 mg/kg, i.v.) were administered. In the detrusor muscle, netupitant produced a concentration-dependent inhibition (mean pKB = 9.24) of the responses to SP-OMe. Under isovolumetric conditions, netupitant or L-733,060 reduced bladder contraction frequency in a dose-dependent manner, but neither drug changed bladder contraction amplitude. In the AA model, netupitant dose-dependently increased intercontraction interval (ICI) but had no effect on the amplitude of micturition (AM). L-733,060 dose-dependently increased ICI also but this effect was paralleled by a significant reduction of AM. Conclusion. Netupitant decreases the frequency of reflex bladder contractions without altering their amplitude, suggesting that this drug targets the afferent limb of the micturition reflex

  2. Stimulation of large-conductance calcium-activated potassium channels inhibits neurogenic contraction of human bladder from patients with urinary symptoms and reverses acetic acid-induced bladder hyperactivity in rats.

    PubMed

    La Fuente, José M; Fernández, Argentina; Cuevas, Pedro; González-Corrochano, Rocío; Chen, Mao Xiang; Angulo, Javier

    2014-07-15

    We have analysed the effects of large-conductance calcium-activated potassium channel (BK) stimulation on neurogenic and myogenic contraction of human bladder from healthy subjects and patients with urinary symptoms and evaluated the efficacy of activating BK to relief bladder hyperactivity in rats. Bladder specimens were obtained from organ donors and from men with benign prostatic hyperplasia (BPH). Contractions elicited by electrical field stimulation (EFS) and carbachol (CCh) were evaluated in isolated bladder strips. in vivo cystometric recordings were obtained in anesthetized rats under control and acetic acid-induced hyperactive conditions. Neurogenic contractions of human bladder were potentiated by blockade of BK and small-conductance calcium-activated potassium channels (SK) but were unaffected by the blockade of intermediate calcium-activated potassium channels (IK). EFS-induced contractions were inhibited by BK stimulation with NS-8 or NS1619 or by SK/IK stimulation with NS309 (3µM). CCh-induced contractions were not modified by blockade or stimulation of BK, IK or SK. The anti-cholinergic agent, oxybutynin (0.3µM) inhibited either neurogenic or CCh-induced contractions. Neurogenic contractions of bladders from BPH patients were less sensitive to BK inhibition and more sensitive to BK activation than healthy bladders. The BK activator, NS-8 (5mg/kg; i.v.), reversed bladder hyperactivity induced by acetic acid in rats, while oxybutynin was ineffective. NS-8 did not significantly impact blood pressure or heart rate. BK stimulation specifically inhibits neurogenic contractions in patients with urinary symptoms and relieves bladder hyperactivity in vivo without compromising bladder contractile capacity or cardiovascular safety, supporting its potential therapeutic use for relieving bladder overactivity.

  3. Bak Foong Pills induce an analgesic effect by inhibiting nociception via the somatostatin pathway in mice.

    PubMed

    Rowlands, Dewi Kenneth; Cui, Yu Gui; So, Siu Cheung; Tsang, Lai Ling; Chung, Yiu Wa; Chan, Hsiao Chang

    2012-01-01

    Dysmenorrhoea, defined as cramping pain in the lower abdomen occurring before or during menstruation, affects, to varying degrees, up to 90% of women of child-bearing age. We investigated whether BFP (Bak Foong Pills), a traditional Chinese medicine treatment for dysmenorrhoea, possesses analgesic properties. Results showed that BFP was able to significantly reduce pain responses following subchronic treatment for 3 days, but not following acute (1 h) treatment in response to acetic acid-induced writhing in C57/B6 mice. The analgesic effect was not due to inhibition of COX (cyclo-oxygenase) activity, evidenced by the lack of inhibition of prostacyclin and PGE2 (prostaglandin E2) production. Molecular analysis revealed that BFP treatment modulated the expression of a number of genes in the spinal cord of mice subjected to acetic acid writhing. RT-PCR (reverse transcription-PCR) analysis of spinal cord samples showed that both sst4 (somatostatin receptor 4) and sst2 receptor mRNA, but not μOR (μ-opiate receptor) and NK1 (neurokinin-1) receptor mRNA, were down-regulated following BFP treatment, thus implicating somatostatin involvement in BFP-induced analgesia. Administration of c-som (cyclo-somatostatin), a somatostatin antagonist, prior to acetic acid-induced writhing inhibited the analgesic effect. Thus subchronic treatment with BFP has anti-nociceptive qualities mediated via the somatostatin pathway.

  4. Anti-Inflammatory and Analgesic Effects of Pyeongwisan on LPS-Stimulated Murine Macrophages and Mouse Models of Acetic Acid-Induced Writhing Response and Xylene-Induced Ear Edema

    PubMed Central

    Oh, You-Chang; Jeong, Yun Hee; Cho, Won-Kyung; Ha, Jeong-Ho; Gu, Min Jung; Ma, Jin Yeul

    2015-01-01

    Pyeongwisan (PW) is an herbal medication used in traditional East Asian medicine to treat anorexia, abdominal distension, borborygmus and diarrhea caused by gastric catarrh, atony and dilatation. However, its effects on inflammation-related diseases are unknown. In this study, we investigated the biological effects of PW on lipopolysaccharide (LPS)-mediated inflammation in macrophages and on local inflammation in vivo. We investigated the biological effects of PW on the production of inflammatory mediators, pro-inflammatory cytokines and related products as well as the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) in LPS-stimulated macrophages. Additionally, we evaluated the analgesic effect on the acetic acid-induced writhing response and the inhibitory activity on xylene-induced ear edema in mice. PW showed anti-inflammatory effects by inhibiting the production of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and interleukin-1β (IL-1β). In addition, PW strongly suppressed inducible nitric oxide synthase (iNOS), a NO synthesis enzyme, induced heme oxygenase-1 (HO-1) expression and inhibited NF-κB activation and MAPK phosphorylation. Also, PW suppressed TNF-α, IL-6 and IL-1β cytokine production in LPS-stimulated peritoneal macrophage cells. Furthermore, PW showed an analgesic effect on the writhing response and an inhibitory effect on mice ear edema. We demonstrated the anti-inflammatory effects and inhibitory mechanism in macrophages as well as inhibitory activity of PW in vivo for the first time. Our results suggest the potential value of PW as an inflammatory therapeutic agent developed from a natural substance. PMID:25569097

  5. Anti-inflammatory and analgesic effects of pyeongwisan on LPS-stimulated murine macrophages and mouse models of acetic acid-induced writhing response and xylene-induced ear edema.

    PubMed

    Oh, You-Chang; Jeong, Yun Hee; Cho, Won-Kyung; Ha, Jeong-Ho; Gu, Min Jung; Ma, Jin Yeul

    2015-01-06

    Pyeongwisan (PW) is an herbal medication used in traditional East Asian medicine to treat anorexia, abdominal distension, borborygmus and diarrhea caused by gastric catarrh, atony and dilatation. However, its effects on inflammation-related diseases are unknown. In this study, we investigated the biological effects of PW on lipopolysaccharide (LPS)-mediated inflammation in macrophages and on local inflammation in vivo. We investigated the biological effects of PW on the production of inflammatory mediators, pro-inflammatory cytokines and related products as well as the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) in LPS-stimulated macrophages. Additionally, we evaluated the analgesic effect on the acetic acid-induced writhing response and the inhibitory activity on xylene-induced ear edema in mice. PW showed anti-inflammatory effects by inhibiting the production of nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and interleukin-1β (IL-1β). In addition, PW strongly suppressed inducible nitric oxide synthase (iNOS), a NO synthesis enzyme, induced heme oxygenase-1 (HO-1) expression and inhibited NF-κB activation and MAPK phosphorylation. Also, PW suppressed TNF-α, IL-6 and IL-1β cytokine production in LPS-stimulated peritoneal macrophage cells. Furthermore, PW showed an analgesic effect on the writhing response and an inhibitory effect on mice ear edema. We demonstrated the anti-inflammatory effects and inhibitory mechanism in macrophages as well as inhibitory activity of PW in vivo for the first time. Our results suggest the potential value of PW as an inflammatory therapeutic agent developed from a natural substance.

  6. [Physiology of nociception].

    PubMed

    Guirimand, F; Le Bars, D

    1996-01-01

    Nociception is related to the mechanisms elicited by stimuli threatening the integrity of the organism. At the peripheral level, unmyelinated C fibres (C polymodal nociceptores) or fine myelinated A delta fibres are excited by noxious stimulation, directly or indirectly by inflammatory processes. Nociceptive afferent fibres terminate in the superficial laminae of the dorsal horn of the spinal cord where informations are integrated and controlled. These first synapses are modulated by excitatory amino acids (glutamate and aspartate) and many peptides (substance P, CGRP, CCK, endogenous opiods). The majority of ascending pathways involved in nociception are located in the ventrolateral controlateral quadrant of the cord (spinorelicular and spinothalamic tracts). Many supraspinal sites are activated following nociceptive stimuli, with relays in the reticular formation of the brain stem (including the subnucleus reticularis dorsalis), the ponto-mesencephalic regions (periaqueducal gray matter and parabrachial area) and thalamic sites. Amygdala and hypothamic targets could be involved in motivational reactions and neuroendocrine adaptations to a noxious event. The cingular, insular and somatosensory cortices also receive nociceptive informations. Nociceptive signals are modulated at all levels of their transmission; the more extensively studied controls are located at the spinal level. Segmental controls are inhibitory effects produced by non-noxious mechanical stimuli. Spinal signals can also be inhibited following activation of bulbopinal descending inhibitor pathways and release of serotonin, norepinephrine and, indirectly, endogenous opiods. Inhibitory controls triggered by noxious stimuli could facilitate the extraction of the nociceptive tone of informations having priority over other stimuli.

  7. Cyclo-Gly-Pro, a cyclic dipeptide, attenuates nociceptive behaviour and inflammatory response in mice.

    PubMed

    Ferro, Jamylle Nunes de Souza; de Aquino, Fernanda Lima Torres; de Brito, Renan Guedes; dos Santos, Priscila Laíse; Quintans, Jullyana de Souza Siqueira; de Souza, Lucas Costa; de Araújo, Almair Ferreira; Diaz, Bruno Lourenço; Lucca-Júnior, Waldecy; Quintans-Júnior, Lucindo José; Barreto, Emiliano

    2015-12-01

    The present study aimed to investigate the antinociceptive and anti-inflammatory effects of the cyclic dipeptide cyclo-Gly-Pro (CGP) in mice. Antinociceptive activity was assessed by employing different pain models, such as formalin test, acetic acid-induced writhing, hot plate test, and carrageenan-induced hyperalgesia, in mice. The number of c-Fos-immunoreactive cells in the periaqueductal gray (PAG) was evaluated in CGP-treated mice. Anti-inflammatory activity was evaluated using paw oedema induced by carrageenan, compound 48/80, serotonin, and prostaglandin E2 (PGE2) and analyzed by plethysmometry. Quantitation of myeloperoxidase (MPO) in the paw was carried out to analyze the presence of neutrophils in the tissue. Intraperitoneal injection of CGP produced a significant inhibition in both neurogenic and inflammatory phases of formalin-induced pain. The antinociceptive effect of CGP, evaluated in the acetic acid-induced writhing test, was detected for up to 6 h after treatment. Further, in the hot plate test, antinociceptive behaviour was evoked by CGP, and this response was inhibited by naloxone. Animals treated with CGP did not present changes in motor performance. In CGP-treated mice there was an increase in the number of c-Fos-positive neurons in the periaqueductal gray. In another set of experiments, CGP attenuated the hyperalgesic response induced by carrageenan. Furthermore, CGP also reduced the carrageenan-increased MPO activity in paws. In addition, CGP also reduced the paw oedema evoked by compound 48/80, serotonin, and PGE2 . Taken together, these results may support a possible therapeutic application of the cyclic dipeptide cyclo-Gly-Pro toward alleviating nociception and damage caused by inflammation conditions.

  8. The effects of aqueous extract of Aloe vera leaves on the gastric acid secretion and brain and intestinal water content following acetic acid- induced gastric ulcer in male rats

    PubMed Central

    Keshavarzi, Zakieh; Rezapour, Taha Mohammad; Vatanchian, Mehran; Zare Hesari, Mohammad; Nabizade Haghighi, Hadi; Izanlu, Mostafa; Sabaghian, Maryam; Shahveisi, Kaveh

    2014-01-01

    Objective: Gut–brain axis (GBA) is very important in creation and modulation of gastrointestinal problems. Aloe vera gel has gastroprotective properties. The purpose of this study was to evaluate the effect of aqueous extract of Aloe vera leaves on the gastric acid secretion and brain and intestinal water content following acetic acid gastric ulcer induction. Materials and Methods: Gastric ulcer was induced by injection of 20% acetic acid into the subserosal layer in male rats. Rats were randomly assigned into three groups: intact group, gastric ulcer group and Aloe vera group (treatment with Aloe vera following gastric ulcer induction). The acid levels and brain and intestinal water content of each sample were measured eight days after the gastric ulcer induction. Results: Gastric acid levels were significantly decreased in Aloe vera group when compared with gastric ulcer group (p<0.05). However, there were no differences in acid output between gastric ulcer and Aloe vera groups with intact group. After Aloe vera administration, the amount of brain water content had no difference with intact and gastric ulcer groups (p<0.05). The duodenal water content in Aloe vera group was significantly reduced compared with intact group (p<0.05) but gastric ulcer group had no significant difference with intact and Aloe vera group. Conclusions: The administration of Aloe vera has an inhibitory effect on the gastric acid output. PMID:25050311

  9. Anti-nociceptive, anti-inflammatory and sedative activities of the extracts and chemical constituents of Diospyros lotus L.

    PubMed

    Uddin, Ghias; Rauf, Abdur; Siddiqui, Bina S; Muhammad, Naveed; Khan, Ajmal; Shah, Syed Uzair Ali

    2014-06-15

    Diospyros lotus L. is traditionally used in various diseases including pain and sleep disorders. The pain and inflammation are the common problems, which are treated with various synthetic analgesic drugs, and associated the side effects. The natural products have gained significant importance over synthetic drugs. The importance of phyto-medicine the current study has been designed with the aim to investigate the analgesic and anti-inflammatory effects of Diospyros lotus and bioassay guided isolation from its crude fractions. Seven known compounds; lupeol (1), 7-methyljuglone (2), β-Sitosterol (3), stigmasterol (4) betulinic acid (5), diospyrin (6; DS) and 8-hydroxyisodiospyrin (7; HDS) which were hitherto unreported from D. lotus. The chloroform fraction (CFDL) and isolated compounds DS and HDS were evaluated for anti-nociceptive, sedative and anti-inflammatory effects. The acetic acid induced writing was significantly (p<0.001) protected by CFDL (72.43%), DS (40.87%) and HDS (65.76%) at higher doses which exhibited peripheral and central analgesic effects in acetic acid and hot-plat pain paradigms. Regarding the anti-inflammatory effect the CFDL (77.43%), DS (80.54%) and HDS (75.87%) protected the carrageenan paw edema after 3rd h. The central analgesic effect was significantly antagonized with naloxone (0.5 mg/kg), showing opiodergic mechanism of action. The CFDL, DS and HDS were also proved sedative in open field animal models. In acute toxicity study the chloroform fraction [CFDL (50, 100 and 150 mg/kg)], DS (5 and 10 mg/kg) and HDS (5 and 10 mg/kg) were found safe. Our study concluded that CFDL, DS and HDS have marked anti-nociceptive, anti-inflammatory and sedative effect. The anti-nociceptive and anti-inflammatory effects of the roots of D. lotus are partially attributed due to the presence of analgesic constituents like diospyrin (DS), 8-hydroxyisodiospyrin (HDS) and strongly supports the ethno-pharmacological uses of D. lotus as anti-nociceptive, anti

  10. Cleavage of INDOLE-3-ACETIC ACID INDUCIBLE28 mRNA by microRNA847 upregulates auxin signaling to modulate cell proliferation and lateral organ growth in Arabidopsis.

    PubMed

    Wang, Jing-Jing; Guo, Hui-Shan

    2015-03-01

    MicroRNAs function in a range of developmental processes. Here, we demonstrate that miR847 targets the mRNA of the auxin/indole acetic acid (Aux/IAA) repressor-encoding gene IAA28 for cleavage. The rapidly increased accumulation of miR847 in Arabidopsis thaliana coincided with reduced IAA28 mRNA levels upon auxin treatment. This induction of miR847 by auxin was abolished in auxin receptor tir1-1 and auxin-resistant axr1-3 mutants. Further analysis demonstrates that miR847 functions as a positive regulator of auxin-mediated lateral organ development by cleaving IAA28 mRNA. Importantly, the ectopic expression of miR847 increases the expression of cell cycle genes as well as the neoplastic activity of leaf cells, prolonging later-stage rosette leaf growth and producing leaves with serrated margins. Moreover, both miR847 and IAA28 mRNAs are specifically expressed in marginal meristems of rosette leaves and lateral root initiation sites. Our data indicate that auxin-dependent induction of miR847 positively regulates meristematic competence by clearing IAA28 mRNA to upregulate auxin signaling, thereby determining the duration of cell proliferation and lateral organ growth in Arabidopsis. IAA28 mRNA encodes an Aux/IAA repressor protein, which is degraded through the proteasome in response to auxin. Altered signal sensitization to IAA28 mRNA levels, together with targeted IAA28 degradation, ensures a robust signal derepression.

  11. Capsaicin, Nociception and Pain.

    PubMed

    Frias, Bárbara; Merighi, Adalberto

    2016-06-18

    Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem centers, as well as the integration of diverse painful stimuli. In this review, we first describe the chemical and pharmacological properties of capsaicin and its derivatives in relation to their analgesic properties. We then consider the biochemical and functional characteristics of TRPV1, focusing on its distribution and biological effects within the somatosensory and viscerosensory nociceptive systems. Finally, we discuss the use of capsaicin as an agonist of TRPV1 to model acute inflammation in slices and other ex vivo preparations.

  12. In vivo and in vitro anti-inflammatory and anti-nociceptive effects of the methanol extract of Inonotus obliquus.

    PubMed

    Park, Young-Mi; Won, Jong-Heon; Kim, Yang-Hee; Choi, Jong-Won; Park, Hee-Juhn; Lee, Kyung-Tae

    2005-10-03

    The mushroom Inonotus obliquus (Fr.) Pilát (Hymenochaetaceae), has been traditionally used for the treatment of gastrointestinal cancer, cardiovascular disease and diabetes in Russia, Poland and most of Baltic countries. This study was designed to investigate the anti-inflammatory and anti-nociceptive effects of the methanol extract from Inonotus obliquus (MEIO) in vivo and in vitro. MEIO (100 or 200 mg/(kgday), p.o.) reduced acute paw edema induced by carrageenin in rats, and showed analgesic activity, as determined by an acetic acid-induced abdominal constriction test and a hot plate test in mice. To reveal the mechanism of the anti-inflammatory effect of MEIO, we examined its effect on lipopolysaccharide (LPS)-induced responses in a murine macrophage cell line RAW 264.7. MEIO was found to significantly inhibit the productions of nitric oxide (NO), prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) in LPS-stimulated RAW 264.7 macrophages. Consistent with these observations, MEIO potently inhibited the protein and mRNA expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, MEIO inhibited the LPS-induced DNA binding activity of nuclear factor-kappaB (NF-kappaB), and this was associated with the prevention of inhibitor kappaB degradation and a reduction in nuclear p65 protein levels. Taken together, our data indicate that the anti-inflammatory and anti-nociceptive properties of MEIO may be due to the inhibition of iNOS and COX-2 expression via the down-regulation of NF-kappaB binding activity.

  13. Taste modulation of nociception differently affects chronically stressed rats.

    PubMed

    Fontella, Fernanda Urruth; Nunes, Marcele Leon; Crema, Leonardo M; Balk, Rodrigo S; Dalmaz, Carla; Netto, Carlos Alexandre

    2004-01-01

    Stress responses cover a wide range of physiological changes, including alterations in the perception of and response to pain. Animals submitted to repeated stress present altered nociception and this effect is part of this process of adaptation; in addition pleasant and unpleasant experiences with tastes and odors have been shown to affect distinct behavioral aspects, such as pain perception. The aim of the present study is to verify the responses of repeatedly stressed rats (1 h of daily immobilization during 40 days) to pleasant and unpleasant tastes on nociception, when compared to control animals. An increase in the tail-flick latency (TFL) was observed 5 min after exposure to a sweet taste in the control group, whereas no effect was observed in chronically stressed animals. When submitted to an unpleasant taste (5% acetic acid), the chronically stressed group presented an increase in TFL, whereas no effect was observed in the control group. In conclusion, chronically stressed animals present different nociceptive responses to sweet and acid tastes; although control animals suitably respond to a sweet stimulus, stressed animals seem to be more apt to react to the unpleasant stimulus.

  14. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice.

    PubMed

    Neelakantan, Harshini; Tallarida, Ronald J; Reichenbach, Zachary W; Tuma, Ronald F; Ward, Sara J; Walker, Ellen A

    2015-04-01

    Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced antinociceptive effects in all three models of acute nociception, whereas CBD alone produced antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions between morphine and CBD combinations were assessed quantitatively based on the principle of dose equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine in the three different behavioral assays and that the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality.

  15. Effects of anethole in nociception experimental models.

    PubMed

    Ritter, Alessandra Mileni Versuti; Ames, Franciele Queiroz; Otani, Fernando; de Oliveira, Rubia Maria Weffort; Cuman, Roberto Kenji Nakamura; Bersani-Amado, Ciomar Aparecida

    2014-01-01

    This study investigated the antinociceptive activity of anethole (anethole 1-methoxy-4-benzene (1-propenyl)), major compound of the essential oil of star anise (Illicium verum), in different experimental models of nociception. The animals were pretreated with anethole (62.5, 125, 250, and 500 mg/kg) one hour before the experiments. To eliminate a possible sedative effect of anethole, the open field test was conducted. Anethole (62.5, 125, 250, and 500 mg/kg) showed an antinociceptive effect in the writhing model induced by acetic acid, in the second phase of the formalin test (125 and 250 mg/kg) in the test of glutamate (62.5, 125, and 250 mg/kg), and expresses pain induced by ACF (250 mg/kg). In contrast, anethole was not able to increase the latency time on the hot plate and decrease the number of flinches during the initial phase of the formalin test in any of the doses tested. It was also demonstrated that anethole has no association with sedative effects. Therefore, these data showed that anethole, at all used doses, has no sedative effect and has an antinociceptive effect. This effect may be due to a decrease in the production/release of inflammatory mediators.

  16. Effects of Anethole in Nociception Experimental Models

    PubMed Central

    Ritter, Alessandra Mileni Versuti; Ames, Franciele Queiroz; Otani, Fernando; de Oliveira, Rubia Maria Weffort; Cuman, Roberto Kenji Nakamura; Bersani-Amado, Ciomar Aparecida

    2014-01-01

    This study investigated the antinociceptive activity of anethole (anethole 1-methoxy-4-benzene (1-propenyl)), major compound of the essential oil of star anise (Illicium verum), in different experimental models of nociception. The animals were pretreated with anethole (62.5, 125, 250, and 500 mg/kg) one hour before the experiments. To eliminate a possible sedative effect of anethole, the open field test was conducted. Anethole (62.5, 125, 250, and 500 mg/kg) showed an antinociceptive effect in the writhing model induced by acetic acid, in the second phase of the formalin test (125 and 250 mg/kg) in the test of glutamate (62.5, 125, and 250 mg/kg), and expresses pain induced by ACF (250 mg/kg). In contrast, anethole was not able to increase the latency time on the hot plate and decrease the number of flinches during the initial phase of the formalin test in any of the doses tested. It was also demonstrated that anethole has no association with sedative effects. Therefore, these data showed that anethole, at all used doses, has no sedative effect and has an antinociceptive effect. This effect may be due to a decrease in the production/release of inflammatory mediators. PMID:25506382

  17. EEG frequency-tagging to dissociate the cortical responses to nociceptive and non-nociceptive stimuli

    PubMed Central

    Colon, Elisabeth; Legrain, Valéry; Mouraux, André

    2017-01-01

    Whether the cortical processing of nociceptive input relies on the activity of nociceptive-specific neurons or whether it relies on the activity of neurons also involved in processing non-nociceptive sensory input remains a matter of debate. Here, we combined EEG “frequency-tagging” of steady-state evoked-potentials (SS-EPs) with an intermodal selective attention paradigm to test whether the cortical processing of nociceptive input relies on nociceptive-specific neuronal populations that can be selectively modulated by top-down attention. Trains of nociceptive and vibrotactile stimuli (experiment 1) and trains of nociceptive and visual stimuli (experiment 2) were applied concomitantly to the same hand, thus eliciting nociceptive, vibrotactile and visual SS-EPs. In each experiment, a target detection task was used to focus attention towards one of the two concurrent streams of sensory input. We found that selectively attending to nociceptive or vibrotactile somatosensory input indistinctly enhances the magnitude of nociceptive and vibrotactile SS-EPs, whereas selectively attending to nociceptive or visual input independently enhances the magnitude of the SS-EP elicited by the attended sensory input. This differential effect indicates that the processing of nociceptive input involves neuronal populations also involved in the processing of touch, but distinct from the neuronal populations involved in vision. PMID:24738772

  18. Borneol, a bicyclic monoterpene alcohol, reduces nociceptive behavior and inflammatory response in mice.

    PubMed

    Almeida, Jackson Roberto Guedes da Silva; Souza, Grasielly Rocha; Silva, Juliane Cabral; Saraiva, Sarah Raquel Gomes de Lima; Júnior, Raimundo Gonçalves de Oliveira; Quintans, Jullyana de Souza Siqueira; Barreto, Rosana de Souza Siqueira; Bonjardim, Leonardo Rigoldi; Cavalcanti, Sócrates Cabral de Holanda; Quintans, Lucindo José

    2013-01-01

    Borneol, a bicyclic monoterpene, has been evaluated for antinociceptive and anti-inflammatory activities. Antinociceptive and anti-inflammatory activities were studied by measuring nociception by acetic acid, formalin, hot plate, and grip strength tests, while inflammation was prompted by carrageenan-induced peritonitis. The rotarod test was used to evaluate motor coordination. Borneol produced a significant (P < 0.01) reduction of the nociceptive behavior at the early and late phases of paw licking and reduced the writhing reflex in mice (formalin and writhing tests, resp.). When the hot plate test was conducted, borneol (in higher dose) produced an inhibition (P < 0.05) of the nociceptive behavior. Such results were unlikely to be provoked by motor abnormality. Additionally, borneol-treated mice reduced the carrageenan-induced leukocytes migration to the peritoneal cavity. Together, our results suggest that borneol possess significant central and peripheral antinociceptive activity; it has also anti-inflammatory activity. In addition, borneol did not impair motor coordination.

  19. Flecainide acetate acetic acid solvates.

    PubMed

    Veldre, Kaspars; Actiņs, Andris; Eglite, Zane

    2011-02-01

    Flecainide acetate forms acetic acid solvates with 0.5 and 2 acetic acid molecules. Powder X-ray diffraction, differential thermal analysis/thermogravimetric, infrared, and potentiometric titration were used to determine the composition of solvates. Flecainide acetate hemisolvate with acetic acid decomposes to form a new crystalline form of flecainide acetate. This form is less stable than the already known polymorphic form at all temperatures, and it is formed due to kinetic reasons. Both flecainide acetate nonsolvated and flecainide acetate hemisolvate forms crystallize in monoclinic crystals, but flecainide triacetate forms triclinic crystals. Solvate formation was not observed when flecainide base was treated with formic acid, propanoic acid, and butanoic acid. Only nonsolvated flecainide salts were obtained in these experiments.

  20. Operant nociception in nonhuman primates.

    PubMed

    Kangas, Brian D; Bergman, Jack

    2014-09-01

    The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative translational research, including new preclinical assays. Most current in vivo procedures (eg, tail flick, hot plate, warm water tail withdrawal) assay the effects of nociceptive stimuli on simple spinal reflexes or unconditioned behavioral reactions. However, clinical treatment goals may include the restoration of previous behavioral activities, which can be limited by medication-related side effects that are not measured in such procedures. The present studies describe an apparatus and procedure to study the disruptive effects of nociceptive stimuli on voluntary behavior in nonhuman primates, and the ability of drugs to restore such behavior through their analgesic actions. Squirrel monkeys were trained to pull a cylindrical thermode for access to a highly palatable food. Next, sessions were conducted in which the temperature of the thermode was increased stepwise until responding stopped, permitting the determination of stable nociceptive thresholds. Tests revealed that several opioid analgesics, but not d-amphetamine or Δ(9)-THC, produced dose-related increases in threshold that were antagonist sensitive and efficacy dependent, consistent with their effects using traditional measures of antinociception. Unlike traditional reflex-based measures, however, the results also permitted the concurrent evaluation of response disruption, providing an index with which to characterize the behavioral selectivity of antinociceptive drugs.

  1. Mesoxalaldehyde acetals

    SciTech Connect

    Gordeeva, G.N.; Kalashnikov, S.M.; Popov, Yu.N.; Kruglov, E.A.; Imashev, U.B.

    1987-11-10

    The treatment of methylglyoxal acetals by alkyl nitrites in the presence of the corresponding aliphatic alcohols and hydrochloric acid leads to the formation of linear mesoxalaldehyde acetals, whose structure was established by NMR spectroscopy and mass spectrometry. The major pathways for the decomposition of these molecules upon electron impact were established.

  2. Lateral Inhibition during Nociceptive Processing.

    PubMed

    Quevedo, Alexandre S; Mørch, Carsten Dahl; Andersen, Ole K; Coghill, Robert C

    2017-02-11

    Spatial summation of pain is the increase of perceived intensity that occurs as the stimulated area increases. Spatial summation of pain is sub-additive in that increasing the stimulus area produces a disproportionately small increase in the perceived intensity of pain. A possible explanation for sub-additive summation may be that convergent excitatory information is modulated by lateral inhibition. To test the hypothesis that lateral inhibition may limit spatial summation of pain, we delivered different patterns of noxious thermal stimuli to the abdomens of 15 subjects using a computer-controlled CO2-laser. Lines (5mm wide) of variable lengths (4cm, 8cm) were compared to two-point stimuli delivered at the same position/separation as the length of lines. When compared to one-point control stimuli, two-point stimulus patterns produced statistically significant spatial summation of pain, while no such summation was detected during line stimulus patterns. Direct comparison of pain intensity evoked by two-point pattern stimuli with line pattern stimuli revealed that two-point patterns were perceived as significantly more painful, despite the fact that the two-point pattern stimulated far smaller areas of skin. Thus, the stimulation of the skin region between the endpoints of the lines appears to produce inhibition. These findings indicate that lateral inhibition limits spatial summation of pain and is an intrinsic component of nociceptive information processing. Disruption of such lateral inhibition may contribute substantially to the radiation of some types of chronic pain.

  3. Role of NHE1 in Nociception.

    PubMed

    Torres-López, Jorge Elías; Guzmán-Priego, Crystell Guadalupe; Rocha-González, Héctor Isaac; Granados-Soto, Vinicio

    2013-01-01

    Intracellular pH is a fundamental parameter to cell function that requires tight homeostasis. In the absence of any regulation, excessive acidification of the cytosol would have the tendency to produce cellular damage. Mammalian Na(+)/H(+) exchangers (NHEs) are electroneutral Na(+)-dependent proteins that exchange extracellular Na(+) for intracellular H(+). To date, there are 9 identified NHE isoforms where NHE1 is the most ubiquitous member, known as the housekeeping exchanger. NHE1 seems to have a protective role in the ischemia-reperfusion injury and other inflammatory diseases. In nociception, NHE1 is found in neurons along nociceptive pathways, and its pharmacological inhibition increases nociceptive behavior in acute pain models at peripheral and central levels. Electrophysiological studies also show that NHE modulates electrical activity of primary nociceptive terminals. However, its role in neuropathic pain still remains controversial. In humans, NHE1 may be responsible for inflammatory bowel diseases since its expression is reduced in Crohn's disease and ulcerative colitis. The purpose of this work is to provide a review of the evidence about participation of NHE1 in the nociceptive processing.

  4. Quantifying cerebral contributions to pain beyond nociception

    PubMed Central

    Woo, Choong-Wan; Schmidt, Liane; Krishnan, Anjali; Jepma, Marieke; Roy, Mathieu; Lindquist, Martin A.; Atlas, Lauren Y.; Wager, Tor D.

    2017-01-01

    Cerebral processes contribute to pain beyond the level of nociceptive input and mediate psychological and behavioural influences. However, cerebral contributions beyond nociception are not yet well characterized, leading to a predominant focus on nociception when studying pain and developing interventions. Here we use functional magnetic resonance imaging combined with machine learning to develop a multivariate pattern signature—termed the stimulus intensity independent pain signature-1 (SIIPS1)—that predicts pain above and beyond nociceptive input in four training data sets (Studies 1–4, N=137). The SIIPS1 includes patterns of activity in nucleus accumbens, lateral prefrontal and parahippocampal cortices, and other regions. In cross-validated analyses of Studies 1–4 and in two independent test data sets (Studies 5–6, N=46), SIIPS1 responses explain variation in trial-by-trial pain ratings not captured by a previous fMRI-based marker for nociceptive pain. In addition, SIIPS1 responses mediate the pain-modulating effects of three psychological manipulations of expectations and perceived control. The SIIPS1 provides an extensible characterization of cerebral contributions to pain and specific brain targets for interventions. PMID:28195170

  5. Antinociceptive activity of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone, on nociception-induced models in mice.

    PubMed

    Ming-Tatt, Lee; Khalivulla, Shaik Ibrahim; Akhtar, Muhammad Nadeem; Mohamad, Azam Shah; Perimal, Enoch Kumar; Khalid, Mohamed Hanief; Akira, Ahmad; Lajis, Nordin; Israf, Daud Ahmad; Sulaiman, Mohd Roslan

    2012-03-01

    This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC), using chemical- and thermal-induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose-related inhibition in the acetic acid-induced abdominal constriction test in mice with an ID(50) of 0.15 (0.13-0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin-induced paw licking test with an ID(50) of 0.35 (0.27-0.46) mg/kg and 0.07 (0.06-0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot-plate test. Moreover, the antinociceptive effect of the BHMC in the formalin-induced paw licking test and the hot-plate test was antagonized by pre-treatment with the non-selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID(50) of 0.66 (0.41-1.07) mg/kg and 0.42 (0.38-0.51) mg/kg, respectively. Finally, it was also shown that BHMC-induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of

  6. Thallium acetate

    Integrated Risk Information System (IRIS)

    Jump to main content . Integrated Risk Information System Recent Additions | Contact Us Search : All EPA IRIS • You are here : EPA Home • Research • Environmental Assessment • IRIS • IRIS Summaries Redirect Page As of September 30 , 2009 , the assessment summary for Thallium acetate is included in t

  7. Phenylmercuric acetate

    Integrated Risk Information System (IRIS)

    Phenylmercuric acetate ; CASRN 62 - 38 - 4 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinog

  8. Ethyl acetate

    Integrated Risk Information System (IRIS)

    Ethyl acetate ; CASRN 141 - 78 - 6 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Eff

  9. Ammonium acetate

    Integrated Risk Information System (IRIS)

    Ammonium acetate ; CASRN 631 - 61 - 8 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic

  10. Vinyl acetate

    Integrated Risk Information System (IRIS)

    Vinyl acetate ; CASRN 108 - 05 - 4 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Eff

  11. Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception

    PubMed Central

    Liberati, Giulia; Klöcker, Anne; Safronova, Marta M.; Ferrão Santos, Susana; Ribeiro Vaz, Jose-Geraldo; Raftopoulos, Christian; Mouraux, André

    2016-01-01

    The insula, particularly its posterior portion, is often regarded as a primary cortex for pain. However, this interpretation is largely based on reverse inference, and a specific involvement of the insula in pain has never been demonstrated. Taking advantage of the high spatiotemporal resolution of direct intracerebral recordings, we investigated whether the human insula exhibits local field potentials (LFPs) specific for pain. Forty-seven insular sites were investigated. Participants received brief stimuli belonging to four different modalities (nociceptive, vibrotactile, auditory, and visual). Both nociceptive stimuli and non-nociceptive vibrotactile, auditory, and visual stimuli elicited consistent LFPs in the posterior and anterior insula, with matching spatial distributions. Furthermore, a blind source separation procedure showed that nociceptive LFPs are largely explained by multimodal neural activity also contributing to non-nociceptive LFPs. By revealing that LFPs elicited by nociceptive stimuli reflect activity unrelated to nociception and pain, our results confute the widespread assumption that these brain responses are a signature for pain perception and its modulation. PMID:26734726

  12. Nociception, Pain, Negative Moods, and Behavior Selection.

    PubMed

    Baliki, Marwan N; Apkarian, A Vania

    2015-08-05

    Recent neuroimaging studies suggest that the brain adapts with pain, as well as imparts risk for developing chronic pain. Within this context, we revisit the concepts for nociception, acute and chronic pain, and negative moods relative to behavior selection. We redefine nociception as the mechanism protecting the organism from injury, while acute pain as failure of avoidant behavior, and a mesolimbic threshold process that gates the transformation of nociceptive activity to conscious pain. Adaptations in this threshold process are envisioned to be critical for development of chronic pain. We deconstruct chronic pain into four distinct phases, each with specific mechanisms, and outline current state of knowledge regarding these mechanisms: the limbic brain imparting risk, and the mesolimbic learning processes reorganizing the neocortex into a chronic pain state. Moreover, pain and negative moods are envisioned as a continuum of aversive behavioral learning, which enhance survival by protecting against threats.

  13. Nociception, pain, negative moods and behavior selection

    PubMed Central

    Baliki, Marwan N.; Apkarian, A. Vania

    2015-01-01

    Recent neuroimaging studies suggest that the brain adapts with pain, as well as imparts risk for developing chronic pain. Within this context we revisit the concepts for nociception, acute and chronic pain, and negative moods relative to behavior selection. We redefine nociception as the mechanism protecting the organism from injury; while acute pain as failure of avoidant behavior; and a mesolimbic threshold process that gates the transformation of nociceptive activity to conscious pain. Adaptations in this threshold process are envisioned to be critical for development of chronic pain. We deconstruct chronic pain into four distinct phases, each with specific mechanisms; and outline current state of knowledge regarding these mechanisms: The limbic brain imparting risk, while mesolimbic learning processes reorganizing the neocortex into a chronic pain state. Moreover, pain and negative moods are envisioned as a continuum of aversive behavioral learning, which enhance survival by protecting against threats. PMID:26247858

  14. Nociceptor-enriched genes required for normal thermal nociception

    PubMed Central

    Honjo, Ken; Mauthner, Stephanie E.; Wang, Yu; Skene, J.H. Pate; Tracey, W. Daniel

    2016-01-01

    Summary Here, we describe a targeted reverse genetic screen for thermal nociception genes in Drosophila larvae. Using laser capture microdissection and microarray analyses of nociceptive and non-nociceptive neurons we identified 275 nociceptor-enriched genes. We then tested the function of the enriched genes with nociceptor-specific RNAi and thermal nociception assays. Tissue-specific RNAi targeted against 14 genes caused insensitive thermal nociception while targeting of 22 genes caused hypersensitive thermal nociception. Previously uncategorized genes were named for heat resistance (ie. boilerman, fire dancer, oven mitt, trivet, thawb and bunker gear) or heat sensitivity (firelighter, black match, eucalyptus, primacord, jet fuel, detonator, gasoline, smoke alarm, and jetboil). Insensitive nociception phenotypes were often associated with severely reduced branching of nociceptor neurites and hyperbranched dendrites were seen in two of the hypersensitive cases. Many genes that we identified are conserved in mammals. PMID:27346357

  15. Nociceptor-Enriched Genes Required for Normal Thermal Nociception.

    PubMed

    Honjo, Ken; Mauthner, Stephanie E; Wang, Yu; Skene, J H Pate; Tracey, W Daniel

    2016-07-12

    Here, we describe a targeted reverse genetic screen for thermal nociception genes in Drosophila larvae. Using laser capture microdissection and microarray analyses of nociceptive and non-nociceptive neurons, we identified 275 nociceptor-enriched genes. We then tested the function of the enriched genes with nociceptor-specific RNAi and thermal nociception assays. Tissue-specific RNAi targeted against 14 genes caused insensitive thermal nociception while targeting of 22 genes caused hypersensitive thermal nociception. Previously uncategorized genes were named for heat resistance (i.e., boilerman, fire dancer, oven mitt, trivet, thawb, and bunker gear) or heat sensitivity (firelighter, black match, eucalyptus, primacord, jet fuel, detonator, gasoline, smoke alarm, and jetboil). Insensitive nociception phenotypes were often associated with severely reduced branching of nociceptor neurites and hyperbranched dendrites were seen in two of the hypersensitive cases. Many genes that we identified are conserved in mammals.

  16. Antinociceptive activity of atranorin in mice orofacial nociception tests.

    PubMed

    Siqueira, Rosana S; Bonjardim, Leonardo R; Araújo, Adriano A S; Araújo, Bruno E S; Melo, Marcélia G D; Oliveira, Marília G B; Gelain, Daniel P; Silva, Francilene A; DeSantana, Josimari M; Albuquerque-Júnior, Ricardo L C; Rocha, Ricardo F; Moreira, José C F; Antoniolli, Angelo R; Quintans-Júnior, Lucindo J

    2010-01-01

    Physicochemical characterization and antinociceptive and anti-inflammatory activities of atranorin (AT) extracted from Cladina kalbii Ahti in formalin- and capsaicin-induced orofacial pain and anti-inflammatory tests in rodents were studied. Physicochemical characterization showed that AT has the general formula C19H18O8. Male Swiss mice were pretreated with AT (100, 200, and 400 mg/kg, i.p.), morphine (3 mg/kg, i.p.), or vehicle (0.9% saline with two drops of 0.2% Tween 80) before formalin (20 microl, 2%) or capsaicin (20 microl, 2.5 microg) were injected into the right vibrissa. Our results showed that i.p. treatment with AT displayed marked inhibitory effects in different orofacial pain tests in mice. AT (400 mg/kg, i.p.) was effective in reducing the nociceptive face-rubbing behavioural response in both phases of the formalin test, which was also naloxone-sensitive. Additionally, AT produced a significant antinociceptive effect at all doses in the capsaicin test. Such results were unlikely to be provoked by motor abnormality, since AT-treated mice exhibited no performance alteration on the rota rod apparatus. AT exhibited significant anti-inflammatory activity in the acute model of inflammation (leukocyte migration to the peritoneal cavity), carrageenan- and arachidonic acid-induced hind paw edema in rats. Additionally, AT exhibited a dose-dependent antioxidant activity in vitro, as assessed by total radical-trapping antioxidant parameter and total antioxidant reactivity assays. All these findings suggest that AT might represent an important tool for the management of orofacial pain and/or inflammatory disorders.

  17. Effects of opioid blockade on nociceptive flexion reflex thresholds and nociceptive responding in hypertensive and normotensive individuals

    PubMed Central

    Edwards, Louisa; Ring, Christopher; France, Christopher R.; McIntyre, David; Martin, Una

    2008-01-01

    Hypertension and risk for hypertension have been associated with reduced pain sensitivity. It has been hypothesised that endogenous opioids contribute to this hypertensive hypoalgesia. The nociceptive flexion reflex can be used as a tool to investigate modulation of nociceptive transmission at spinal level. The current study employed a double-blind placebo-controlled design to compare the effects of naltrexone, an opioid antagonist, and placebo on nociceptive flexion reflex thresholds and nociceptive responding in unmedicated patients with essential hypertension and normotensive individuals. Neither nociceptive flexion reflex thresholds nor nociceptive responding differed between hypertensives and normotensives during placebo or naltrexone. These data provide no support for the hypothesis that essential hypertension is characterised by higher levels endogenous opioids in the central nervous system and reveal no association between blood pressure status and nociceptive flexion reflex responses. PMID:18436318

  18. Hypergravity modulates behavioral nociceptive responses in rats

    NASA Astrophysics Data System (ADS)

    Kumei, Y.; Shimokawa, R.; Toda, K.; Kawauchi, Y.; Makita, K.; Terasawa, M.; Ohya, K.; Shimokawa, H.

    Hypergravity (2G) exposure elevated the nociceptive threshold (pain suppression) concomitantly with evoked neuronal activity in the hypothalamus. Young Wistar male rats were exposed to 2G by centrifugal rotation for 10 min. Before and after 2G exposure, the nociceptive threshold was measured as the withdrawal reflex by using the von Frey type needle at a total of 8 sites of each rat (nose, four quarters, upper and lower back, tail), and then rats were sacrificed. Fos expression was examined immunohistochemically in the hypothalamic slices of the 2G-treated rats. When rats were exposed to 2G hypergravity, the nociceptive threshold was significantly elevated to approximately 150 to 250% of the 1G baseline control levels in all the examination sites. The 2G hypergravity remarkably induced Fos expression in the paraventricular and arcuate nuclei of the hypothalamus. The analgesic effects of 2G hypergravity were attenuated by naloxone pretreatment. Data indicate that hypergravity induces analgesic effects in rats, mediated through hypothalamic neuronal activity in the endogenous opioid system and hypothalamo-pituitary-adrenal axis.

  19. ZBTB20 regulates nociception and pain sensation by modulating TRP channel expression in nociceptive sensory neurons.

    PubMed

    Ren, An-Jing; Wang, Kai; Zhang, Huan; Liu, Anjun; Ma, Xianhua; Liang, Qing; Cao, Dongmei; Wood, John N; He, David Z; Ding, Yu-Qiang; Yuan, Wen-Jun; Xie, Zhifang; Zhang, Weiping J

    2014-11-05

    In mammals, pain sensation is initiated by the detection of noxious stimuli through specialized transduction ion channels and receptors in nociceptive sensory neurons. Transient receptor potential (TRP) channels are the key sensory transducers that confer nociceptors distinct sensory modalities. However, the regulatory mechanisms about their expression are poorly defined. Here we show that the zinc-finger protein ZBTB20 regulates TRP channels expression in nociceptors. ZBTB20 is highly expressed in nociceptive sensory neurons of dorsal root ganglia. Disruption of ZBTB20 in nociceptors led to a marked decrease in the expression levels of TRPV1, TRPA1 and TRPM8 and the response of calcium flux and whole-cell currents evoked by their respective specific agonists. Phenotypically, the mice lacking ZBTB20 specifically in nociceptors showed a defect in nociception and pain sensation in response to thermal, mechanical and inflammatory stimulation. Our findings point to ZBTB20 as a critical regulator of nociception and pain sensation by modulating TRP channels expression in nociceptors.

  20. Factors affecting mechanical (nociceptive) thresholds in piglets

    PubMed Central

    Janczak, Andrew M; Ranheim, Birgit; Fosse, Torunn K; Hild, Sophie; Nordgreen, Janicke; Moe, Randi O; Zanella, Adroaldo J

    2012-01-01

    Objective To evaluate the stability and repeatability of measures of mechanical (nociceptive) thresholds in piglets and to examine potentially confounding factors when using a hand held algometer. Study design Descriptive, prospective cohort. Animals Forty-four piglets from four litters, weighing 4.6 ± 1.0 kg (mean ± SD) at 2 weeks of age. Methods Mechanical thresholds were measured twice on each of 2 days during the first and second week of life. Data were analyzed using a repeated measures design to test the effects of behavior prior to testing, sex, week, day within week, and repetition within day. The effect of body weight and the interaction between piglet weight and behaviour were also tested. Piglet was entered into the model as a random effect as an additional test of repeatability. The effect of repeated testing was used to test the stability of measures. Pearson correlations between repeated measures were used to test the repeatability of measures. Variance component analysis was used to describe the variability in the data. Results Variance component analysis indicated that piglet explained only 17% of the variance in the data. All variables in the model (behaviour prior to testing, sex, week, day within week, repetition within day, body weight, the interaction between body weight and behaviour, piglet identity) except sex had a significant effect (p < 0.04 for all). Correlations between repeated measures increased from the first to the second week. Conclusions and Clinical relevance Repeatability was acceptable only during the second week of testing and measures changed with repeated testing and increased with increasing piglet weight, indicating that time (age) and animal body weight should be taken into account when measuring mechanical (nociceptive) thresholds in piglets. Mechanical (nociceptive) thresholds can be used both for testing the efficacy of anaesthetics and analgesics, and for assessing hyperalgesia in chronic pain states in research and

  1. The primary somatosensory cortex and the insula contribute differently to the processing of transient and sustained nociceptive and non-nociceptive somatosensory inputs.

    PubMed

    Hu, Li; Zhang, Li; Chen, Rui; Yu, Hongbo; Li, Hong; Mouraux, André

    2015-11-01

    Transient nociceptive stimuli elicit consistent brain responses in the primary and secondary somatosensory cortices (S1, S2), the insula and the anterior and mid-cingulate cortex (ACC/MCC). However, the functional significance of these responses, especially their relationship with sustained pain perception, remains largely unknown. Here, using functional magnetic resonance imaging, we characterize the differential involvement of these brain regions in the processing of sustained nociceptive and non-nociceptive somatosensory input. By comparing the spatial patterns of activity elicited by transient (0.5 ms) and long-lasting (15 and 30 s) stimuli selectively activating nociceptive or non-nociceptive afferents, we found that the contralateral S1 responded more strongly to the onset of non-nociceptive stimulation as compared to the onset of nociceptive stimulation and the sustained phases of nociceptive and non-nociceptive stimulation. Similarly, the anterior insula responded more strongly to the onset of nociceptive stimulation as compared to the onset of non-nociceptive stimulation and the sustained phases of nociceptive and non-nociceptive stimulation. This suggests that S1 is specifically sensitive to changes in incoming non-nociceptive input, whereas the anterior insula is specifically sensitive to changes in incoming nociceptive input. Second, we found that the MCC responded more strongly to the onsets as compared to the sustained phases of both nociceptive and non-nociceptive stimulation, suggesting that it could be involved in the detection of change regardless of sensory modality. Finally, the posterior insula and S2 responded maximally during the sustained phase of non-nociceptive stimulation but not nociceptive stimulation, suggesting that these regions are preferentially involved in processing non-nociceptive somatosensory input.

  2. The anoctamin family channel subdued mediates thermal nociception in Drosophila.

    PubMed

    Jang, Wijeong; Kim, Ji Young; Cui, Shanyu; Jo, Juyeon; Lee, Byoung-Cheol; Lee, Yeonwoo; Kwon, Ki-Sun; Park, Chul-Seung; Kim, Changsoo

    2015-01-23

    Calcium-permeable and thermosensitive transient receptor potential (TRP) channels mediate the nociceptive transduction of noxious temperature in Drosophila nociceptors. However, the underlying molecular mechanisms are not completely understood. Here we find that Subdued, a calcium-activated chloride channel of the Drosophila anoctamin family, functions in conjunction with the thermo-TRPs in thermal nociception. Genetic analysis with deletion and the RNAi-mediated reduction of subdued show that subdued is required for thermal nociception in nociceptors. Further genetic analysis of subdued mutant and thermo-TRP mutants show that they interact functionally in thermal nociception. We find that Subdued expressed in heterologous cells mediates a strong chloride conductance in the presence of both heat and calcium ions. Therefore, our analysis suggests that Subdued channels may amplify the nociceptive neuronal firing that is initiated by thermo-TRP channels in response to thermal stimuli.

  3. Cellular and molecular mechanisms of dental nociception.

    PubMed

    Chung, G; Jung, S J; Oh, S B

    2013-11-01

    Due, in part, to the unique structure of the tooth, dental pain is initiated via distinct mechanisms. Here we review recent advances in our understanding of inflammatory tooth pain and discuss 3 hypotheses proposed to explain dentinal hypersensitivity: The first hypothesis, supported by functional expression of temperature-sensitive transient receptor potential channels, emphasizes the direct transduction of noxious temperatures by dental primary afferent neurons. The second hypothesis, known as hydrodynamic theory, attributes dental pain to fluid movement within dentinal tubules, and we discuss several candidate cellular mechanical transducers for the detection of fluid movement. The third hypothesis focuses on the potential sensory function of odontoblasts in the detection of thermal or mechanical stimuli, and we discuss the accumulating evidence that supports their excitability. We also briefly update on a novel strategy for local nociceptive anesthesia via nociceptive transducer molecules in dental primary afferents with the potential to specifically silence pain fibers during dental treatment. Further understanding of the molecular mechanisms of dental pain would greatly enhance the development of therapeutics that target dental pain.

  4. Differential effects of GABA in modulating nociceptive vs. non-nociceptive synapses.

    PubMed

    Wang, Y; Summers, T; Peterson, W; Miiller, E; Burrell, B D

    2015-07-09

    GABA (γ-amino-butyric acid) -mediated signaling is normally associated with synaptic inhibition due to ionotropic GABA receptors that gate an inward Cl(-) current, hyperpolarizing the membrane potential. However, there are also situations where ionotropic GABA receptors trigger a Cl(-) efflux that results in depolarization. The well-characterized central nervous system of the medicinal leech was used to study the functional significance of opposing effects of GABA at the synaptic circuit level. Specifically, we focused on synapses made by the nociceptive N cell and the non-nociceptive P (pressure) cell that converge onto a common postsynaptic target. It is already known that GABA hyperpolarizes the P cell, but depolarizes the N cell and that inhibition of ionotropic GABA receptors by bicuculline (BIC) has opposing effects on the synapses made by these two inputs; enhancing P cell synaptic transmission, but depressing N cell synapses. The goal of the present study was to determine whether the opposing effects of GABA were due to differences in Cl(-) homeostasis between the two presynaptic neurons. VU 0240551 (VU), an inhibitor of the Cl(-) exporter K-Cl co-transporter isoform 2 (KCC2), attenuated GABA-mediated hyperpolarization of the non-nociceptive afferent while bumetanide (BUM), an inhibitor of the Cl(-) importer Na-K-Cl co-transporter isoform 1 (NKCC1), reduced GABA-mediated depolarization of the nociceptive neuron. VU treatment also enhanced P cell synaptic signaling, similar to the previously observed effects of BIC and consistent with the idea that GABA inhibits synaptic signaling at the presynaptic level. BUM treatment depressed N cell synapses, again similar to what is observed following BIC treatment and suggests that GABA has an excitatory effect on these synapses. The opposing effects of GABA could also be observed at the behavioral level with BIC and VU increasing responsiveness to non-nociceptive stimulation while BIC and BUM decreased responsiveness

  5. Acetal phosphatidic acids: novel platelet aggregating agents.

    PubMed

    Brammer, J P; Maguire, M H; Walaszek, E J; Wiley, R A

    1983-05-01

    1 Palmitaldehyde, olealdehyde and linolealdehyde acetal phosphatidic acids induced rapid shape change and dose-dependent biphasic aggregation of human platelets in platelet-rich plasma; aggregation was reversible at low doses and irreversible at high doses of the acetal phosphatidic acids. The palmitaldehyde congener elicited monophasic dose-dependent aggregation of sheep platelets in platelet-rich plasma.2 The threshold concentration for palmitaldehyde acetal phosphatidic acid (PGAP)-induced platelet aggregation was 2.5-5 muM for human platelets and 0.25-0.5 muM for sheep platelets. PGAP was 4-5 times as potent versus human platelets as the olealdehyde and linolealdehyde acetal phosphatidic acids, which were equipotent.3 PGAP-induced irreversible aggregation of [(14)C]-5-hydroxytryptamine ([(14)C]-5-HT)-labelled human platelets in platelet-rich plasma was accompanied by release of 44.0+/-2.4% (s.e.) of the platelet [(14)C]-5-HT; reversible aggregation was not associated with release. In contrast, PGAP-induced release of [(14)C]-5-HT-labelled sheep platelets was dose-dependent.4 The adenosine diphosphate (ADP) antagonist, 2-methylthio-AMP, and the cyclo-oxygenase inhibitor, aspirin, abolished PGAP-induced second phase aggregation and release in human platelets but did not affect the first, reversible, phase of aggregation. Both the first and second phases of PGAP-induced aggregation were abolished by chlorpromazine, by the phospholipase A(2) inhibitor, mepacrine, and by nmolar concentrations of prostaglandin E(1) (PGE(1)); these agents abolished the second, but not the first phase of ADP-induced aggregation.5 The related phospholipids, lecithin, lysolecithin and phosphatidic acid, at <100 muM, neither induced aggregation of human platelets in platelet-rich plasma, nor modified PGAP-induced aggregation; 1-palmityl lysophosphatidic acid elicited aggregation of human platelets at a threshold concentration of 100 muM.6 It is concluded that the acetal phosphatidic acids

  6. Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission

    PubMed Central

    Du, Xiaona; Hao, Han; Gigout, Sylvain; Huang, Dongyang; Yang, Yuehui; Li, Li; Wang, Caixue; Sundt, Danielle; Jaffe, David B.; Zhang, Hailin; Gamper, Nikita

    2014-01-01

    Peripheral sensory ganglia contain somata of afferent fibres conveying somatosensory inputs to the central nervous system. Growing evidence suggests that the somatic/perisomatic region of sensory neurons can influence peripheral sensory transmission. Control of resting membrane potential (Erest) is an important mechanism regulating excitability, but surprisingly little is known about how Erest is regulated in sensory neuron somata or how changes in somatic/perisomatic Erest affect peripheral sensory transmission. We first evaluated the influence of several major ion channels on Erest in cultured small-diameter, mostly capsaicin-sensitive (presumed nociceptive) dorsal root ganglion (DRG) neurons. The strongest and most prevalent effect on Erest was achieved by modulating M channels, K2P and 4-aminopiridine-sensitive KV channels, while hyperpolarization-activated cyclic nucleotide-gated, voltage-gated Na+, and T-type Ca2+ channels to a lesser extent also contributed to Erest. Second, we investigated how varying somatic/perisomatic membrane potential, by manipulating ion channels of sensory neurons within the DRG, affected peripheral nociceptive transmission in vivo. Acute focal application of M or KATP channel enhancers or a hyperpolarization-activated cyclic nucleotide-gated channel blocker to L5 DRG in vivo significantly alleviated pain induced by hind paw injection of bradykinin. Finally, we show with computational modelling how somatic/perisomatic hyperpolarization, in concert with the low-pass filtering properties of the t-junction within the DRG, can interfere with action potential propagation. Our study deciphers a complement of ion channels that sets the somatic Erest of nociceptive neurons and provides strong evidence for a robust filtering role of the somatic and perisomatic compartments of peripheral nociceptive neuron. PMID:25168672

  7. Spinal modulation of nociception by music.

    PubMed

    Roy, M; Lebuis, A; Hugueville, L; Peretz, I; Rainville, P

    2012-07-01

    Numerous studies have demonstrated the capacity of music to modulate pain. However, the neurophysiological mechanisms responsible for this phenomenon remain unknown. In order to assess the involvement of descending modulatory mechanisms in the modulation of pain by music, we evaluated the effects of musical excerpts conveying different emotions (pleasant-stimulating, pleasant-relaxing, unpleasant-stimulating) on the spinally mediated nociceptive flexion reflex (or RIII), as well as on pain ratings and skin conductance responses. The RIII reflex and pain ratings were increased during the listening of unpleasant music compared with pleasant music, suggesting the involvement of descending pain-modulatory mechanisms in the effects of musical emotions on pain. There were no significant differences between the pleasant-stimulating and pleasant-relaxing musical condition, indicating that the arousal of music had little influence on pain processing.

  8. Mast Cell-Mediated Mechanisms of Nociception.

    PubMed

    Aich, Anupam; Afrin, Lawrence B; Gupta, Kalpna

    2015-12-04

    Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner.

  9. Mast Cell-Mediated Mechanisms of Nociception

    PubMed Central

    Aich, Anupam; Afrin, Lawrence B.; Gupta, Kalpna

    2015-01-01

    Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner. PMID:26690128

  10. Acetic acid enhances endurance capacity of exercise-trained mice by increasing skeletal muscle oxidative properties.

    PubMed

    Pan, Jeong Hoon; Kim, Jun Ho; Kim, Hyung Min; Lee, Eui Seop; Shin, Dong-Hoon; Kim, Seongpil; Shin, Minkyeong; Kim, Sang Ho; Lee, Jin Hyup; Kim, Young Jun

    2015-01-01

    Acetic acid has been shown to promote glycogen replenishment in skeletal muscle during exercise training. In this study, we investigated the effects of acetic acid on endurance capacity and muscle oxidative metabolism in the exercise training using in vivo mice model. In exercised mice, acetic acid induced a significant increase in endurance capacity accompanying a reduction in visceral adipose depots. Serum levels of non-esterified fatty acid and urea nitrogen were significantly lower in acetic acid-fed mice in the exercised mice. Importantly, in the mice, acetic acid significantly increased the muscle expression of key enzymes involved in fatty acid oxidation and glycolytic-to-oxidative fiber-type transformation. Taken together, these findings suggest that acetic acid improves endurance exercise capacity by promoting muscle oxidative properties, in part through the AMPK-mediated fatty acid oxidation and provide an important basis for the application of acetic acid as a major component of novel ergogenic aids.

  11. Understanding the mechanisms through which spatial attention acts on nociception.

    PubMed

    Torta, Diana M E

    2015-11-01

    Previous studies have shown that spatial attention can influence the magnitude of brain responses to nociceptive inputs. In their recent article (Franz M, Nickel MM, Ritter A, Miltner WH, Weiss T. J Neurophysiol 113: 2760-2768, 2015), Franz and colleagues expand this observation by showing that spatial attention is further able to modify the chronometry of nociceptive processing by modulating the latency and temporal jitter of the recorded responses. The mechanisms through which attention could possibly modulate nociceptive processing are discussed here, with a particular focus on novel findings and future perspectives.

  12. Altered Nociceptive Neuronal Circuits After Neonatal Peripheral Inflammation

    NASA Astrophysics Data System (ADS)

    Ruda, M. A.; Ling, Qing-Dong; Hohmann, Andrea G.; Peng, Yuan Bo; Tachibana, Toshiya

    2000-07-01

    Nociceptive neuronal circuits are formed during embryonic and postnatal times when painful stimuli are normally absent or limited. Today, medical procedures for neonates with health risks can involve tissue injury and pain for which the long-term effects are unknown. To investigate the impact of neonatal tissue injury and pain on development of nociceptive neuronal circuitry, we used an animal model of persistent hind paw peripheral inflammation. We found that, as adults, these animals exhibited spinal neuronal circuits with increased input and segmental changes in nociceptive primary afferent axons and altered responses to sensory stimulation.

  13. Nociceptive primary afferents: they have a mind of their own

    PubMed Central

    Carlton, Susan M

    2014-01-01

    Nociceptive primary afferents have three surprising properties: they are highly complex in their expression of neurotransmitters and receptors and most probably participate in autocrine and paracrine interactions; they are capable of exerting tonic and activity-dependent inhibitory control over incoming nociceptive input; they can generate signals in the form of dorsal root reflexes that are transmitted antidromically out to the periphery and these signals can result in neurogenic inflammation in the innervated tissue. Thus, nociceptive primary afferents are highly complicated structures, capable of modifying input before it is ever transmitted to the central nervous system and capable of altering the tissue they innervate. PMID:24879874

  14. Sensory TRP channels: the key transducers of nociception and pain.

    PubMed

    Mickle, Aaron D; Shepherd, Andrew J; Mohapatra, Durga P

    2015-01-01

    Peripheral detection of nociceptive and painful stimuli by sensory neurons involves a complex repertoire of molecular detectors and/or transducers on distinct subsets of nerve fibers. The majority of such molecular detectors/transducers belong to the transient receptor potential (TRP) family of cation channels, which comprise both specific receptors for distinct nociceptive stimuli, as well as for multiple stimuli. This chapter discusses the classification, distribution, and functional properties of individual TRP channel types that have been implicated in various nociceptive and/or painful conditions.

  15. The ankyrin repeat domain of the TRPA protein painless is important for thermal nociception but not mechanical nociception.

    PubMed

    Hwang, Richard Y; Stearns, Nancy A; Tracey, W Daniel

    2012-01-01

    The Drosophila TRPA channel Painless is required for the function of polymodal nociceptors which detect noxious heat and noxious mechanical stimuli. These functions of Painless are reminiscent of mammalian TRPA channels that have also been implicated in thermal and mechanical nociception. A popular hypothesis to explain the mechanosensory functions of certain TRP channels proposes that a string of ankyrin repeats at the amino termini of these channels acts as an intracellular spring that senses force. Here, we describe the identification of two previously unknown Painless protein isoforms which have fewer ankyrin repeats than the canonical Painless protein. We show that one of these Painless isoforms, that essentially lacks ankyrin repeats, is sufficient to rescue mechanical nociception phenotypes of painless mutant animals but does not rescue thermal nociception phenotypes. In contrast, canonical Painless, which contains Ankyrin repeats, is sufficient to largely rescue thermal nociception but is not capable of rescuing mechanical nociception. Thus, we propose that in the case of Painless, ankryin repeats are important for thermal nociception but not for mechanical nociception.

  16. Roles of phosphotase 2A in nociceptive signal processing.

    PubMed

    Wang, Yun; Lei, Yongzhong; Fang, Li; Mu, Yonggao; Wu, Jing; Zhang, Xuan

    2013-09-08

    Multiple protein kinases affect the responses of dorsal horn neurons through phosphorylation of synaptic receptors and proteins involved in intracellular signal transduction pathways, and the consequences of this modulation may be spinal central sensitization. In contrast, the phosphatases catalyze an opposing reaction of de-phosphorylation, which may also modulate the functions of crucial proteins in signaling nociception. This is an important mechanism in the regulation of intracellular signal transduction pathways in nociceptive neurons. Accumulated evidence has shown that phosphatase 2A (PP2A), a serine/threonine specific phosphatase, is implicated in synaptic plasticity of the central nervous system and central sensitization of nociception. Therefore, targeting protein phosphotase 2A may provide an effective and novel strategy for the treatment of clinical pain. This review will characterize the structure and functional regulation of neuronal PP2A and bring together recent advances on the modulation of PP2A in targeted downstream substrates and relevant multiple nociceptive signaling molecules.

  17. Antinociceptive effects of systemic tanshinone IIA on visceral and somatic persistent nociception and pain hypersensitivity in rats.

    PubMed

    Cao, Fa-Le; Su, Xue-Jia; Wang, Yan; Xu, Min; Shan, Liang

    2014-09-01

    Previous studies showed that tanshinone IIA (TIIA), an important lipophilic component of Danshen, has been well-established to exhibit various neuroprotective actions in the nervous system. Although we previously reported that TIIA had a significant anti-nociceptive effect in complete Freund's adjuvant (CFA)-induced pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA in animals and the appropriate indications for treatment of clinical pain remain unclear. Therefore, in the present study, by using both somatic and visceral pain models, the antinociceptive and antihyperalgesic effects of TIIA were evaluated by intraperitoneal administration in rats. In the bee venom (BV) test, when compared with saline controls, systemic pre- and post-treatment with TIIA resulted in an apparent antinociception against persistent spontaneous nociception (PSN) and primary heat and mechanical hypersensitivity, while for the mirror-image heat hypersensitivity, only pre-treatment was effective. Moreover, in the formalin test, the antinociception of TIIA was significant for both phases 1 and 2 in the pretreatment groups, but only effective for phase 2 in the post-treatment group. In the acetic acid writhing test, the number of writhes was effectively blocked by both pre- and post-treatment of TIIA. Taken together, these results provide a new line of evidence showing that TIIA is also able to produce analgesia against various 'phenotypes' of nociception and hypersensitivity.

  18. Learned control over spinal nociception reduces supraspinal nociception as quantified by late somatosensory evoked potentials.

    PubMed

    Ruscheweyh, Ruth; Bäumler, Maximilian; Feller, Moritz; Krafft, Stefanie; Sommer, Jens; Straube, Andreas

    2015-12-01

    We have recently shown that subjects can learn to use cognitive-emotional strategies to suppress their spinal nociceptive flexor reflex (RIII reflex) under visual RIII feedback and proposed that this reflects learned activation of descending pain inhibition. Here, we investigated whether learned RIII suppression also affects supraspinal nociception and whether previous relaxation training increases success. Subjects were trained over 3 sessions to reduce their RIII size by self-selected cognitive-emotional strategies. Two groups received true RIII feedback (with or without previous relaxation training) and a sham group received false feedback (15 subjects per group). RIII reflexes, late somatosensory evoked potentials (SEPs), and F-waves were recorded and pain intensity ratings collected. Both true feedback groups achieved significant (P < 0.01) but similar RIII suppression (to 79% ± 21% and 70% ± 17% of control). Somatosensory evoked potential amplitude (100-150 milliseconds after stimulation) was reduced in parallel with the RIII size (r = 0.57, P < 0.01). In the sham group, neither RIII size nor SEP amplitude was significantly reduced during feedback training. Pain intensity was significantly reduced in all 3 groups and also correlated with RIII reduction (r = 0.44, P < 0.01). F-wave parameters were not affected during RIII suppression. The present results show that learned RIII suppression also affects supraspinal nociception as quantified by SEPs, although effects on pain ratings were less clear. Lower motor neuron excitability as quantified by F-waves was not affected. Previous relaxation training did not significantly improve RIII feedback training success.

  19. Voltage-Gated Calcium Channels in Nociception

    NASA Astrophysics Data System (ADS)

    Yasuda, Takahiro; Adams, David J.

    Voltage-gated calcium channels (VGCCs) are a large and functionally diverse group of membrane ion channels ubiquitously expressed throughout the central and peripheral nervous systems. VGCCs contribute to various physiological processes and transduce electrical activity into other cellular functions. This chapter provides an overview of biophysical properties of VGCCs, including regulation by auxiliary subunits, and their physiological role in neuronal functions. Subsequently, then we focus on N-type calcium (Cav2.2) channels, in particular their diversity and specific antagonists. We also discuss the role of N-type calcium channels in nociception and pain transmission through primary sensory dorsal root ganglion neurons (nociceptors). It has been shown that these channels are expressed predominantly in nerve terminals of the nociceptors and that they control neurotransmitter release. To date, important roles of N-type calcium channels in pain sensation have been elucidated genetically and pharmacologically, indicating that specific N-type calcium channel antagonists or modulators are particularly useful as therapeutic drugs targeting chronic and neuropathic pain.

  20. Hypochlorous and peracetic acid induced oxidation of dairy proteins.

    PubMed

    Kerkaert, Barbara; Mestdagh, Frédéric; Cucu, Tatiana; Aedo, Philip Roger; Ling, Shen Yan; De Meulenaer, Bruno

    2011-02-09

    Hypochlorous and peracetic acids, both known disinfectants in the food industry, were compared for their oxidative capacity toward dairy proteins. Whey proteins and caseins were oxidized under well controlled conditions at pH 8 as a function of the sanitizing concentration. Different markers for protein oxidation were monitored. The results established that the protein carbonyl content was a rather unspecific marker for protein oxidation, which did not allow one to differentiate the oxidant used especially at the lower concentrations. Cysteine, tryptophan, and methionine were proven to be the most vulnerable amino acids for degradation upon hypochlorous and peracetic acid treatment, while tyrosine was only prone to degradation in the presence of hypochlorous acid. Hypochlorous acid induced oxidation gave rise to protein aggregation, while during peracetic acid induced oxidation, no high molecular weight aggregates were observed. Protein aggregation upon hypochlorous acid oxidation could primarily be linked to tryptophan and tyrosine degradation.

  1. Protective Mechanisms of Nitrone Antioxidants in Kanic Acid Induced Neurodegeneration

    DTIC Science & Technology

    2004-01-01

    L., Hong, J.S. (1996) Expression of) FosB in the rat hippocampus and striatum after systemic administration of kainic acid. Neurosci. Abstr. 22...gene expression in the hippocampus . Immunohistochemical methods and electromobility gel shift assays (EMSAs) demonstrate the concerted activation of...acid-induced neurodegenerative diseases. The major focus will be on the pathophysiological changes in the hippocampus . Special attention will be given

  2. Roles of substance P and somatostatin on transmission of nociceptive information induced by formalin in spinal cord

    SciTech Connect

    Ohkubo, T.; Shibata, M.; Takahashi, H.; Inoki, R. )

    1990-03-01

    Nociceptive response induced by 0.5% Formalin in the hindpaw of mice had two peaks, 0-5 min (first phase) and 15-20 min (second phase). By using the distinct biphasic response, the nature of the transmitter systems activated by Formalin in the spinal cord was studied for the purpose of determining the difference of the role of substance P (SP) and somatostatin (SST). The injection of (D-Pro2, D-Trp7,9)SP, (D-Arg1, D-Pro2, D-Trp7,9, Leu11)SP and SP antiserum inhibited only the first phase response. The i.t. injection of -Aminoheptanoyl-Phe-D-Trp-Lys-(OBz)-Thr- (an SST antagonist), SST antiserum and cysteamine (an SST depletor) inhibited only the second phase. This result indicates that SP is involved in the transmission of the first phase, and SST is involved in the transmission of the second phase of the Formalin-induced nociceptive response. With regard to other nociceptive stimuli, two i.t. SP antagonists produced a significant analgesia in the hot plate and tail pinch tests but had no effect in the acetic acid writhing test. However, i.t. SST antagonist and cysteamine produced a significant analgesia in the writhing test but had no effect in the hot plate and tail pinch test. These results suggest that SP participates in the transient pain induced by such acute stimuli as hot plate, tail pinch and the first phase of Formalin response and that SST participates in the prolonged and inflammatory pain induced by stimuli such as acetic acid and the second phase response.

  3. Anti-inflammatory, Anti-nociceptive and Total polyphenolic Content of Hydroethanolic Extract of Ocimum gratissimum L. Leaves

    PubMed Central

    Ajayi, AM; Tanayen, JK; Ezeonwumelu, JOC; Dare, S; Okwanachi, A; Adzu, B; Ademowo, OG

    2015-01-01

    Ocimum gratissimum has been reported in several ethnopharmacological surveys as a plant readily accessible to the communities and widely used with a lot of therapeutic potentials. In this study, we aimed to experimentally evaluate the anti-inflammatory effects of hydro-ethanolic extract in animal models of inflammation and nociception and membrane stabilization assay. O gratissimum leaves hydroethanolic extract was subjected to phytochemical screening and spectrophotometric quantification of polyphenolics. The extract was investigated for anti-inflammatory effects in carrageenan –induced paw oedema and cotton pellet - induced granuloma in rats. The antinociceptive effects were investigated in acetic acid –induced writhing in mice and formalin test in rats. Animals were randomly divided into groups; negative control, extract treated (200 -800 mg/kg) and indomethacin (10 mg/kg) standard reference groups. In- vitro anti-inflammatory activity was performed by testing for membrane stability in heat/hypotonic solution –induced rat erythrocytes destabilization assay. Phytochemical screening revealed presence of saponins, tannins, alkaloids, flavonoids, terpenoids, and cardenolides. Quantification of the polyphenolic content revealed the presence of appreciable quantities of phenolics and flavonoids. Carrageenan-induced paw oedema, cotton-pellet granuloma, acetic acid –induced writhing and formalin induced paw licking tests showed that hydroethanolic extract of O gratissimum possess anti-inflammatory and anti-nociceptive effects. The extract did not induce gastric lesion formation in stomach of cotton-pellet granuloma rats. The extract was more efficient at reducing membrane destabilization than indomethacin in the membrane stability assay. These results suggest that hydroethanolic extract of O gratissimum leaves exhibits anti-inflammatory and anti-nociceptive effects in the animals. PMID:26689550

  4. Intraplantar injection of bergamot essential oil into the mouse hindpaw: effects on capsaicin-induced nociceptive behaviors.

    PubMed

    Sakurada, Tsukasa; Kuwahata, Hikari; Katsuyama, Soh; Komatsu, Takaaki; Morrone, Luigi Antonio; Corasaniti, Maria Tiziana; Bagetta, Giacinto; Sakurada, Shinobu

    2009-01-01

    Despite the increasing use of aromatherapy oils, there have not been many studies exploring the biological activities of bergamot (Citrus bergamia, Risso) essential oil (BEO). Recently, we have investigated the effects of BEO injected into the plantar surface of the hindpaw in the capsaicin test in mice. The intraplantar injection of capsaicin produced an intense and short-lived licking/biting response toward the injected hindpaw. The capsaicin-induced nociceptive response was reduced significantly by intraplantar injection of BEO. The essential oils of Clary Sage (Salvia sclarea), Thyme ct. linalool (linalool chemotype of Thymus vulgaris), Lavender Reydovan (Lavandula hybrida reydovan), and True Lavender (Lavandula angustifolia), had similar antinociceptive effects on the capsaicin-induced nociceptive response, while Orange Sweet (Citrus sinensis) essential oil was without effect. In contrast to a small number of pharmacological studies of BEO, there is ample evidence regarding isolated components of BEO which are also found in other essential oils. The most abundant compounds found in the volatile fraction are the monoterpene hydrocarbons, such as limonene, gamma-terpinene, beta-pinene, and oxygenated derivatives, linalool and linalyl acetate. Of these monoterpenes, the pharmacological activities of linalool have been examined. Following intraperitoneal (i.p.) administration in mice, linalool produces antinociceptive and antihyperalgesic effects in different animal models in addition to anti-inflammatory properties. Linalool also possesses anticonvulsant activity in experimental models of epilepsy. We address the importance of linalool or linalyl acetate in BEO-or the other essential oil-induced antinociception.

  5. Individual cells of Saccharomyces cerevisiae and Zygosaccharomyces bailii exhibit different short-term intracellular pH responses to acetic acid.

    PubMed

    Arneborg, N; Jespersen, L; Jakobsen, M

    2000-01-01

    The effects of perfusion with 2.7 and 26 mM undissociated acetic acid in the absence or presence of glucose on short-term intracellular pH (pH(i)) changes in individual Saccharormyces cerevisiae and Zygosaccharomyces bailii cells were studied using fluorescence-ratio-imaging microscopy and a perfusion system. In the S. cerevisiae cells, perfusion with acetic acid induced strong short-term pH(i) responses, which were dependent on the undissociated acetic acid concentration and the presence of glucose in the perfusion solutions. In the Z. bailii cells, perfusion with acetic acid induced only very weak short-term pH(i) responses, which were neither dependent on the undissociated acetic acid concentration nor on the presence of glucose in the perfusion solutions. These results clearly show that Z. bailii is more resistant than S. cerevisiae to short-term pH(i) changes caused by acetic acid.

  6. Looking at the hand modulates the brain responses to nociceptive and non-nociceptive somatosensory stimuli but does not necessarily modulate their perception.

    PubMed Central

    Torta, DM; Legrain, V; Mouraux, A

    2017-01-01

    Looking at the hand can reduce the perception of pain and the magnitude of the event-related potentials (ERPs) elicited by nociceptive stimuli delivered onto the hand, whereas it can increase that of tactile ERPs. These differences could be related to the use of different experimental designs. Importantly, most studies on the effects of vision on pain have relied on a mirror to create the illusion that the reflected hand is a direct view of the stimulated hand. Here, we compared the effects of direct vs. mirror vision of the hand vs. an object on the perception and ERPs elicited by non-nociceptive and nociceptive stimuli. We did not observe any significant effect of vision on the perceived intensity. Vision of the hand reduced the nociceptive N240, and enhanced the non-nociceptive P200. Our results confirm that vision of the body differentially affects nociceptive and non-nociceptive processing, but question the robustness of visual analgesia. PMID:25917217

  7. The anti-nociceptive potential of tilmicosin against chemical-induced but not thermal-induced pain in mice.

    PubMed

    El-Mahmoudy, A; Gheith, I

    2016-03-01

    The aim of the present study was to assess the analgesic activity of the macrolide antibiotic tilmicosin at dose levels of 20 and 40 mg/kg of body weight, subcutaneously, against chemical- and thermal-induced acute pains, using acetic acid-induced writhing, formalin-induced pain, hot-plate, and tail-flick models in mice. Tilmicosin showed a dose-dependent significant decrease in the number of writhes in the acetic acid-induced writhing test and significant decrease in hind paw-licking time in the late phase of the formalin test. However, it did not cause any significant changes in the reaction times to heat stimuli in the hot-plate and tail-flick models. In chemically-induced pains, both dose levels of tilmicosin showed significant effects compared to those of the corresponding standard peripheral analgesic, acetylsalicylic acid (200 mg/kg of body weight, subcutaneously) being 26.37±2.88 and 43.64±3.85% vs. 73.35±1.44% in acetic acid test; and 19.23±3.85 and 44.90±1.80% vs. 73.63±2.39% in the late phase of formalin test, respectively. These results may indicate that tilmicosin possesses a significant peripheral but not central analgesic potential that may be beneficial in symptomatic relief of pain when it is used in therapy, in addition to its well-established antibacterial effect.

  8. Larval defense against attack from parasitoid wasps requires nociceptive neurons.

    PubMed

    Robertson, Jessica L; Tsubouchi, Asako; Tracey, W Daniel

    2013-01-01

    Parasitoid wasps are a fierce predator of Drosophila larvae. Female Leptopilina boulardi (LB) wasps use a sharp ovipositor to inject eggs into the bodies of Drosophila melanogaster larvae. The wasp then eats the Drosophila larva alive from the inside, and an adult wasp ecloses from the Drosophila pupal case instead of a fly. However, the Drosophila larvae are not defenseless as they may resist the attack of the wasps through somatosensory-triggered behavioral responses. Here we describe the full range of behaviors performed by the larval prey in immediate response to attacks by the wasps. Our results suggest that Drosophila larvae primarily sense the wasps using their mechanosensory systems. The range of behavioral responses included both "gentle touch" like responses as well as nociceptive responses. We found that the precise larval response depended on both the somatotopic location of the attack, and whether or not the larval cuticle was successfully penetrated during the course of the attack. Interestingly, nociceptive responses are more likely to be triggered by attacks in which the cuticle had been successfully penetrated by the wasp. Finally, we found that the class IV neurons, which are necessary for mechanical nociception, were also necessary for a nociceptive response to wasp attacks. Thus, the class IV neurons allow for a nociceptive behavioral response to a naturally occurring predator of Drosophila.

  9. Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state

    PubMed Central

    de Tommaso, Marina; Navarro, Jorge; Lanzillotti, Crocifissa; Ricci, Katia; Buonocunto, Francesca; Livrea, Paolo; Lancioni, Giulio E.

    2015-01-01

    Aims: Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient visual, acoustic, somatosensory electric non-nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation. Methods: Five Vegetative State (VS), 4 Minimally Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 s. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2) vertex complex in the 500 ms post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R) and Coma Recovery Scale (CRS-R) for clinical evaluation of pain perception and consciousness impairment. Results: The laser evoked potentials (LEPs) were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. Discussion: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the degree of cognitive and motor

  10. Modulatory Mechanism of Nociceptive Neuronal Activity by Dietary Constituent Resveratrol

    PubMed Central

    Takeda, Mamoru; Takehana, Shiori; Sekiguchi, Kenta; Kubota, Yoshiko; Shimazu, Yoshihito

    2016-01-01

    Changes to somatic sensory pathways caused by peripheral tissue, inflammation or injury can result in behavioral hypersensitivity and pathological pain, such as hyperalgesia. Resveratrol, a plant polyphenol found in red wine and various food products, is known to have several beneficial biological actions. Recent reports indicate that resveratrol can modulate neuronal excitability, including nociceptive sensory transmission. As such, it is possible that this dietary constituent could be a complementary alternative medicine (CAM) candidate, specifically a therapeutic agent. The focus of this review is on the mechanisms underlying the modulatory effects of resveratrol on nociceptive neuronal activity associated with pain relief. In addition, we discuss the contribution of resveratrol to the relief of nociceptive and/or pathological pain and its potential role as a functional food and a CAM. PMID:27727178

  11. Valproic acid-induced hyperammonaemic coma and unrecognised portosystemic shunt.

    PubMed

    Nzwalo, Hipólito; Carrapatoso, Leonor; Ferreira, Fátima; Basilio, Carlos

    2013-06-01

    Hyperammonaemic encephalopathy is a rare and potentially fatal complication of valproic acid treatment. The clinical presentation of hyperammonaemic encephalopathy is wide and includes seizures and coma. We present a case of hyperammonaemic coma precipitated by sodium valproate use for symptomatic epilepsy in a patient with unrecognised portosystemic shunt, secondary to earlier alcoholism. The absence of any stigmata of chronic liver disease and laboratory markers of liver dysfunction delayed the recognition of this alcohol-related complication. The portal vein bypass led to a refractory, valproic acid-induced hyperammonaemic coma. The patient fully recovered after dialysis treatment.

  12. Preparation of vinyl acetate

    DOEpatents

    Tustin, Gerald Charles; Zoeller, Joseph Robert; Depew, Leslie Sharon

    1998-01-01

    This invention pertains to the preparation of vinyl acetate by contacting a mixture of hydrogen and ketene with a heterogeneous catalyst containing a transition metal to produce acetaldehyde, which is then reacted with ketene in the presence of an acid catalyst to produce vinyl acetate.

  13. Preparation of vinyl acetate

    DOEpatents

    Tustin, G.C.; Zoeller, J.R.; Depew, L.S.

    1998-03-24

    This invention pertains to the preparation of vinyl acetate by contacting a mixture of hydrogen and ketene with a heterogeneous catalyst containing a transition metal to produce acetaldehyde, which is then reacted with ketene in the presence of an acid catalyst to produce vinyl acetate.

  14. Nanofabrication in cellulose acetate.

    PubMed

    Zeng, Hongjun; Lajos, Robert; Metlushko, Vitali; Elzy, Ed; An, Se Young; Sautner, Joshua

    2009-03-07

    We have demonstrated nanofabrication with commercialized cellulose acetate. Cellulose acetate is used for bulk nanofabrication and surface nanofabrication. In bulk nanofabrication, cellulose acetate reacts with an e-beam and permanent patterns are formed in it instead of being transferred to other substrates. We have studied the nano relief modulation performance of cellulose acetate before and after development. The depth of the nanopatterns is magnified after development, and is varied by exposing dosage and line width of the pattern. The thinnest 65 nm wide line is achieved in the bulk fabrication. We also demonstrate a binary phase Fresnel lens array which is directly patterned in a cellulose acetate sheet. Because of its unique mechanical and optical properties, cellulose is a good candidate for a template material for soft imprinting lithography. In the surface nanofabrication, cellulose acetate thin film spin-coated on silicon wafers is employed as a new resist for e-beam lithography. We achieved 50 nm lines with 100 nm pitches, dots 50 nm in diameter, and single lines with the smallest width of 20 nm. As a new resist of e-beam lithography, cellulose acetate has high resolution comparable with conventional resists, while having several advantages such as low cost, long stock time and less harmfulness to human health.

  15. Effect of royal jelly on experimental colitis induced by acetic acid and alteration of mast cell distribution in the colon of rats

    PubMed Central

    Karaca, T.; Bayiroglu, F.; Yoruk, M.; Kaya, M.S.; Uslu, S.; Comba, B.; Mis, L.

    2010-01-01

    This study investigated the effects of royal jelly (RJ) on acetic acid-induced colitis in rats. Twenty adult female Wistar albino rats were divided into four treatment groups of 5 animals each, including a control group (Group I); Group II was treated orally with RJ (150 mg kg−1 body weight); Group III had acetic acid-induced colitis; and Group IV had acetic acid-induced colitis treated orally with RJ (150 mg kg−1 body weight) for 4 weeks. Colitis was induced by intracolonic instillation of 4% acetic acid; the control group received physiological saline (10 mL kg−1). Colon samples were obtained under deep anaesthesia from animals in all groups. Tissues were fixed in 10% formalin neutral buffer solution for 24 h and embedded in paraffin. Six-micrometre-thick sections were stained with Mallory’s triple stain and toluidine blue in 1% aqueous solution at pH 1.0 for 5 min (for Mast Cells). RJ was shown to protect the colonic mucosa against the injurious effect of acetic acid. Colitis (colonic damage) was confirmed histomorphometrically as significant increases in the number of mast cells (MC) and colonic erosions in rats with acetic acid-induced colitis. The RJ treatment significantly decreased the number of MC and reduced the area of colonic erosion in the colon of RJ-treated rats compared with rats with untreated colitis. The results suggest that oral treatment with RJ could be used to treat colitis. PMID:21263740

  16. Nociception at the diabetic foot, an uncharted territory

    PubMed Central

    Chantelau, Ernst A

    2015-01-01

    The diabetic foot is characterised by painless foot ulceration and/or arthropathy; it is a typical complication of painless diabetic neuropathy. Neuropathy depletes the foot skin of intraepidermal nerve fibre endings of the afferent A-delta and C-fibres, which are mostly nociceptors and excitable by noxious stimuli only. However, some of them are cold or warm receptors whose functions in diabetic neuropathy have frequently been reported. Hence, it is well established by quantitative sensory testing that thermal detection thresholds at the foot skin increase during the course of painless diabetic neuropathy. Pain perception (nociception), by contrast, has rarely been studied. Recent pilot studies of pinprick pain at plantar digital skinfolds showed that the perception threshold was always above the upper limit of measurement of 512 mN (equivalent to 51.2 g) at the diabetic foot. However, deep pressure pain perception threshold at musculus abductor hallucis was beyond 1400 kPa (equivalent to 14 kg; limit of measurement) only in every fifth case. These discrepancies of pain perception between forefoot and hindfoot, and between skin and muscle, demand further study. Measuring nociception at the feet in diabetes opens promising clinical perspectives. A critical nociception threshold may be quantified (probably corresponding to a critical number of intraepidermal nerve fibre endings), beyond which the individual risk of a diabetic foot rises appreciably. Staging of diabetic neuropathy according to nociception thresholds at the feet is highly desirable as guidance to an individualised injury prevention strategy. PMID:25897350

  17. Nociception at the diabetic foot, an uncharted territory.

    PubMed

    Chantelau, Ernst A

    2015-04-15

    The diabetic foot is characterised by painless foot ulceration and/or arthropathy; it is a typical complication of painless diabetic neuropathy. Neuropathy depletes the foot skin of intraepidermal nerve fibre endings of the afferent A-delta and C-fibres, which are mostly nociceptors and excitable by noxious stimuli only. However, some of them are cold or warm receptors whose functions in diabetic neuropathy have frequently been reported. Hence, it is well established by quantitative sensory testing that thermal detection thresholds at the foot skin increase during the course of painless diabetic neuropathy. Pain perception (nociception), by contrast, has rarely been studied. Recent pilot studies of pinprick pain at plantar digital skinfolds showed that the perception threshold was always above the upper limit of measurement of 512 mN (equivalent to 51.2 g) at the diabetic foot. However, deep pressure pain perception threshold at musculus abductor hallucis was beyond 1400 kPa (equivalent to 14 kg; limit of measurement) only in every fifth case. These discrepancies of pain perception between forefoot and hindfoot, and between skin and muscle, demand further study. Measuring nociception at the feet in diabetes opens promising clinical perspectives. A critical nociception threshold may be quantified (probably corresponding to a critical number of intraepidermal nerve fibre endings), beyond which the individual risk of a diabetic foot rises appreciably. Staging of diabetic neuropathy according to nociception thresholds at the feet is highly desirable as guidance to an individualised injury prevention strategy.

  18. Comparison of trigeminal and spinal modulation of pain and nociception.

    PubMed

    Rehberg, Benno; Baars, Jan H; Kotsch, Julia; Koppe, Peter; von Dincklage, Falk

    2012-06-01

    Modulation of pain and nociception by noxious counterstimulation, also called "diffuse noxious inhibitory controls" or DNIC-like effect, is often used in studies of pain disorders. It can be elicited in the trigeminal and spinal innervation areas, but no study has previously compared effects in both innervation areas. Therefore, we performed a study comparing DNIC-like effects on the nociceptive flexion reflex (NFR) and the nociceptive blink reflex as well as the respective pain sensations. In 50 healthy volunteers, the blink reflex elicited with a concentric electrode and the NFR were recorded before and after immersion of the contralateral hand in cold water. Responses were recorded as the subjective pain sensation and the reflex size. The cold water immersion of the contralateral hand elicited a reduction of both subjective pain sensation and reflex amplitude following the stimulation of both reflexes. However, there were no strong correlations between the individual reductions of both subjective pain sensation and reflex amplitude for both reflexes, and neither when results of the two reflexes were compared with each other. The dissociation between DNIC-like effects on pain and on nociception, which had been found previously already for the NFR, implies that both effects need to be studied separately.

  19. Tests and models of nociception and pain in rodents.

    PubMed

    Barrot, M

    2012-06-01

    Nociception and pain is a large field of both neuroscience and medical research. Over time, various tests and models were developed in rodents to provide tools for fundamental and translational research on the topic. Tests using thermal, mechanical, and chemical stimuli, measures of hyperalgesia and allodynia, models of inflammatory or neuropathic pain, constitute a toolbox available to researchers. These tests and models allowed rapid progress on the anatomo-molecular basis of physiological and pathological pain, even though they have yet to translate into new analgesic drugs. More recently, a growing effort has been put forth trying to assess pain in rats or mice, rather than nociceptive reflexes, or at studying complex states affected by chronic pain. This aids to further improve the translational value of preclinical research in a field with balanced research efforts between fundamental research, preclinical work, and human studies. This review describes classical tests and models of nociception and pain in rodents. It also presents some recent and ongoing developments in nociceptive tests, recent trends for pain evaluation, and raises the question of the appropriateness between tests, models, and procedures.

  20. Emotional modulation of pain and spinal nociception in fibromyalgia

    PubMed Central

    Rhudy, Jamie L.; DelVentura, Jennifer L.; Terry, Ellen L.; Bartley, Emily J.; Olech, Ewa; Palit, Shreela; Kerr, Kara L.

    2013-01-01

    Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (e.g., depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in four blocks; two blocks assessed only physiological-emotional reactions (i.e., pleasure/arousal ratings, corrugator EMG, startle modulation, skin conductance) in the absence of pain and two blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (e.g., reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all three groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes. PMID:23622762

  1. Oxidation Sensitive Nociception Involved in Endometriosis Associated Pain

    PubMed Central

    Ray, Kristeena; Fahrmann, Johannes; Mitchell, Brenda; Paul, Dennis; King, Holly; Crain, Courtney; Cook, Carla; Golovko, Mikhail; Brose, Stephen; Golovko, Svetlana; Santanam, Nalini

    2015-01-01

    Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu, rich in inflammatory markers and pain-inducing prostaglandins PGE2/PGF2α and lipid peroxides, and the endometriotic tissue is innervated with nociceptors. Our clinical study showed the abundance of oxidatively-modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively-modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (i) the detection of lipoprotein derived oxidation-sensitive pain molecules, (ii) the ability of such molecules to induce nociception, and (iii) the ability of antioxidants to suppress this nociception. LC-MS/MS showed the generation of eicosanoids by oxidized-lipoproteins similar to that seen in the PF. The oxidatively-modified lipoproteins induced hypothermia (intra-cerebroventricular) in CD-1 mice and nociception in the Hargreaves paw-withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin-E and N-acetylcysteine and the NSAID, indomethacin suppressed the pain inducing ability of oxidatively-modified lipoproteins. Treatment of human endometrial cells with oxidatively-modified lipoproteins or PF from women with endometriosis showed up-regulation of similar genes belonging to the opioid and inflammatory pathways. Our finding that oxidatively-modified lipoproteins can induce nociception has a broader impact not only in the treatment of endometriosis-associated pain but also in other diseases associated with chronic pain. PMID:25599233

  2. Reticular thalamic responses to nociceptive inputs in anesthetized rats.

    PubMed

    Yen, Chen-Tung; Shaw, Fu-Zen

    2003-04-11

    The present study compares nociceptive responses of neurons in the reticular thalamic nucleus (RT) to those of the ventroposterior lateral nucleus (VPL). Extracellular single-unit activities of cells in the RT and VPL were recorded in anesthetized rats. Only units with identified tactile receptive fields in the forepaw or hindpaw were studied. In the first series of experiments, RT and VPL responses to pinching with a small artery clamp were tested with the rats under pentobarbital, urethane, ketamine, or halothane anesthesia. Under all types of anesthesia, many RT units were inhibited. Second, the specificity of the nociceptive response was tested by pinching and noxious heating of the unit's tactile receptive field. Of the 39 VPL units tested, 20 were excited by both types of noxious stimuli. In sharp contrast, of the 30 RT units tested, none were excited and 17 were inhibited. In a third series of experiments, low-intensity and beam-diffused CO(2) laser irradiation was used to activate peripheral nociceptive afferents. Wide-dynamic-range VPL units responded with short- and long-latency excitations. In contrast, RT units had short-latency excitation followed by long-latency inhibition. Nociceptive input inhibited RT units in less than 500 ms. We conclude that a significant portion of RT neurons were polysynaptically inhibited by nociceptive inputs. Since all the cells tested were excited by light tactile inputs, the somatosensory RT may serve in the role of a modality gate, which modifies (i.e. inhibits) tactile inputs while letting noxious inputs pass.

  3. Emotional modulation of pain and spinal nociception in fibromyalgia.

    PubMed

    Rhudy, Jamie L; DelVentura, Jennifer L; Terry, Ellen L; Bartley, Emily J; Olech, Ewa; Palit, Shreela; Kerr, Kara L

    2013-07-01

    Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (eg, depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in 4 blocks; 2 blocks assessed only physiological-emotional reactions (ie, pleasure/arousal ratings, corrugator electromyography, startle modulation, skin conductance) in the absence of pain, and 2 blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (eg, reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all 3 groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes.

  4. Oxidation-sensitive nociception involved in endometriosis-associated pain.

    PubMed

    Ray, Kristeena; Fahrmann, Johannes; Mitchell, Brenda; Paul, Dennis; King, Holly; Crain, Courtney; Cook, Carla; Golovko, Mikhail; Brose, Stephen; Golovko, Svetlana; Santanam, Nalini

    2015-03-01

    Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu and is rich in inflammatory markers, pain-inducing prostaglandins prostaglandin E2 and prostaglandin F2α, and lipid peroxides; and the endometriotic tissue is innervated with nociceptors. Our clinical study showed that the abundance of oxidatively modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (1) the detection of lipoprotein-derived oxidation-sensitive pain molecules, (2) the ability of such molecules to induce nociception, and (3) the ability of antioxidants to suppress this nociception. LC-MS/MS showed the generation of eicosanoids by oxidized-lipoproteins to be similar to that seen in the PF. Oxidatively modified lipoproteins induced hypothermia (intracerebroventricular) in CD-1 mice and nociception in the Hargreaves paw withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin E and N-acetylcysteine, and the nonsteroidal anti-inflammatory drug indomethacin suppressed the pain-inducing ability of oxidatively modified lipoproteins. Treatment of human endometrial cells with oxidatively modified lipoproteins or PF from women with endometriosis showed upregulation of similar genes belonging to opioid and inflammatory pathways. Our finding that oxidatively modified lipoproteins can induce nociception has a broader impact not only on the treatment of endometriosis-associated pain but also on other diseases associated with chronic pain.

  5. Intraplantar injection of tetrahydrobiopterin induces nociception in mice.

    PubMed

    Nasser, Arafat; Ali, Sawsan; Wilsbech, Signe; Bjerrum, Ole J; Møller, Lisbeth B

    2015-01-01

    Tetrahydrobiopterin (BH4) is implicated in the development and maintenance of chronic pain. After injury/inflammation, the biosynthesis of BH4 is markedly increased in sensory neurons, and the pharmacological and genetic inhibition of BH4 shows analgesic effects in pre-clinical animal pain models. Intrathecal injections of BH4 have been shown to induce and enhance pain-like behaviours in rats, suggesting that under chronic pain conditions BH4 may act by facilitating central sensitisation. So far it is unknown whether BH4 acts on peripheral sites of the somatosensory system or whether BH4 per se provokes nociceptive pain behaviours. The purpose of this study was therefore to investigate the acute nociceptive effects of intraplantar injection of BH4. BH4 was found to induce dose-dependent licking/biting of the paw lasting 5 min, which was not observed following an injection of biopterin (inactive BH4 metabolite). Paw swelling, measured as paw thickness and weight, was not observed after BH4 injection. To explore possible mechanisms of action of BH4, the effect of local pre-treatment with indomethacin, Nω-nitro-L-arginine methyl ester, Nω-nitro-L-arginine, capsazepine and ruthenium red was tested. Morphine served as a positive control. Intraplantar pre-injection of morphine dose-dependently inhibited BH4-induced nociception, while none of the other compounds showed any statistical significant antinociception. These results suggest that BH4 exhibits nociceptive properties at peripheral sites of the somatosensory system, proposing an as yet unexplored involvement of BH4 in peripheral nociceptive processes. However, this appears not to be mediated through nitric oxide and prostaglandin release or by activation of the transient receptor potential vanilloid 1.

  6. Nociception originating from the crural fascia in rats.

    PubMed

    Taguchi, Toru; Yasui, Masaya; Kubo, Asako; Abe, Masahiro; Kiyama, Hiroshi; Yamanaka, Akihiro; Mizumura, Kazue

    2013-07-01

    Little is documented in the literature as to the function of muscle fascia in nociception and pain. The aim of this study was to examine the distribution of presumptive nociceptive nerve fibers, to characterize fascial thin-fiber sensory receptors, and to examine the spinal projection of nociceptive input from the rat crural fascia (CF). Nerve fibers labeled with specific antibodies to calcitonin gene-related peptide (CGRP) and peripherin were found to be densely distributed in the distal third of the CF. Thin-fiber receptors (Aδ- and C-fibers) responding to pinching stimuli to the CF with sharpened watchmaker's forceps, identified in vivo with the teased fiber technique from the common peroneal nerve, exist in the CF. Forty-three percent of the mechano-responsive fascial C-fibers were polymodal receptors (nociceptors) responding to mechanical, chemical (bradykinin), and heat stimuli, whereas almost all Aδ-fibers were responsive only to mechanical stimuli. Repetitive pinching stimulus to the CF induced c-Fos protein expression in the middle to medial part of superficial layers ie, laminae I-II of the spinal dorsal horn at segments L2 to L4, peaking at L3. These results clearly demonstrate the following: 1) peptidergic and non-peptidergic axons of unmyelinated C-fibers with nerve terminals are distributed in the CF; 2) peripheral afferents responding to noxious stimuli exist in the fascia, and 3) nociceptive information from the CF is mainly processed in the spinal dorsal horn at the segments L2 to L4. These results together indicate that the "muscle fascia," a tissue often overlooked in pain research, can be an important source of nociception under normal conditions.

  7. Impact of Behavioral Control on the Processing of Nociceptive Stimulation

    PubMed Central

    Grau, James W.; Huie, J. Russell; Garraway, Sandra M.; Hook, Michelle A.; Crown, Eric D.; Baumbauer, Kyle M.; Lee, Kuan H.; Hoy, Kevin C.; Ferguson, Adam R.

    2012-01-01

    How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain. PMID:22934018

  8. Glutamate and capsaicin effects on trigeminal nociception I: Activation and peripheral sensitization of deep craniofacial nociceptive afferents.

    PubMed

    Lam, David K; Sessle, Barry J; Hu, James W

    2009-01-28

    We have examined the effect of the peripheral application of glutamate and capsaicin to deep craniofacial tissues in influencing the activation and peripheral sensitization of deep craniofacial nociceptive afferents. The activity of single trigeminal nociceptive afferents with receptive fields in deep craniofacial tissues were recorded extracellularly in 55 halothane-anesthetized rats. The mechanical activation threshold (MAT) of each afferent was assessed before and after injection of 0.5 M glutamate (or vehicle) and 1% capsaicin (or vehicle) into the receptive field. A total of 68 afferents that could be activated by blunt noxious mechanical stimulation of the deep craniofacial tissues (23 masseter, 5 temporalis, 40 temporomandibular joint) were studied. When injected alone, glutamate and capsaicin activated and induced peripheral sensitization reflected as MAT reduction in many afferents. Following glutamate injection, capsaicin-evoked activity was greater than that evoked by capsaicin alone, whereas following capsaicin injection, glutamate-evoked responses were similar to glutamate alone. These findings indicate that peripheral application of glutamate or capsaicin may activate or induce peripheral sensitization in a subpopulation of trigeminal nociceptive afferents innervating deep craniofacial tissues, as reflected in changes in MAT and other afferent response properties. The data further suggest that peripheral glutamate and capsaicin receptor mechanisms may interact to modulate the activation and peripheral sensitization in some deep craniofacial nociceptive afferents.

  9. Increased isoprostane levels in oleic acid-induced lung injury

    SciTech Connect

    Ono, Koichi; Koizumi, Tomonobu; Tsushima, Kenji; Yoshikawa, Sumiko; Yokoyama, Toshiki; Nakagawa, Rikimaru; Obata, Toru

    2009-10-16

    The present study was performed to examine a role of oxidative stress in oleic acid-induced lung injury model. Fifteen anesthetized sheep were ventilated and instrumented with a lung lymph fistula and vascular catheters for blood gas analysis and measurement of isoprostanes (8-epi prostaglandin F2{alpha}). Following stable baseline measurements, oleic acid (0.08 ml/kg) was administered and observed 4 h. Isoprostane was measured by gas chromatography mass spectrometry with the isotope dilution method. Isoprostane levels in plasma and lung lymph were significantly increased 2 h after oleic acid administration and then decreased at 4 h. The percent increases in isoprostane levels in plasma and lung lymph at 2 h were significantly correlated with deteriorated oxygenation at the same time point, respectively. These findings suggest that oxidative stress is involved in the pathogenesis of the pulmonary fat embolism-induced acute lung injury model in sheep and that the increase relates with the deteriorated oxygenation.

  10. [Sunitinib and zoledronic acid induced osteonecrosis of the jaw].

    PubMed

    Soós, Balázs; Vajta, László; Szalma, József

    2015-11-15

    The tendency for bisphosphonate and non-bisphosphonate (eg.: antiresorptive or anti-angiogenesis drugs) induced osteonecrosis is increasing. Treatment of these patients is a challenge both for dentists and for oral and maxillofacial surgeons. Cooperation with the drug prescribing general medicine colleagues to prevent osteonecrosis is extremely important. Furthermore, prevention should include dental focus elimination, oral hygienic instructions and education, dental follow-up and, in case of manifest necrosis, referral to maxillofacial departments. Authors outline the difficulties of conservative and surgical treatment of a patient with sunitinib and zoledronic acid induced osteonecrosis. The patient became symptomless and the operated area healed entirely six and twelve months postoperatively. A long term success further follow-up is necessary to verify long-term success.

  11. Improved Acetic Acid Resistance in Saccharomyces cerevisiae by Overexpression of the WHI2 Gene Identified through Inverse Metabolic Engineering.

    PubMed

    Chen, Yingying; Stabryla, Lisa; Wei, Na

    2016-01-29

    Development of acetic acid-resistant Saccharomyces cerevisiae is important for economically viable production of biofuels from lignocellulosic biomass, but the goal remains a critical challenge due to limited information on effective genetic perturbation targets for improving acetic acid resistance in the yeast. This study employed a genomic-library-based inverse metabolic engineering approach to successfully identify a novel gene target, WHI2 (encoding a cytoplasmatic globular scaffold protein), which elicited improved acetic acid resistance in S. cerevisiae. Overexpression of WHI2 significantly improved glucose and/or xylose fermentation under acetic acid stress in engineered yeast. The WHI2-overexpressing strain had 5-times-higher specific ethanol productivity than the control in glucose fermentation with acetic acid. Analysis of the expression of WHI2 gene products (including protein and transcript) determined that acetic acid induced endogenous expression of Whi2 in S. cerevisiae. Meanwhile, the whi2Δ mutant strain had substantially higher susceptibility to acetic acid than the wild type, suggesting the important role of Whi2 in the acetic acid response in S. cerevisiae. Additionally, overexpression of WHI2 and of a cognate phosphatase gene, PSR1, had a synergistic effect in improving acetic acid resistance, suggesting that Whi2 might function in combination with Psr1 to elicit the acetic acid resistance mechanism. These results improve our understanding of the yeast response to acetic acid stress and provide a new strategy to breed acetic acid-resistant yeast strains for renewable biofuel production.

  12. Improved Acetic Acid Resistance in Saccharomyces cerevisiae by Overexpression of the WHI2 Gene Identified through Inverse Metabolic Engineering

    PubMed Central

    Chen, Yingying; Stabryla, Lisa

    2016-01-01

    Development of acetic acid-resistant Saccharomyces cerevisiae is important for economically viable production of biofuels from lignocellulosic biomass, but the goal remains a critical challenge due to limited information on effective genetic perturbation targets for improving acetic acid resistance in the yeast. This study employed a genomic-library-based inverse metabolic engineering approach to successfully identify a novel gene target, WHI2 (encoding a cytoplasmatic globular scaffold protein), which elicited improved acetic acid resistance in S. cerevisiae. Overexpression of WHI2 significantly improved glucose and/or xylose fermentation under acetic acid stress in engineered yeast. The WHI2-overexpressing strain had 5-times-higher specific ethanol productivity than the control in glucose fermentation with acetic acid. Analysis of the expression of WHI2 gene products (including protein and transcript) determined that acetic acid induced endogenous expression of Whi2 in S. cerevisiae. Meanwhile, the whi2Δ mutant strain had substantially higher susceptibility to acetic acid than the wild type, suggesting the important role of Whi2 in the acetic acid response in S. cerevisiae. Additionally, overexpression of WHI2 and of a cognate phosphatase gene, PSR1, had a synergistic effect in improving acetic acid resistance, suggesting that Whi2 might function in combination with Psr1 to elicit the acetic acid resistance mechanism. These results improve our understanding of the yeast response to acetic acid stress and provide a new strategy to breed acetic acid-resistant yeast strains for renewable biofuel production. PMID:26826231

  13. The Acetic Acid Tolerance Response induces cross-protection to salt stress in Salmonella typhimurium.

    PubMed

    Greenacre, E J; Brocklehurst, T F

    2006-10-15

    Salmonella typhimurium induces an Acid Tolerance Response (ATR) upon exposure to mildly acidic conditions in order to protect itself against severe acid shock. This response can also induce cross-protection to other stresses such as heat and salt. We investigated whether both the acetic acid induced and lactic acid induced ATR in S. typhimurium provided cross-protection to a salt stress at 20 degrees C. Acid-adapted cells were challenged with both a sodium chloride (NaCl) and potassium chloride (KCl) shock and their ability to survive ascertained. Acetic acid adaptation provided cells with protection against both NaCl and KCl stress. However, lactic acid adaptation did not protect against either osmotic stressor and rendered cells hypersensitive to NaCl. These results have implications for the food industry where hurdle technology means multiple sub-lethal stresses such as mild pH and low salt are commonly used in the preservation of products.

  14. Antinociceptive effect of Aristolochia trilobata stem essential oil and 6-methyl-5-hepten-2yl acetate, its main compound, in rodents.

    PubMed

    Quintans, Jullyana de Souza Siqueira; Alves, Rafael Dos Santos; Santos, Darlisson de Alexandria; Serafini, Mairim Russo; Alves, Péricles Barreto; Costa, Emmanoel Vilaça; Zengin, Gokhan; Quintans-Júnior, Lucindo José; Guimarães, Adriana Gibara

    2017-01-20

    Aristolochia trilobata L. is an aromatic plant, popularly known as "mil-homens", and its essential oil (EO) is generally used to treat colic, diarrhea and dysentery disorders. We evaluated the antinociceptive effect of A. trilobata stem EO and of its major compound, the (R)-(-)-6-methyl-5-hepten-2-yl acetate (sulcatyl acetate: SA), using acetic acid (0.85%)-induced writhing response and formalin-induced (20 μL of 1%) nociceptive behavior in mice. We also evaluated the EO and SA effect on motor coordination, using the rota-rod apparatus. EO (25, 50 and 100 mg/kg) or SA (25 and 50 mg/kg) reduced nociceptive behavior in the writhing test (p<0.001). EO (100 mg/kg) and SA (25 and 50 mg/kg) decreased the nociception on the first phase of the formalin test (p<0.05). On the second phase, EO (25: p<0.01; 50: p<0.05 and 100 mg/kg: p<0.001) and SA (25 and 50 mg/kg; p<0.001) reduced the nociceptive response induced by formalin. EO and SA were not able to cause changes in the motor coordination of animals. Together, our results suggest that EO has an analgesic profile and SA seems to be one of the active compounds in this effect.

  15. Looking at the hand modulates the brain responses to nociceptive and non-nociceptive somatosensory stimuli but does not necessarily modulate their perception.

    PubMed

    Torta, Diana M; Legrain, Valéry; Mouraux, André

    2015-08-01

    Previous studies have suggested that looking at the hand can reduce the perception of pain and the magnitude of the ERPs elicited by nociceptive stimuli delivered onto the hand. In contrast, other studies have suggested that looking at the hand can increase tactile sensory discrimination performance, and enhance the magnitude of the ERPs elicited by tactile stimulation. These opposite effects could be related to differences in the crossmodal effects between vision, nociception, and touch. However, these differences could also be related to the use of different experimental designs. Importantly, most studies on the effects of vision on pain have relied on a mirror to create the illusion that the reflected hand is a direct view of the stimulated hand. Here, we compared the effects of direct versus mirror vision of the hand versus an object on the perception and ERPs elicited by non-nociceptive and nociceptive stimuli. We did not observe any significant effect of vision on the perceived intensity. However, vision of the hand did reduce the magnitude of the nociceptive N240 wave, and enhanced the magnitude of the non-nociceptive P200. Our results confirm that vision of the body differentially affects nociceptive and non-nociceptive processing, but question the robustness of visual analgesia.

  16. Differential Responses of Thalamic Reticular Neurons to Nociception in Freely Behaving Mice

    PubMed Central

    Huh, Yeowool; Cho, Jeiwon

    2016-01-01

    Pain serves an important protective role. However, it can also have debilitating adverse effects if dysfunctional, such as in pathological pain conditions. As part of the thalamocortical circuit, the thalamic reticular nucleus (TRN) has been implicated to have important roles in controlling nociceptive signal transmission. However studies on how TRN neurons, especially how TRN neuronal subtypes categorized by temporal bursting firing patterns—typical bursting, atypical bursting and non-bursting TRN neurons—contribute to nociceptive signal modulation is not known. To reveal the relationship between TRN neuronal subtypes and modulation of nociception, we simultaneously recorded behavioral responses and TRN neuronal activity to formalin induced nociception in freely moving mice. We found that typical bursting TRN neurons had the most robust response to nociception; changes in tonic firing rate of typical TRN neurons exactly matched changes in behavioral nociceptive responses, and burst firing rate of these neurons increased significantly when behavioral nociceptive responses were reduced. This implies that typical TRN neurons could critically modulate ascending nociceptive signals. The role of other TRN neuronal subtypes was less clear; atypical bursting TRN neurons decreased tonic firing rate after the second peak of behavioral nociception and the firing rate of non-bursting TRN neurons mostly remained at baseline level. Overall, our results suggest that different TRN neuronal subtypes contribute differentially to processing formalin induced sustained nociception in freely moving mice. PMID:27917114

  17. Comparative biology of pain: What invertebrates can tell us about how nociception works.

    PubMed

    Burrell, Brian D

    2017-04-01

    The inability to adequately treat chronic pain is a worldwide health care crisis. Pain has both an emotional and a sensory component, and this latter component, nociception, refers specifically to the detection of damaging or potentially damaging stimuli. Nociception represents a critical interaction between an animal and its environment and exhibits considerable evolutionary conservation across species. Using comparative approaches to understand the basic biology of nociception could promote the development of novel therapeutic strategies to treat pain, and studies of nociception in invertebrates can provide especially useful insights toward this goal. Both vertebrates and invertebrates exhibit segregated sensory pathways for nociceptive and nonnociceptive information, injury-induced sensitization to nociceptive and nonnociceptive stimuli, and even similar antinociceptive modulatory processes. In a number of invertebrate species, the central nervous system is understood in considerable detail, and it is often possible to record from and/or manipulate single identifiable neurons through either molecular genetic or physiological approaches. Invertebrates also provide an opportunity to study nociception in an ethologically relevant context that can provide novel insights into the nature of how injury-inducing stimuli produce persistent changes in behavior. Despite these advantages, invertebrates have been underutilized in nociception research. In this review, findings from invertebrate nociception studies are summarized, and proposals for how research using invertebrates can address questions about the fundamental mechanisms of nociception are presented.

  18. The hypothalamic NPVF circuit modulates ventral raphe activity during nociception

    PubMed Central

    Madelaine, Romain; Lovett-Barron, Matthew; Halluin, Caroline; Andalman, Aaron S.; Liang, Jin; Skariah, Gemini M.; Leung, Louis C.; Burns, Vanessa M.; Mourrain, Philippe

    2017-01-01

    RFamide neuropeptide VF (NPVF) is expressed by neurons in the hypothalamus and has been implicated in nociception, but the circuit mechanisms remain unexplored. Here, we studied the structural and functional connections from NPVF neurons to downstream targets in the context of nociception, using novel transgenic lines, optogenetics, and calcium imaging in behaving larval zebrafish. We found a specific projection from NPVF neurons to serotonergic neurons in the ventral raphe nucleus (vRN). We showed NPVF neurons and vRN are suppressed and excited by noxious stimuli, respectively. We combined optogenetics with calcium imaging and pharmacology to demonstrate that stimulation of NPVF cells suppresses neuronal activity in vRN. During noxious stimuli, serotonergic neurons activation was due to a suppression of an inhibitory NPVF-ventral raphe peptidergic projection. This study reveals a novel NPVF-vRN functional circuit modulated by noxious stimuli in vertebrates. PMID:28139691

  19. (-)-α-Bisabolol reduces orofacial nociceptive behavior in rodents.

    PubMed

    Melo, Luana Torres; Duailibe, Mariana Araújo Braz; Pessoa, Luciana Moura; da Costa, Flávio Nogueira; Vieira-Neto, Antonio Eufrásio; de Vasconcellos Abdon, Ana Paula; Campos, Adriana Rolim

    2017-02-01

    The purposes of this study were to evaluate the anti-nociceptive effect of oral and topical administration of (-)-α-bisabolol (BISA) in rodent models of formalin- or cinnamaldehyde-induced orofacial pain and to explore the inhibitory mechanisms involved. Orofacial pain was induced by injecting 1.5% formalin into the upper lip of mice (20 μL) or into the temporomandibular joint (TMJ) of rats (50 μL). In another experiment, orofacial pain was induced with cinnamaldehyde (13.2 μg/lip). Nociceptive behavior was proxied by time (s) spent rubbing the injected area and by the incidence of head flinching. BISA (100, 200, or 400 mg/kg p.o. or 50, 100, or 200 mg/mL topical) or vehicle was administered 60 min before pain induction. The two formulations (lotion and syrup) were compared with regard to efficacy. The effect of BISA remained after incorporation into the formulations, and nociceptive behavior decreased significantly in all tests. The high binding affinity observed for BISA and TRPA1 in the molecular docking study was supported by in vivo experiments in which HC-030031 (a TRPA1 receptor antagonist) attenuated pain in a manner qualitatively and quantitatively similar to that of BISA. Blockers of opioid receptors, NO synthesis, and K(+) ATP channels did not affect orofacial pain, nor inhibit the effect of BISA. In conclusion, BISA had a significant anti-nociceptive effect on orofacial pain. The effect may in part be due to TRPA1 antagonism. The fact that the effect of BISA remained after incorporation into oral and topical formulations suggests that the compound may be a useful adjuvant in the treatment of orofacial pain.

  20. Nociception and Conditioned Fear in Rats: Strains Matter

    PubMed Central

    Schaap, Manon W. H.; van Oostrom, Hugo; Doornenbal, Arie; van 't Klooster, José; Baars, Annemarie M.; Arndt, Saskia S.; Hellebrekers, Ludo J.

    2013-01-01

    When using rats in pain research, strain-related differences in outcomes of tests for pain and nociception are acknowledged. However, very little is known about the specific characteristics of these strain differences. In this study four phylogenetically distant inbred rat strains, i.e. Wistar Kyoto (WKY), Fawn Hooded (FH), Brown Norway (BN) and Lewis (LE), were investigated in different tests related to pain and nociception. During Pavlovian fear conditioning, the LE and WKY showed a significantly longer duration of freezing behaviour than the FH and BN. Additionally, differences in c-Fos expression in subregions of the prefrontal cortex and amygdala between rat strains during retrieval and expression of conditioned fear were found. For example, the BN did not show recruitment of the basolateral amygdala, whereas the WKY, FH and LE did. During the hot plate test, the WKY and LE showed a lower thermal threshold compared to the BN and FH. In a follow-up experiment, the two most contrasting strains regarding behaviour during the hot plate test and Pavlovian fear conditioning (i.e. FH and WKY) were selected and the hot plate test, Von Frey test and somatosensory-evoked potential (SEP) were investigated. During the Von Frey test, the WKY showed a lower mechanical threshold compared to the FH. When measuring the SEP, the FH appeared to be less reactive to increasing stimulus intensities when considering both peak amplitudes and latencies. Altogether, the combined results indicate various differences between rat strains in Pavlovian fear conditioning, nociception related behaviours and nociceptive processing. These findings demonstrate the necessity of using multiple rat strains when using tests including noxious stimuli and suggest that the choice of rat strains should be considered. When selecting a strain for a particular study it should be considered how this strain behaves during the tests used in that study. PMID:24376690

  1. Attention effects on vicarious modulation of nociception and pain.

    PubMed

    Khatibi, Ali; Vachon-Presseau, Etienne; Schrooten, Martien; Vlaeyen, Johan; Rainville, Pierre

    2014-10-01

    The observation of others' facial expressions of pain has been shown to facilitate the observer's nociceptive responses and to increase pain perception. We investigated how this vicarious facilitation effect is modulated by directing the observer's attention toward the meaning of pain expression or the facial movements. In separate trials, participants were instructed to assess the "intensity of the pain expression"(meaning) or to "discriminate the facial movements" in the upper vs lower part of the face shown in 1-second dynamic clips displaying mild, moderate, or strong pain expressions or a neutral control. In 50% of the trials, participants received a painful electrical stimulation to the sural nerve immediately after the presentation of the expression. Low-level nociceptive reactivity was measured with the RIII-response, and pain perception was assessed using pain ratings. Pain induced by the electrical stimulation increased after viewing stronger pain expressions in both tasks, but the RIII-response showed this vicarious facilitation effect only in the movement discrimination task at the strongest expression intensity. These findings are consistent with the notion that vicarious processes facilitate self-pain and may prime automatic nociceptive responses. However, this priming effect is influenced by top-down attentional processes. These results provide another case of dissociation between reflexive and perceptual processes, consistent with the involvement of partly separate brain networks in the regulation of cortical and lower-level nociceptive responses. Combined with previous results, these findings suggest that vicarious pain facilitation is an automatic process that may be diminished by top-down attentional processes directed at the meaning of the expression.

  2. Monitoring the nociception level: a multi-parameter approach.

    PubMed

    Ben-Israel, Nir; Kliger, Mark; Zuckerman, Galit; Katz, Yeshayahu; Edry, Ruth

    2013-12-01

    The aim of the present study was to develop and validate an objective index for nociception level (NoL) of patients under general anesthesia, based on a combination of multiple physiological parameters. Twenty-five patients scheduled for elective surgery were enrolled. For clinical reference of NoL, the combined index of stimulus and analgesia was defined as a composite of the surgical stimulus level and a scaled effect-site concentration of opioid. The physiological parameters heart rate, heart rate variability (0.15-0.4 Hz band power), plethysmograph wave amplitude, skin conductance level, number of skin conductance fluctuations, and their time derivatives, were extracted. Two techniques to incorporate these parameters into a single index representing the NoL have been proposed: NoLlinear, based on an ordinary linear regression, and NoLnon-linear, based on a non-linear Random Forest regression. NoLlinear and NoLnon-linear significantly increased after moderate to severe noxious stimuli (Wilcoxon rank test, p < 0.01), while the individual parameters only partially responded. Receiver operating curve analysis showed that NoL index based on both techniques better discriminated noxious and non-noxious surgical events [area under curve (AUC) = 0.97] compared with individual parameters (AUC = 0.56-0.74). NoLnon-linear better ranked the level of nociception compared with NoLlinear (R = 0.88 vs. 0.77, p < 0.01). These results demonstrate the superiority of multi-parametric approach over any individual parameter in the evaluation of nociceptive response. In addition, advanced non-linear technique may have an advantage over ordinary linear regression for computing NoL index. Further research will define the usability of the NoL index as a clinical tool to assess the level of nociception during general anesthesia.

  3. The influence of gender and sex steroids on craniofacial nociception.

    PubMed

    Cairns, Brian E

    2007-02-01

    Several pain conditions localized to the craniofacial region show a remarkable sex-related difference in their prevalence. These conditions include temporomandibular disorders and burning mouth syndrome as well as tension-type, migraine, and cluster headaches. The mechanisms that underlie sex-related differences in the prevalence of these craniofacial pain conditions remain obscure and likely involve both physiological and psychosocial factors. In terms of physiological factors relevant to the development of headache, direct evidence of sex-related differences in the properties of dural afferent fibers or durally activated second-order trigeminal sensory neurons has yet to be provided. There is, however, evidence for sex-related differences in the response properties of afferent fibers and second-order trigeminal sensory neurons that convey nociceptive input from other craniofacial tissues associated with sex-related differences in chronic pain conditions, such as those that innervate the masseter muscle and temporomandibular joint. Further, modulation of craniofacial nociceptive input by opioidergic receptor mechanisms appears to be dependent on biological sex. Research into mechanisms that may contribute to sex-related differences in trigeminal nociceptive processing has primarily focused on effect of the female sex hormone estrogen, which appears to alter the excitability of trigeminal afferent fibers and sensory neurons to noxious stimulation of craniofacial tissues. This article discusses current knowledge of potential physiological mechanisms that could contribute to sex-related differences in certain craniofacial pain conditions.

  4. Chlorpheniramine produces spinal motor, proprioceptive and nociceptive blockades in rats.

    PubMed

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

    2015-04-05

    This study aimed to assess the local anesthetic effects of chlorpheniramine in spinal anesthesia and is compared with mepivacaine, a widely-used local anesthetic. Spinal anesthesia with chlorpheniramine and mepivacaine was constructed in a dosage-dependent fashion after the rats were injected intrathecally. The spinal block effect of chlorpheniramine in motor function, nociception, and proprioception was compared to that of mepivacaine. We revealed that intrathecal chlorpheniramine and mepivacaine exhibited a dose-dependent spinal block of motor function, nociception, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potencies in motor function, nociception, and proprioception were chlorpheniramine>mepivacaine (P<0.01 for the differences). On the equianesthetic basis (ED25, ED50, ED75), the duration of spinal anesthesia with chlorpheniramine was greater than that of mepivacaine (P<0.01 for the differences). Instead of mepivacaine, chlorpheniramine produced a greater duration of sensory blockade than the motor blockade. These preclinical data showed that chlorpheniramine has a better sensory-selective action over motor block to produce more potent and long-lasting spinal anesthesia than mepivacaine.

  5. The zebrafish as a model for nociception studies.

    PubMed

    Malafoglia, Valentina; Bryant, Bruce; Raffaeli, William; Giordano, Antonio; Bellipanni, Gianfranco

    2013-10-01

    Nociception is the sensory mechanism used to detect cues that can harm an organism. The understanding of the neural networks and molecular controls of the reception of pain remains an ongoing challenge for biologists. While we have made significant progress in identifying a number of molecules and pathways that are involved in transduction of noxious stimuli, from the skin through the sensory receptor cell and from this to the spinal cord on into the central nervous system, we still lack a clear understanding of the perceptual processes, the responses to pain and the regulation of pain perception. Mice and rat animal models have been extensively used for nociception studies. However, the study of pain and noiception in these organisms can be rather laborious, costly and time consuming. Conversely, the use of Drosophila and Caenorhabditis elegans may be affected by the large evolutionary distance between these animals and humans. We outline here the reasons why zebrafish presents a new and attractive model for studying pain reception and responses and the most interesting findings in the study of nociception that have been obtained using the zebrafish model.

  6. Transcranial magnetic stimulation reduces nociceptive threshold in rats.

    PubMed

    Ambriz-Tututi, Mónica; Sánchez-González, Violeta; Drucker-Colín, René

    2012-05-01

    Transcranial magnetic stimulation (TMS) is a procedure that uses magnetic fields to stimulate or inhibit nerve cells in the brain noninvasively. TMS induces an electromagnetic current in the underlying cortical neurons. Varying frequencies and intensities of TMS increase or decrease excitability in the cortical area directly targeted. It has been suggested that TMS has potential in the treatment of some neurological disorders such as Parkinson's disease, stroke, and depression. Initial case reports and open label trials reported by several groups support the use of TMS in pain treatment. In the present study, we evaluated the effect of TMS on the nociceptive threshold in the rat. The parameters used were a frequency of 60 Hz and an intensity of 2 and 6 mT for 2 hr twice per day. After 5 days of TMS treatment, rats were evaluated for mechanical, chemical, and cold stimulation. We observed a significant reduction in the nociceptive threshold in TMS-treated rats but not in sham-treated rats in all behavioral tests evaluated. When TMS treatment was stopped, a slow recovery to normal mechanic threshold was observed. Interestingly, i.c.v. MK-801 or CNQX administration reverted the TMS-induced pronociception. The results suggest that high-frequency TMS can alter the nociceptive threshold and produce allodynia in the rats; results suggest the involvement of NMDA and AMPA/KA receptors on TMS-induced allodynia in the rat.

  7. Oleic acid-induced mucosal injury in developing piglet intestine.

    PubMed

    Velasquez, O R; Henninger, K; Fowler, M; Tso, P; Crissinger, K D

    1993-03-01

    A role for luminal nutrients, in particular products of lipid digestion, in the pathogenesis of mucosal injury to developing intestine has been postulated. We evaluated changes in mucosal permeability and light and electron microscopic histology induced by luminal perfusion with the long-chain fatty acid oleate in developing piglet intestine as a function of age and concentration of the fatty acid. 51Cr-labeled EDTA plasma-to-lumen clearance was measured in jejunum and ileum of 1-day-, 3-day-, 2-wk-, and 1-mo-old piglets during sequential perfusion with saline control (20 min); 0, 1, 5, and 10 mM oleic acid/10 mM taurocholate in saline (20 min); and normal saline (60 min). The jejunum of piglets < or = 2 wk showed significantly greater increases in mucosal permeability compared with 1-mo-old animals after perfusion with oleic acid. This effect was dependent on the luminal concentration of the fatty acid and was associated with mucosal injury evident under light and electron microscopy. In contrast, the overall response in ileum was more attenuated compared with jejunum. Thus oleic acid, a common dietary fatty acid, induces dose- and age-dependent injury in developing piglet intestine. Investigation of the mechanisms of this injury may provide the basis for dietary modifications directed at decreasing the risk of mucosal injury during enteral feeding in neonatal intestine.

  8. Unsaturated fatty acids induce non-canonical autophagy

    PubMed Central

    Niso-Santano, Mireia; Malik, Shoaib Ahmad; Pietrocola, Federico; Bravo-San Pedro, José Manuel; Mariño, Guillermo; Cianfanelli, Valentina; Ben-Younès, Amena; Troncoso, Rodrigo; Markaki, Maria; Sica, Valentina; Izzo, Valentina; Chaba, Kariman; Bauvy, Chantal; Dupont, Nicolas; Kepp, Oliver; Rockenfeller, Patrick; Wolinski, Heimo; Madeo, Frank; Lavandero, Sergio; Codogno, Patrice; Harper, Francis; Pierron, Gérard; Tavernarakis, Nektarios; Cecconi, Francesco; Maiuri, Maria Chiara; Galluzzi, Lorenzo; Kroemer, Guido

    2015-01-01

    To obtain mechanistic insights into the cross talk between lipolysis and autophagy, two key metabolic responses to starvation, we screened the autophagy-inducing potential of a panel of fatty acids in human cancer cells. Both saturated and unsaturated fatty acids such as palmitate and oleate, respectively, triggered autophagy, but the underlying molecular mechanisms differed. Oleate, but not palmitate, stimulated an autophagic response that required an intact Golgi apparatus. Conversely, autophagy triggered by palmitate, but not oleate, required AMPK, PKR and JNK1 and involved the activation of the BECN1/PIK3C3 lipid kinase complex. Accordingly, the downregulation of BECN1 and PIK3C3 abolished palmitate-induced, but not oleate-induced, autophagy in human cancer cells. Moreover, Becn1+/− mice as well as yeast cells and nematodes lacking the ortholog of human BECN1 mounted an autophagic response to oleate, but not palmitate. Thus, unsaturated fatty acids induce a non-canonical, phylogenetically conserved, autophagic response that in mammalian cells relies on the Golgi apparatus. PMID:25586377

  9. Sphingoid bases inhibit acid-induced demineralization of hydroxyapatite.

    PubMed

    Valentijn-Benz, Marianne; van 't Hof, Wim; Bikker, Floris J; Nazmi, Kamran; Brand, Henk S; Sotres, Javier; Lindh, Liselott; Arnebrant, Thomas; Veerman, Enno C I

    2015-01-01

    Calcium hydroxyapatite (HAp), the main constituent of dental enamel, is inherently susceptible to the etching and dissolving action of acids, resulting in tooth decay such as dental caries and dental erosion. Since the prevalence of erosive wear is gradually increasing, there is urgent need for agents that protect the enamel against erosive attacks. In the present study we studied in vitro the anti-erosive effects of a number of sphingolipids and sphingoid bases, which form the backbone of sphingolipids. Pretreatment of HAp discs with sphingosine, phytosphingosine (PHS), PHS phosphate and sphinganine significantly protected these against acid-induced demineralization by 80 ± 17%, 78 ± 17%, 78 ± 7% and 81 ± 8%, respectively (p < 0.001). On the other hand, sphingomyelin, acetyl PHS, octanoyl PHS and stearoyl PHS had no anti-erosive effects. Atomic force measurement revealed that HAp discs treated with PHS were almost completely and homogeneously covered by patches of PHS. This suggests that PHS and other sphingoid bases form layers on the surface of HAp, which act as diffusion barriers against H(+) ions. In principle, these anti-erosive properties make PHS and related sphingosines promising and attractive candidates as ingredients in oral care products.

  10. Modulation of visceral nociception, inflammation and gastric mucosal injury by cinnarizine.

    PubMed

    Abdel-Salam, Omar M E

    2007-01-01

    The effect of cinnarizine, a drug used for the treatment of vertigo was assessed in animal models of visceral nociception, inflammation and gastric mucosal injury. Cinnarizine (1.25-20 mg/kg, s.c.) caused dose-dependent inhibition of the abdominal constrictions evoked by i.p. injection of acetic acid by 38.7-99.4%. This effect of cinnarizine (2.5 mg/kg) was unaffected by co-administration of the centrally acting dopamine D2 receptor antagonists, sulpiride, haloperidol or metoclopramide, the peripherally acting D2 receptor antagonist domperidone, but increased by the D2 receptor agonist bromocryptine and by the non-selective dopamine receptor antagonist chlorpromazine. The antinociception caused by cinnarizine was naloxone insenstive, but enhanced by propranolol, atropine and by yohimbine. The antinociceptive effect of cinnarizine was prevented by co-treatment with the adenosine receptor blocker theophylline or by the ATP-sensitive potassium channel (K(ATP)) blocker glibenclamide. Cinnarizine at 2.5 mg/kg reversed the baclofen-induced antinociception. Cinnarizine at 2.5 mg/kg reduced immobility time in the Porsolt's forced-swimming test by 24%. Cinnarizine inhibited the paw oedema response to carrageenan and reduced gastric mucosal lesions caused by indomethacin in rats. It is suggested that cinnarizine exerts anti-inflammatory, antinociceptive and gastric protective properties. The mechanism by which cinnarizine modulates pain transmission is likely to involve adenosine receptors and K(ATP) channels.

  11. Mildly Increased Mechanical Nociceptive Sensitivity in REV-ERBα Knock-out Mice

    PubMed Central

    Lee, Jaehyun; Ko, Hyoung-Gon; Kim, Kyungjin

    2016-01-01

    Nociception is one of the most complex senses that is affected not only by external stimulation but also internal conditions. Previous studies have suggested that circadian rhythm is important in modulating nociception. REV-ERBα knock-out (KO) mice have disrupted circadian rhythm and altered mood-related phenotypes. In this study, we examined the role of REV-ERBα in inflammatory nociception. We found that the nociceptive sensitivity of KO mice was partially enhanced in mechanical nociception. However, this partial alteration was independent of the circadian rhythm. Taken together, deletion of REV-ERBα induced a mild change in mechanical nociceptive sensitivity but this alteration was not dependent on the circadian rhythm. PMID:28035185

  12. Acid-induced unfolding mechanism of recombinant human endostatin.

    PubMed

    Li, Bing; Wu, Xiaoyu; Zhou, Hao; Chen, Qianjie; Luo, Yongzhang

    2004-03-09

    Endostatin is a potent angiogenesis inhibitor. The structure of endostatin is unique in that its secondary structure is mainly irregular loops and beta-sheets and contains only a small fraction of alpha-helices with two pairs of disulfide bonds in a nested pattern. We choose human endostatin as a model system to study the folding mechanism of this kind. Nuclear magnetic resonance (NMR), tryptophan emission fluorescence, and circular dichroism (CD) were used to monitor the unfolding process of endostatin upon acid titration. Urea-induced unfolding was used to measure the stability of endostatin under different conditions. Our results show that endostatin is very acid-resistant; some native structure still remains even at pH 2 as evidenced by (1)H NMR. Trifluoroethanol (TFE) destabilizes native endostatin, while it makes endostatin even more acid-resistant in the low pH region. Stability measurement of endostatin suggests that endostatin is still in native structure at pH 3.5 despite the decreased stability. Acid-induced unfolding of endostatin is reversible, although it requires a long time to reach equilibrium below pH 3. Surprisingly, the alpha-helical content of endostatin is increased when it is unfolded at pH 1.6, and the alpha-helical content of the polypeptide chain of unfolded endostatin increases linearly with TFE concentration in the range of 0-30%. This observation indicates that the polypeptide chain of unfolded endostatin has an intrinsic alpha-helical propensity. Our discoveries may provide clues for refolding endostatin more efficiently. The acid-resistance property of endostatin may have biological significance in that it cannot be easily digested by proteases in an acidic environment such as in a lysosome in the cell.

  13. High dose of ascorbic acid induces cell death in mesothelioma cells.

    PubMed

    Takemura, Yukitoshi; Satoh, Motohiko; Satoh, Kiyotoshi; Hamada, Hironobu; Sekido, Yoshitaka; Kubota, Shunichiro

    2010-04-02

    Malignant mesothelioma is an asbestos-related fatal disease with no effective cure. Recently, high dose of ascorbate in cancer treatment has been reexamined. We studied whether high dose of ascorbic acid induced cell death of four human mesothelioma cell lines. High dose of ascorbic acid induced cell death of all mesothelioma cell lines in a dose-dependent manner. We further clarified the cell killing mechanism that ascorbic acid induced reactive oxygen species and impaired mitochondrial membrane potential. In vivo experiment, intravenous administration of ascorbic acid significantly decreased the growth rate of mesothelioma tumor inoculated in mice. These data suggest that ascorbic acid may have benefits for patients with mesothelioma.

  14. Thermal nociception in adult Drosophila: behavioral characterization and the role of the painless gene.

    PubMed

    Xu, S Y; Cang, C L; Liu, X F; Peng, Y Q; Ye, Y Z; Zhao, Z Q; Guo, A K

    2006-11-01

    Nociception, warning of injury that should be avoided, serves an important protective function in animals. In this study, we show that adult Drosophila avoids noxious heat by a jump response. To quantitatively analyze this nociceptive behavior, we developed two assays. In the CO2 laser beam assay, flies exhibit this behavior when a laser beam heats their abdomens. The consistency of the jump latency in this assay meets an important criterion for a good nociceptive assay. In the hot plate assay, flies jump quickly to escape from a hot copper plate (>45 degrees C). Our results demonstrate that, as in mammals, the latency of the jump response is inversely related to stimulus intensity, and innoxious thermosensation does not elicit this nociceptive behavior. To explore the genetic mechanisms of nociception, we examined several mutants in both assays. Abnormal nociceptive behavior of a mutant, painless, indicates that painless, a gene essential for nociception in Drosophila larvae, is also required for thermal nociception in adult flies. painless is expressed in certain neurons of the peripheral nervous system and thoracic ganglia, as well as in the definite brain structures, the mushroom bodies. However, chemical or genetic insults to the mushroom bodies do not influence the nociceptive behavior, suggesting that different painless-expressing neurons play diverse roles in thermal nociception. Additionally, no-bridge(KS49), a mutant that has a structural defect in the protocerebral bridge, shows defective response to noxious heat. Thus, our results validate adult Drosophila as a useful model to study the genetic mechanisms of thermal nociception.

  15. (-)-α-Bisabolol attenuates visceral nociception and inflammation in mice.

    PubMed

    Leite, Gerlânia de O; Leite, Laura H I; Sampaio, Renata de S; Araruna, Mariana Késsia A; de Menezes, Irwin Rose A; da Costa, José Galberto M; Campos, Adriana R

    2011-03-01

    The study examined the antiinflammatory and antinociceptive effects of the sesquiterpene (-)-α-bisabolol (BISA). The antiinflammatory effect was evaluated on acute models of dermatitis induced by Croton oil, arachidonic acid, phenol and capsaicin, respectively, in mouse ear. BISA inhibited the dermatitis induced by all noxious agents, except capsaicin. BISA was assessed in two established mouse models of visceral nociception. Mice were pretreated orally with BISA, and the pain-related behavioral responses to intraperitoneal cyclophosphamide or to intracolonic mustard oil were analyzed. BISA showed a dose-unrelated significant antinociception. Collectively, the results suggest that BISA may be an topical antiinflammatory and visceral antinociceptive agent.

  16. Involvement of yeast HSP90 isoforms in response to stress and cell death induced by acetic acid.

    PubMed

    Silva, Alexandra; Sampaio-Marques, Belém; Fernandes, Angela; Carreto, Laura; Rodrigues, Fernando; Holcik, Martin; Santos, Manuel A S; Ludovico, Paula

    2013-01-01

    Acetic acid-induced apoptosis in yeast is accompanied by an impairment of the general protein synthesis machinery, yet paradoxically also by the up-regulation of the two isoforms of the heat shock protein 90 (HSP90) chaperone family, Hsc82p and Hsp82p. Herein, we show that impairment of cap-dependent translation initiation induced by acetic acid is caused by the phosphorylation and inactivation of eIF2α by Gcn2p kinase. A microarray analysis of polysome-associated mRNAs engaged in translation in acetic acid challenged cells further revealed that HSP90 mRNAs are over-represented in this polysome fraction suggesting preferential translation of HSP90 upon acetic acid treatment. The relevance of HSP90 isoform translation during programmed cell death (PCD) was unveiled using genetic and pharmacological abrogation of HSP90, which suggests opposing roles for HSP90 isoforms in cell survival and death. Hsc82p appears to promote survival and its deletion leads to necrotic cell death, while Hsp82p is a pro-death molecule involved in acetic acid-induced apoptosis. Therefore, HSP90 isoforms have distinct roles in the control of cell fate during PCD and their selective translation regulates cellular response to acetic acid stress.

  17. Acetate Kinase Isozymes Confer Robustness in Acetate Metabolism

    PubMed Central

    Chan, Siu Hung Joshua; Nørregaard, Lasse; Solem, Christian; Jensen, Peter Ruhdal

    2014-01-01

    Acetate kinase (ACK) (EC no: 2.7.2.1) interconverts acetyl-phosphate and acetate to either catabolize or synthesize acetyl-CoA dependent on the metabolic requirement. Among all ACK entries available in UniProt, we found that around 45% are multiple ACKs in some organisms including more than 300 species but surprisingly, little work has been done to clarify whether this has any significance. In an attempt to gain further insight we have studied the two ACKs (AckA1, AckA2) encoded by two neighboring genes conserved in Lactococcus lactis (L. lactis) by analyzing protein sequences, characterizing transcription structure, determining enzyme characteristics and effect on growth physiology. The results show that the two ACKs are most likely individually transcribed. AckA1 has a much higher turnover number and AckA2 has a much higher affinity for acetate in vitro. Consistently, growth experiments of mutant strains reveal that AckA1 has a higher capacity for acetate production which allows faster growth in an environment with high acetate concentration. Meanwhile, AckA2 is important for fast acetate-dependent growth at low concentration of acetate. The results demonstrate that the two ACKs have complementary physiological roles in L. lactis to maintain a robust acetate metabolism for fast growth at different extracellular acetate concentrations. The existence of ACK isozymes may reflect a common evolutionary strategy in bacteria in an environment with varying concentrations of acetate. PMID:24638105

  18. Morinda citrifolia Linn leaf extract possesses antioxidant activities and reduces nociceptive behavior and leukocyte migration.

    PubMed

    Serafini, Mairim Russo; Santos, Rodrigo Correia; Guimarães, Adriana Gibara; Dos Santos, João Paulo Almeida; da Conceicão Santos, Alan Diego; Alves, Izabel Almeida; Gelain, Daniel Pens; de Lima Nogueira, Paulo Cesar; Quintans-Júnior, Lucindo José; Bonjardim, Leonardo Rigoldi; de Souza Araújo, Adriano Antunes

    2011-10-01

    Herbal drugs have been used since ancient times to treat a wide range of diseases. Morinda citrifolia Linn (popularly known as "Noni") has been used in folk medicine by Polynesians for over 2,000 years. It is reported to have a broad range of therapeutic effects, including effects against headache, fever, arthritis, gingivitis, respiratory disorders, infections, tuberculosis, and diabetes. The aim of this study was to investigate the antioxidant, anti-inflammatory, antinociceptive, and antibacterial properties of the aqueous extract from M. citrifolia leaves (AEMC). Antioxidant activity was observed against lipid peroxidation, nitric oxide, and hydroxyl radicals. The antinociceptive effect of AEMC was observed in the acetic acid-induced writhing test at the higher dose. Moreover, AEMC significantly reduced the leukocyte migration in doses of 200 and 400 mg/kg and showed mild antibacterial activity. Together, the results suggest that properties of M. citrifolia leaf extract should be explored further in order to achieve newer tools for managing painful and inflammation conditions, including those related to oxidant states.

  19. Ortho-eugenol exhibits anti-nociceptive and anti-inflammatory activities.

    PubMed

    Fonsêca, Diogo V; Salgado, Paula R R; Aragão Neto, Humberto de C; Golzio, Adriana M F O; Caldas Filho, Marcelo R D; Melo, Cynthia G F; Leite, Fagner C; Piuvezam, Marcia R; Pordeus, Liana Clébia de Morais; Barbosa Filho, José M; Almeida, Reinaldo N

    2016-09-01

    Ortho-eugenol is a much used phenylpropanoid whose ability to reduce pain and inflammation has never been studied. Researching ortho-eugenol's antinociceptive and anti-inflammatory activity, and its possible mechanisms of action is therefore of interest. The administration of vehicle, ortho-eugenol (50, 75 and 100mg/kg i.p.), morphine (6mg/kg, i.p.) or dexamethasone (2mg/kg, s.c.) occurred 30min before the completion of pharmacological tests. Pretreatment with ortho-eugenol did not change motor coordination test results, but reduced the number of writhes and licking times in the writhing test and glutamate test, respectively. The reaction time from thermal stimulus was significantly increased in the hot plate test after administration of ortho-eugenol. Treatment with yohimbine reversed the antinociceptive effect of ortho-eugenol, suggesting involvement of the adrenergic system. In anti-inflammatory tests, ortho-eugenol inhibited acetic acid induced vascular permeability and leukocyte migration, reducing TNF-α and IL-1β by virtue of its suppression of NF-κB and p38 phosphorylated forms in the peritonitis test. From these results, ortho-eugenol antinociceptive effects mediated by the adrenergic system and anti-inflammatory activity through regulation of proinflammatory cytokines and phosphorylation of NF-kB and p38 become evident for the first time.

  20. Electrophysiological Measurements and Analysis of Nociception in Human Infants

    PubMed Central

    Patten, D.; Holdridge, S.; Cornelissen, L.; Meek, J.; Boyd, S.; Slater, R.

    2011-01-01

    Pain is an unpleasant sensory and emotional experience. Since infants cannot verbally report their experiences, current methods of pain assessment are based on behavioural and physiological body reactions, such as crying, body movements or changes in facial expression. While these measures demonstrate that infants mount a response following noxious stimulation, they are limited: they are based on activation of subcortical somatic and autonomic motor pathways that may not be reliably linked to central sensory processing in the brain. Knowledge of how the central nervous system responds to noxious events could provide an insight to how nociceptive information and pain is processed in newborns. The heel lancing procedure used to extract blood from hospitalised infants offers a unique opportunity to study pain in infancy. In this video we describe how electroencephalography (EEG) and electromyography (EMG) time-locked to this procedure can be used to investigate nociceptive activity in the brain and spinal cord. This integrative approach to the measurement of infant pain has the potential to pave the way for an effective and sensitive clinical measurement tool. PMID:22214879

  1. Quantification of Nociceptive Escape Response in C.elegans

    NASA Astrophysics Data System (ADS)

    Leung, Kawai; Mohammadi, Aylia; Ryu, William; Nemenman, Ilya

    2013-03-01

    Animals cannot rank and communicate their pain consciously. Thus in pain studies on animal models, one must infer the pain level from high precision experimental characterization of behavior. This is not trivial since behaviors are very complex and multidimensional. Here we explore the feasibility of C.elegans as a model for pain transduction. The nematode has a robust neurally mediated noxious escape response, which we show to be partially decoupled from other sensory behaviors. We develop a nociceptive behavioral response assay that allows us to apply controlled levels of pain by locally heating worms with an IR laser. The worms' motions are captured by machine vision programming with high spatiotemporal resolution. The resulting behavioral quantification allows us to build a statistical model for inference of the experienced pain level from the behavioral response. Based on the measured nociceptive escape of over 400 worms, we conclude that none of the simple characteristics of the response are reliable indicators of the laser pulse strength. Nonetheless, a more reliable statistical inference of the pain stimulus level from the measured behavior is possible based on a complexity-controlled regression model that takes into account the entire worm behavioral output. This work was partially supported by NSF grant No. IOS/1208126 and HFSP grant No. RGY0084/2011.

  2. Collecting and Measuring Nociceptive and Inflammatory Mediators in Surgical Wounds

    PubMed Central

    Carvalho, Brendan; Clark, David J.; Yeomans, David; Angst, Martin S.

    2008-01-01

    The objectives of this study were to test the feasibility of collecting and measuring inflammatory and nociceptive biochemical mediators at the surgical site; to evaluate the relationship between wound and serum levels; and to determine any associations between mediator release, pain and analgesic consumption post-cesarean delivery. Twenty healthy women undergoing elective cesarean delivery with spinal anesthesia were enrolled. Wound exudate and serum mediators, pain scores and analgesics consumption were measured at 1, 6, 24, and 48 hours post-cesarean. In wound exudate, 19 out of 20 mediators were reliably detected including IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNFα, INFγ, G-CSF, GM-CSF, MCP-1 and MIP-1β, nerve growth factor (NGF), prostaglandin E2 (PG-E2) and substance P. Wound PG-E2 and various cytokines peaked early, whereas NGF showed a more delayed release. There were no correlations between the concentration versus time profile of wound and serum cytokines. This study demonstrates the feasibility of collecting and measuring nociceptive and inflammatory mediators in surgical wounds at specific time points. The lack of significant correlations between wound and serum levels emphasizes the importance of determining site-specific release if localized pathologies are to be studied. PMID:19078937

  3. Comparison of operant escape and reflex tests of nociceptive sensitivity.

    PubMed

    Vierck, Charles J; Yezierski, Robert P

    2015-04-01

    Testing of reflexes such as flexion/withdrawal or licking/guarding is well established as the standard for evaluating nociceptive sensitivity and its modulation in preclinical investigations of laboratory animals. Concerns about this approach have been dismissed for practical reasons - reflex testing requires no training of the animals; it is simple to instrument; and responses are characterized by observers as latencies or thresholds for evocation. In order to evaluate this method, the present review summarizes a series of experiments in which reflex and operant escape responding are compared in normal animals and following surgical models of neuropathic pain or pharmacological intervention for pain. Particular attention is paid to relationships between reflex and escape responding and information on the pain sensitivity of normal human subjects or patients with pain. Numerous disparities between results for reflex and operant escape measures are described, but the results of operant testing are consistent with evidence from humans. Objective reasons are given for experimenters to choose between these and other methods of evaluating the nociceptive sensitivity of laboratory animals.

  4. Physiological Signal Processing for Individualized Anti-nociception Management During General Anesthesia: A Review

    PubMed Central

    Bonhomme, V.; Jeanne, M.; Boselli, E.; Gruenewald, M.; Logier, R.; Richebé, P.

    2015-01-01

    Summary Objective The aim of this paper is to review existing technologies for the nociception / anti-nociception balance evaluation during surgery under general anesthesia. Methods General anesthesia combines the use of analgesic, hypnotic and muscle-relaxant drugs in order to obtain a correct level of patient non-responsiveness during surgery. During the last decade, great efforts have been deployed in order to find adequate ways to measure how anesthetic drugs affect a patient’s response to surgical nociception. Nowadays, though some monitoring devices allow obtaining information about hypnosis and muscle relaxation, no gold standard exists for the nociception / anti-nociception balance evaluation. Articles from the PubMed literature search engine were reviewed. As this paper focused on surgery under general anesthesia, articles about nociception monitoring on conscious patients, in post-anesthesia care unit or in intensive care unit were not considered. Results In this article, we present a review of existing technologies for the nociception / anti-nociception balance evaluation, which is based in all cases on the analysis of the autonomous nervous system activity. Presented systems, based on sensors and physiological signals processing algorithms, allow studying the patients’ reaction regarding anesthesia and surgery. Conclusion Some technological solutions for nociception / antinociception balance monitoring were described. Though presented devices could constitute efficient solutions for individualized anti-nociception management during general anesthesia, this review of current literature emphasizes the fact that the choice to use one or the other mainly relies on the clinical context and the general purpose of the monitoring. PMID:26293855

  5. Kallolide A acetate pyrazoline.

    PubMed

    Rodríguez-Escudero, Idaliz; Marrero, Jeffrey; Rodríguez, Abimael D

    2012-01-01

    IN THE CRYSTAL STRUCTURE OF KALLOLIDE A ACETATE PYRAZOLINE [SYSTEMATIC NAME: 7-methyl-16-oxo-4,10-bis-(prop-1-en-2-yl)-17,18-dioxa-14,15-diaza-tetra-cyclo-[9.4.2.1(6,9).0(1,12)]octa-deca-6,8,14-trien-5-yl acetate], C(23)H(28)N(2)O(5), there is a 12-member-ed carbon macrocyclic structure. In addition, there is a tris-ubstituted furan ring, an approximately planar γ-lactone ring [maximum deviation of 0.057 (3) Å] and a pyraz-oline ring, the latter in an envelope conformation. The pyrazoline and the γ-lactone rings are fused in a cis configuration. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming a two-dimensional network parallel to (001). An intra-molecular C-H⋯O hydrogen bond is also present.

  6. Kallolide A acetate pyrazoline

    PubMed Central

    Rodríguez-Escudero, Idaliz; Marrero, Jeffrey; Rodríguez, Abimael D.

    2012-01-01

    In the crystal structure of kallolide A acetate pyrazoline [systematic name: 7-methyl-16-oxo-4,10-bis­(prop-1-en-2-yl)-17,18-dioxa-14,15-diaza­tetra­cyclo­[9.4.2.16,9.01,12]octa­deca-6,8,14-trien-5-yl acetate], C23H28N2O5, there is a 12-member­ed carbon macrocyclic structure. In addition, there is a tris­ubstituted furan ring, an approximately planar γ-lactone ring [maximum deviation of 0.057 (3) Å] and a pyraz­oline ring, the latter in an envelope conformation. The pyrazoline and the γ-lactone rings are fused in a cis configuration. In the crystal, mol­ecules are linked by weak C—H⋯O inter­actions, forming a two-dimensional network parallel to (001). An intra­molecular C—H⋯O hydrogen bond is also present. PMID:22259545

  7. Role of spinal metabotropic glutamate receptor 5 in pudendal inhibition of the nociceptive bladder reflex in cats.

    PubMed

    Reese, Jeremy N; Rogers, Marc J; Xiao, Zhiying; Shen, Bing; Wang, Jicheng; Schwen, Zeyad; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2015-04-15

    This study examined the role of spinal metabotropic glutamate receptor 5 (mGluR5) in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in the inhibtion of this reflex by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats after spinal cord transection at the T9/T10 level, intravesical infusion of 0.25% acetic acid irritated the bladder, activated nociceptive C-fiber afferents, and induced spinal reflex bladder contractions of low amplitude (<50 cmH2O) and short duration (<20 s) at a smaller bladder capacity ∼80% of saline control capacity. PNS significantly (P < 0.01) increased bladder capacity from 85.5 ± 10.1 to 137.3 ± 14.1 or 148.2 ± 11.2% at 2T or 4T stimulation, respectively, where T is the threshold intensity for PNS to induce anal twitch. MTEP {3-[(2-methyl-4-thiazolyl)ethynyl]pyridine; 3 mg/kg iv, a selective mGluR5 antagonist} completely removed the PNS inhibition and significantly (P < 0.05) increased bladder capacity from 71.8 ± 9.9 to 94.0 ± 13.9% of saline control, but it did not change the bladder contraction amplitude. After propranolol (3 mg/kg iv, a β1/β2-adrenergic receptor antagonist) treatment, PNS inhibition remained but MTEP significantly (P < 0.05) reduced the bladder contraction amplitude from 18.6 ± 2.1 to 6.6 ± 1.2 cmH2O and eliminated PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg iv, a ganglionic blocker) significantly (P < 0.05) reduced the bladder contraction amplitude from 20.9 ± 3.2 to 8.1 ± 1.5 cmH2O on average demonstrating that spinal reflexes were responsible for a major component of the contractions. This study shows that spinal mGluR5 plays an important role in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in pudendal inhibition of this spinal reflex.

  8. Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores

    PubMed Central

    Zutz, Christoph; Bacher, Markus; Parich, Alexandra; Kluger, Bernhard; Gacek-Matthews, Agnieszka; Schuhmacher, Rainer; Wagner, Martin; Rychli, Kathrin; Strauss, Joseph

    2016-01-01

    One of the biggest challenges in public health is the rising number of antibiotic resistant pathogens and the lack of novel antibiotics. In recent years there is a rising focus on fungi as sources of antimicrobial compounds due to their ability to produce a large variety of bioactive compounds and the observation that virtually every fungus may still contain yet unknown so called “cryptic,” often silenced, compounds. These putative metabolites could include novel bioactive compounds. Considerable effort is spent on methods to induce production of these “cryptic” metabolites. One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi. We observed that the supernatant of the fungus Doratomyces (D.) microsporus treated with valproic acid (VPA) displayed antimicrobial activity against Staphylococcus (S.) aureus and two methicillin resistant clinical S. aureus isolates. VPA treatment resulted in enhanced production of seven antimicrobial compounds: cyclo-(L-proline-L-methionine) (cPM), p-hydroxybenzaldehyde, cyclo-(phenylalanine-proline) (cFP), indole-3-carboxylic acid, phenylacetic acid (PAA) and indole-3-acetic acid. The production of the antimicrobial compound phenyllactic acid was exclusively detectable after VPA treatment. Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains. In conclusion we could show in this study that VPA treatment is a potent tool for induction of “cryptic” antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism. Furthermore this is the first discovery of the rare diketopiperazine cPM in fungi. Additionally we could demonstrate that cPM and PAA boost antibiotic activity

  9. Tranexamic acid induces kaolin intake stimulating a pathway involving tachykinin neurokinin 1 receptors in rats.

    PubMed

    Kakiuchi, Hitoshi; Kawarai-Shimamura, Asako; Kuwagata, Makiko; Orito, Kensuke

    2014-01-15

    Tranexamic acid suppresses post-partum haemorrhage and idiopathic menorrhagia through its anti-fibrinolytic action. Although it is clinically useful, it is associated with high risks of side effects such as emesis. Understanding the mechanisms underlying tranexamic acid-induced emesis is very important to explore appropriate anti-emetic drugs for the prevention and/or suppression of emesis. In this study, we examined the receptors involved in tranexamic acid-induced kaolin intake in rats, which reflects the drug's clinical emetogenic potential in humans. Further, we examined the brain regions activated by administration of tranexamic acid and elucidated pivotal pathways of tranexamic acid-induced kaolin intake. We examined the effects of ondansetron, a 5-hydroxytryptamine 3 receptor antagonist, domperidone, a dopamine 2 receptor antagonist, and aprepitant, a tachykinin neurokinin 1 (NK1) receptor antagonist, on tranexamic acid-induced kaolin intake in rats. Then, we determined the brain regions that showed increased numbers of c-Fos immunoreactive cells. Finally, we examined the effects of an antagonist(s) that reduced tranexamic acid-induced kaolin intake on the increase in c-Fos immunoreactive cells. Aprepitant significantly decreased tranexamic acid-induced kaolin intake. However, neither ondansetron nor domperidone decreased kaolin intake. Tranexamic acid significantly increased c-Fos immunoreactive cells by approximately 5.5-fold and 22-fold in the area postrema and nucleus of solitary tract, respectively. Aprepitant decreased the number of c-Fos immunoreactive cells in both areas. Tranexamic acid induced kaolin intake possibly via stimulation of tachykinin NK1 receptors in rats. The tachykinin NK1 receptor could be targeted to prevent and/or suppress emesis in patients receiving tranexamic acid.

  10. Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information.

    PubMed

    Nahman-Averbuch, Hadas; Martucci, Katherine T; Granovsky, Yelena; Weissman-Fogel, Irit; Yarnitsky, David; Coghill, Robert C

    2014-12-01

    The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intraparietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM-related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information.

  11. Changes in Activity of the Same Thalamic Neurons to Repeated Nociception in Behaving Mice.

    PubMed

    Huh, Yeowool; Cho, Jeiwon

    2015-01-01

    The sensory thalamus has been reported to play a key role in central pain sensory modulation and processing, but its response to repeated nociception at thalamic level is not well known. Current study investigated thalamic response to repeated nociception by recording and comparing the activity of the same thalamic neuron during the 1st and 2nd formalin injection induced nociception, with a week interval between injections, in awake and behaving mice. Behaviorally, the 2nd injection induced greater nociceptive responses than the 1st. Thalamic activity mirrored these behavioral changes with greater firing rate during the 2nd injection. Analysis of tonic and burst firing, characteristic firing pattern of thalamic neurons, revealed that tonic firing activity was potentiated while burst firing activity was not significantly changed by the 2nd injection relative to the 1st. Likewise, burst firing property changes, which has been consistently associated with different phases of nociception, were not induced by the 2nd injection. Overall, data suggest that repeated nociception potentiated responsiveness of thalamic neurons and confirmed that tonic firing transmits nociceptive signals.

  12. Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray

    PubMed Central

    Grajales-Reyes, Jose G.; Copits, Bryan A.; O’Brien, Daniel E.; Trigg, Sarah L.; Gomez, Adrian M.

    2017-01-01

    Abstract The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception. PMID:28374016

  13. Specific activation of the paralemniscal pathway during nociception.

    PubMed

    Frangeul, Laura; Porrero, Cesar; Garcia-Amado, Maria; Maimone, Benedetta; Maniglier, Madlyne; Clascá, Francisco; Jabaudon, Denis

    2014-05-01

    Two main neuronal pathways connect facial whiskers to the somatosensory cortex in rodents: (i) the lemniscal pathway, which originates in the brainstem principal trigeminal nucleus and is relayed in the ventroposterior thalamic nucleus and (ii) the paralemniscal pathway, originating in the spinal trigeminal nucleus and relayed in the posterior thalamic nucleus. While lemniscal neurons are readily activated by whisker contacts, the contribution of paralemniscal neurons to perception is less clear. Here, we functionally investigated these pathways by manipulating input from the whisker pad in freely moving mice. We report that while lemniscal neurons readily respond to neonatal infraorbital nerve sectioning or whisker contacts in vivo, paralemniscal neurons do not detectably respond to these environmental changes. However, the paralemniscal pathway is specifically activated upon noxious stimulation of the whisker pad. These findings reveal a nociceptive function for paralemniscal neurons in vivo that may critically inform context-specific behaviour during environmental exploration.

  14. Contribution of peripheral vanilloid receptor to the nociception induced by injection of spermine in mice.

    PubMed

    Gewehr, Camila; da Silva, Mariane Arnoldi; dos Santos, Gabriela Trevisan; Rossato, Mateus Fortes; de Oliveira, Sara Marchesan; Drewes, Carine Cristiane; Pazini, Andréia Martini; Guerra, Gustavo Petri; Rubin, Maribel A; Ferreira, Juliano

    2011-10-01

    Polyamines (putrescine, spermidine and spermine) are important endogenous regulators of ion channels, such as vanilloid (TRPV1), glutamatergic (NMDA or AMPA/kainate) and acid-sensitive (ASIC) receptors. In the present study, we have investigated the possible nociceptive effect induced by polyamines and the mechanisms involved in this nociception in vivo. The subcutaneous (s.c.) injection of capsaicin (as positive control), spermine, spermidine or putrescine produced nociception with ED(50) of 0.16 (0.07-0.39)nmol/paw, 0.4 (0.2-0.7) μmol/paw, 0.3 (0.1-0.9) μmol/paw and 3.2 (0.9-11.5) μmol/paw, respectively. The antagonists of NMDA (MK801, 1 nmol/paw), AMPA/kainate (DNQX, 1 nmol/paw) or ASIC receptors (amiloride, 100 nmol/paw) failed to reduce the spermine-trigged nociception. However, the TRPV1 antagonists capsazepine or SB366791 (1 nmol/paw) reduced spermine-induced nociception, with inhibition of 81 ± 10 and 68 ± 9%, respectively. The previous desensitization with resiniferatoxin (RTX) largely reduced the spermine-induced nociception and TRPV1 expression in the sciatic nerve, with reductions of 82 ± 9% and 67 ± 11%, respectively. Furthermore, the combination of spermine (100 nmol/paw) and RTX (0.005 fmol/paw), in doses which alone were not capable of inducing nociception, produced nociceptive behaviors. Moreover, different concentrations of spermine (3-300 μM) enhanced the specific binding of [(3)H]-RTX to TRPV1 receptor. Altogether, polyamines produce spontaneous nociceptive effect through the stimulation of TRPV1, but not of ionotropic glutamate or ASIC receptors.

  15. Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

    NASA Astrophysics Data System (ADS)

    Casey, Kenneth L.

    1999-07-01

    Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

  16. A role for nociceptive, myelinated nerve fibers in itch sensation.

    PubMed

    Ringkamp, Matthias; Schepers, Raf J; Shimada, Steven G; Johanek, Lisa M; Hartke, Timothy V; Borzan, Jasenka; Shim, Beom; LaMotte, Robert H; Meyer, Richard A

    2011-10-19

    Despite its clinical importance, the underlying neural mechanisms of itch sensation are poorly understood. In many diseases, pruritus is not effectively treated with antihistamines, indicating the involvement of nonhistaminergic mechanisms. To investigate the role of small myelinated afferents in nonhistaminergic itch, we tested, in psychophysical studies in humans, the effect of a differential nerve block on itch produced by intradermal insertion of spicules from the pods of a cowhage plant (Mucuna pruriens). Electrophysiological experiments in anesthetized monkey were used to investigate the responsiveness of cutaneous, nociceptive, myelinated afferents to different chemical stimuli (cowhage spicules, histamine, capsaicin). Our results provide several lines of evidence for an important role of myelinated fibers in cowhage-induced itch: (1) a selective conduction block in myelinated fibers substantially reduces itch in a subgroup of subjects with A-fiber-dominated itch, (2) the time course of itch sensation differs between subjects with A-fiber- versus C-fiber-dominated itch, (3) cowhage activates a subpopulation of myelinated and unmyelinated afferents in monkey, (4) the time course of the response to cowhage is different in myelinated and unmyelinated fibers, (5) the time of peak itch sensation for subjects with A-fiber-dominated itch matches the time for peak response in myelinated fibers, and (6) the time for peak itch sensation for subjects with C-fiber-dominated itch matches the time for the peak response in unmyelinated fibers. These findings demonstrate that activity in nociceptive, myelinated afferents contributes to cowhage-induced sensations, and that nonhistaminergic itch is mediated through activity in both unmyelinated and myelinated afferents.

  17. Attenuation of thermal nociception and hyperalgesia by VR1 blockers

    PubMed Central

    García-Martínez, Carolina; Humet, Marc; Planells-Cases, Rosa; Gomis, Ana; Caprini, Marco; Viana, Felix; De la Peña, Elvira; Sanchez-Baeza, Francisco; Carbonell, Teresa; De Felipe, Carmen; Pérez-Payá, Enrique; Belmonte, Carlos; Messeguer, Angel; Ferrer-Montiel, Antonio

    2002-01-01

    Vanilloid receptor subunit 1 (VR1) appears to play a critical role in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues. Thus, VR1 antagonists are useful compounds to unravel the contribution of this receptor to pain perception, as well as to induce analgesia. We have used a combinatorial approach to identify new, nonpeptidic channel blockers of VR1. Screening of a library of trimers of N-alkylglycines resulted in the identification of two molecules referred to as DD161515 {N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide} and DD191515 {[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide} that selectively block VR1 channel activity with micromolar efficacy, rivaling that characteristic of vanilloid-related inhibitors. These compounds appear to be noncompetitive VR1 antagonists that recognize a receptor site distinct from that of capsaicin. Intraperitoneal administration of both trialkylglycines into mice significantly attenuated thermal nociception as measured in the hot plate test. It is noteworthy that these compounds eliminated pain and neurogenic inflammation evoked by intradermal injection of capsaicin into the animal hindpaw, as well as the thermal hyperalgesia induced by tissue irritation with nitrogen mustard. In contrast, responses to mechanical stimuli were not modified by either compound. Modulation of sensory nerve fibers excitability appears to underlie the peptoid analgesic activity. Collectively, these results indicate that blockade of VR1 activity attenuates chemical and thermal nociception and hyperalgesia, supporting the tenet that this ionotropic receptor contributes to chemical and thermal sensitivity and pain perception in vivo. These trialkylglycine-based, noncompetitive VR1 antagonists may likely be developed into analgesics to treat inflammatory pain. PMID:11854530

  18. Anti-Inflammatory and Anti-Nociceptive Activities of Stem-Bark Extracts and Fractions of Carpolobia Lutea (Polygalaceae)

    PubMed Central

    Nwidu, Lucky Legbosi; Airhihen, Blessing; Ahmadu, Augustine

    2016-01-01

    Background: In Niger Delta, ethnomedicine hydroalcoholic extract of Carpolobia lutea (CL) (Polygalaceae) is used to relieve inflammatory pains. Objectives: The purpose of this study is to evaluate the anti-inflammatory and antinociceptive effects of ethanolic stem extract (ESE) and to fractionate the ESE for the elucidation of bioactive molecules. Materials and Methods: The antinociceptive effects for ESE were tested against two noxious stimuli; chemical (acetic acid-induced writhing and formalin-induced pain) and thermal (hot plate) stimuli. The effects of paracetamol (130 mg/kg), indomethacin (10 mg/kg), and morphine (5 mg/kg) pretreatment were investigated. To isolate the bioactive compounds with anti-inflammatory effect, two doses (86.6 and 173.2 mg/kg) of four fractions (methanol fraction MTF, ethyl acetate fraction EAF, chloroform fraction CHF, and n-hexane fraction n-HF) obtained from fractionating ESE were utilized. Carrageenan, egg albumin, and capsaicin-induced edema of the hind paw of the rats were the models adopted. Paw volume was measured by a digital vernier caliper from 0 to 6 h after injection. This was compared to standard drugs. The results were subjected to statistical analysis. Results: The ESE decreased significantly (P < 0.001) the writhing of acetic acid-induced abdominal contractions and licking of formalin-induced pains but does not have any effects on the hot plate test. Of the four fractions obtained, the EAFs demonstrated a significant (P < 0.001) inflammatory inhibition of 98.97% and 41.91% at 86.6 and 173.2 mg/kg, respectively, compared to 65.75% inhibition demonstrated by the reference drug, acetylsalicylic acid (100 mg/kg) on the carrageenan model while 36.36% and 29.87% inhibition of inflammation at 86.6 and 173.2 mg/kg, respectively, on the egg albumin models; there was no significant effect on the capsaicin model. Conclusion: The isolation of quercetin and kaemferol from CL gave credence to its anti-inflammatory and

  19. Mechanical sensibility of nociceptive and non-nociceptive fast-conducting afferents is modulated by skin temperature.

    PubMed

    Boada, M Danilo; Eisenach, James C; Ririe, Douglas G

    2016-01-01

    The ability to distinguish mechanical from thermal input is a critical component of peripheral somatosensory function. Polymodal C fibers respond to both stimuli. However, mechanosensitive, modality-specific fast-conducting tactile and nociceptor afferents theoretically carry information only about mechanical forces independent of the thermal environment. We hypothesize that the thermal environment can nonetheless modulate mechanical force sensibility in fibers that do not respond directly to change in temperature. To study this, fast-conducting mechanosensitive peripheral sensory fibers in male Sprague-Dawley rats were accessed at the soma in the dorsal root ganglia from T11 or L4/L5. Neuronal identification was performed using receptive field characteristics and passive and active electrical properties. Neurons responded to mechanical stimuli but failed to generate action potentials in response to changes in temperature alone, except for the tactile mechanical and cold sensitive neurons. Heat and cold ramps were utilized to determine temperature-induced modulation of response to mechanical stimuli. Mechanically evoked electrical activity in non-nociceptive, low-threshold mechanoreceptors (tactile afferents) decreased in response to changes in temperature while mechanically induced activity was increased in nociceptive, fast-conducting, high-threshold mechanoreceptors in response to the same changes in temperature. These data suggest that mechanical activation does not occur in isolation but rather that temperature changes appear to alter mechanical afferent activity and input to the central nervous system in a dynamic fashion. Further studies to understand the psychophysiological implications of thermal modulation of fast-conducting mechanical input to the spinal cord will provide greater insight into the implications of these findings.

  20. The integrative role of orexin/hypocretin neurons in nociceptive perception and analgesic regulation

    PubMed Central

    Inutsuka, Ayumu; Yamashita, Akira; Chowdhury, Srikanta; Nakai, Junichi; Ohkura, Masamichi; Taguchi, Toru; Yamanaka, Akihiro

    2016-01-01

    The level of wakefulness is one of the major factors affecting nociception and pain. Stress-induced analgesia supports an animal’s survival via prompt defensive responses against predators or competitors. Previous studies have shown the pharmacological effects of orexin peptides on analgesia. However, orexin neurons contain not only orexin but also other co-transmitters such as dynorphin, neurotensin and glutamate. Thus, the physiological importance of orexin neuronal activity in nociception is unknown. Here we show that adult-stage selective ablation of orexin neurons enhances pain-related behaviors, while pharmacogenetic activation of orexin neurons induces analgesia. Additionally, we found correlative activation of orexin neurons during nociception using fiber photometry recordings of orexin neurons in conscious animals. These findings suggest an integrative role for orexin neurons in nociceptive perception and pain regulation. PMID:27385517

  1. The calcium-activated chloride channel anoctamin 1 acts as a heat sensor in nociceptive neurons.

    PubMed

    Cho, Hawon; Yang, Young Duk; Lee, Jesun; Lee, Byeongjoon; Kim, Tahnbee; Jang, Yongwoo; Back, Seung Keun; Na, Heung Sik; Harfe, Brian D; Wang, Fan; Raouf, Ramin; Wood, John N; Oh, Uhtaek

    2012-05-27

    Nociceptors are a subset of small primary afferent neurons that respond to noxious chemical, thermal and mechanical stimuli. Ion channels in nociceptors respond differently to noxious stimuli and generate electrical signals in different ways. Anoctamin 1 (ANO1 also known as TMEM16A) is a Ca(2+)-activated chloride channel that is essential for numerous physiological functions. We found that ANO1 was activated by temperatures over 44 °C with steep heat sensitivity. ANO1 was expressed in small sensory neurons and was highly colocalized with nociceptor markers, which suggests that it may be involved in nociception. Application of heat ramps to dorsal root ganglion (DRG) neurons elicited robust ANO1-dependent depolarization. Furthermore, knockdown or deletion of ANO1 in DRG neurons substantially reduced nociceptive behavior in thermal pain models. These results indicate that ANO1 is a heat sensor that detects nociceptive thermal stimuli in sensory neurons and possibly mediates nociception.

  2. Oxytocin, but not vassopressin, modulates nociceptive responses in dorsal horn neurons.

    PubMed

    Rojas-Piloni, Gerardo; Gerardo, Rojas-Piloni; Mejía-Rodríguez, Rosalinda; Rosalinda, Mejía-Rodríguez; Martínez-Lorenzana, Guadalupe; Guadalupe, Martínez-Lorenzana; Condés-Lara, Miguel; Miguel, Condés-Lara

    2010-05-26

    Oxytocin (OT) and vasopressin (VP) are synthesized and secreted by the paraventricular hypothalamic nucleus (PVN), and both peptides have been implicated in the pain modulatory system. In the spinal cord, activation of OT-containing axons modulates nociceptive neuronal responses in dorsal horn neurons; however, it is not known whether the direct VPergic descending projection participates. Here, we show that both PVN electrical stimulation and topical application of OT in the vicinity of identified and recorded dorsal horn WDR selectively inhibit Adelta and C-fiber responses. In contrast, the topical administration of VP on the same neurons did not affect the nociceptive responses. In addition, the reduction in nociceptive responses caused by PVN stimulation or OT administration was blocked with a selective OT antagonist. The results suggest that the VP descending projection does not modulate the antinociceptive effects mediated by the PVN on dorsal horn neurons; instead, it is the hypothalamic-spinal OT projection that regulates nociceptive information.

  3. Role of L-DOPA in spinal nociceptive reflex activity: higher sensitivity of Aδ versus C fibre-evoked nociceptive reflexes to L-DOPA.

    PubMed

    Schomburg, E D; Dibaj, P; Steffens, H

    2011-01-01

    The role of L-DOPA in spinal nociceptive reflex activity has been re-evaluated. In high spinal cats, with supraspinal loops being excluded, the onset of reflex facilitation induced by noxious radiant heat is delayed after injection of L-DOPA by 4 to 10 s, i.e. the early component of nociceptive reflex facilitation is blocked, while the late component persisted. Further investigations have shown that the early component of reflex facilitation induced by noxious radiant heat is mediated by Adelta-fibres and the late component by C-fibres. Therefore, it can be assumed that L-DOPA, like opioids, preferentially blocks the transmission in nociceptive reflex pathways from Adelta-fibres.

  4. Scopolamine into the anterior cingulate cortex diminishes nociception in a neuropathic pain model in the rat: an interruption of 'nociception-related memory acquisition'?

    PubMed

    Ortega-Legaspi, J Manuel; López-Avila, Alberto; Coffeen, Ulises; del Angel, Rosendo; Pellicer, Francisco

    2003-01-01

    The cingulate cortex plays a key role in the affective component related to pain perception. This structure receives cholinergic projections and also plays a role in memory processing. Therefore, we propose that the cholinergic system in the anterior cingulate cortex is involved in the nociceptive memory process. We used scopolamine (10 microg in 0.25 mircrol/saline) microinjected into the anterior cingulate cortex, either before thermonociception followed by a sciatic denervation, between thermonociception and denervation or after both procedures (n=10 each). The vehicle group (saline solution 0.9%, n=14) was microinjected before thermonociception. Chronic nociception was measured by the autotomy score, which onset and incidence were also determined. Group scopolamine-thermonociception-denervation (STD) presented the lowest autotomy score as compared to vehicle and group thermonociception-denervation-scopolamine (TDS) (vehicle vs. STD, p=0.002, STD vs. TDS, p=0.001). Group thermonociception-scopolamine-denervation (TSD) showed a diminished autotomy score when compared to TDS (p=0.053). STD group showed a delay in the onset of AB as compared to the rest of the groups. Group TSD presented a significative delay (p=0.048) in AB onset when compared to group TDS. There were no differences in the incidence between groups. The results show that nociception-related memory processed in the anterior cingulate cortex is susceptible of being modified by the cholinergic transmission blockade. When scopolamine is microinjected prior to the nociceptive stimuli, nociception-related memory acquisition is prevented. The evidence obtained in this study shows the role of the anterior cingulate cortex in the acquisition of nociception-related memory.

  5. Pain hypersensitivity and spinal nociceptive hypersensitivity in chronic pain: prevalence and associated factors.

    PubMed

    Curatolo, Michele; Müller, Monika; Ashraf, Aroosiah; Neziri, Alban Y; Streitberger, Konrad; Andersen, Ole K; Arendt-Nielsen, Lars

    2015-11-01

    Hypersensitivity of pain pathways is considered a relevant determinant of symptoms in chronic pain patients, but data on its prevalence are very limited. To our knowledge, no data on the prevalence of spinal nociceptive hypersensitivity are available. We studied the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity in 961 consecutive patients with various chronic pain conditions. Pain threshold and nociceptive withdrawal reflex threshold to electrical stimulation were used to assess pain hypersensitivity and spinal nociceptive hypersensitivity, respectively. Using 10th percentile cutoff of previously determined reference values, the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity (95% confidence interval) was 71.2 (68.3-74.0) and 80.0 (77.0-82.6), respectively. As a secondary aim, we analyzed demographic, psychosocial, and clinical characteristics as factors potentially associated with pain hypersensitivity and spinal nociceptive hypersensitivity using logistic regression models. Both hypersensitivity parameters were unaffected by most factors analyzed. Depression, catastrophizing, pain-related sleep interference, and average pain intensity were significantly associated with hypersensitivity. However, none of them was significant for both unadjusted and adjusted analyses. Furthermore, the odds ratios were very low, indicating modest quantitative impact. To our knowledge, this is the largest prevalence study on central hypersensitivity and the first one on the prevalence of spinal nociceptive hypersensitivity in chronic pain patients. The results revealed an impressively high prevalence, supporting a high clinical relevance of this phenomenon. Electrical pain thresholds and nociceptive withdrawal reflex explore aspects of pain processing that are mostly independent of sociodemographic, psychological, and clinical pain-related characteristics.

  6. Physiological brainstem mechanisms of trigeminal nociception: An fMRI study at 3T.

    PubMed

    Schulte, Laura H; Sprenger, Christian; May, Arne

    2016-01-01

    The brainstem is a major site of processing and modulation of nociceptive input and plays a key role in the pathophysiology of various headache disorders. However, human imaging studies on brainstem function following trigeminal nociceptive stimulation are scarce as brainstem specific imaging approaches have to address multiple challenges such as magnetic field inhomogeneities and an enhanced level of physiological noise. In this study we used a viable protocol for brainstem fMRI of standardized trigeminal nociceptive stimulation to achieve detailed insight into physiological brainstem mechanisms of trigeminal nociception. We conducted a study of 21 healthy participants using a nociceptive ammonia stimulation of the left nasal mucosa with an optimized MR acquisition protocol for high resolution brainstem echoplanar imaging in combination with two different noise correction techniques. Significant BOLD responses to noxious ammonia stimulation were observed in areas typically involved in trigeminal nociceptive processing such as the spinal trigeminal nuclei (sTN), thalamus, secondary somatosensory cortex, insular cortex and cerebellum as well as in a pain modulating network including the periaqueductal gray area, hypothalamus (HT), locus coeruleus and cuneiform nucleus (CNF). Activations of the left CNF were positively correlated with pain intensity ratings. Employing psychophysiological interaction (PPI) analysis we found enhanced functional connectivity of the sTN with the contralateral sTN and HT following trigeminal nociception. We also observed enhanced functional connectivity of the CNF with the RVM during painful stimulation thus implying an important role of these two brainstem regions in central pain processing. The chosen approach to study trigeminal nociception with high-resolution fMRI offers new insight into human pain processing and might thus lead to a better understanding of headache pathophysiology.

  7. Forebrain medial septum region facilitates nociception in a rat formalin model of inflammatory pain.

    PubMed

    Lee, Andy Thiam-Huat; Ariffin, Mohammed Zacky; Zhou, Mingyi; Ye, Jenn Zhou; Moochhala, Shabbir M; Khanna, Sanjay

    2011-11-01

    The medial septum is anatomically and functionally linked to the hippocampus, a region implicated in nociception. However, the role of medial septum in nociception remains unclear. To investigate the role of the region in nociception in rats, muscimol, a GABA agonist, or zolpidem, a positive allosteric modulator of GABA(A) receptors, was microinjected into medial septum to attenuate the activity of neurons in the region. Electrophysiological studies in anesthetized rats indicated that muscimol evoked a stronger and longer-lasting suppression of medial septal-mediated activation of hippocampal theta field activity than zolpidem. Similarly, microinjection of muscimol (1 or 2 μg/0.5 μl) into the medial septum of awake rats suppressed both licking and flinching behaviors in the formalin test of inflammatory pain, whereas only the latter behavior was affected by zolpidem (8 or 12 μg/0.5 μl) administered into the medial septum. Interestingly, both drugs selectively attenuated nociceptive behaviors in the second phase of the formalin test that are partly driven by central plasticity. Indeed, muscimol reduced the second phase behaviors by 30% to 60%, which was comparable to the reduction seen with systemic administration of a moderate dose of the analgesic morphine. The reduction was accompanied by a decrease in formalin-induced expression of spinal c-Fos protein that serves as an index of spinal nociceptive processing. The drug effects on nociceptive behaviors were without overt sedation and were distinct from the effects observed after septal lateral microinjections. Taken together, these findings suggest that the activation of medial septum is pro-nociceptive and facilitates aspects of central neural processing underlying nociception.

  8. 21 CFR 184.1185 - Calcium acetate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    .... No. 62-54-4), also known as acetate of lime or vinegar salts, is the calcium salt of acetic acid. It may be produced by the calcium hydroxide neutralization of acetic acid. (b) The ingredient meets...

  9. 21 CFR 184.1185 - Calcium acetate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    .... No. 62-54-4), also known as acetate of lime or vinegar salts, is the calcium salt of acetic acid. It may be produced by the calcium hydroxide neutralization of acetic acid. (b) The ingredient meets...

  10. 21 CFR 184.1185 - Calcium acetate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    .... No. 62-54-4), also known as acetate of lime or vinegar salts, is the calcium salt of acetic acid. It may be produced by the calcium hydroxide neutralization of acetic acid. (b) The ingredient meets...

  11. 21 CFR 184.1185 - Calcium acetate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... as acetate of lime or vinegar salts, is the calcium salt of acetic acid. It may be produced by the calcium hydroxide neutralization of acetic acid. (b) The ingredient meets the specifications of the...

  12. Application of calibrated forceps for assessing mechanical nociception with high time resolution in mice

    PubMed Central

    Kashiwadani, Hideki; Kanmura, Yuichi; Kuwaki, Tomoyuki

    2017-01-01

    In order to investigate the basic physiological mechanisms of pain and the anti-nociceptive effects of analgesics, development of pain assays in mice is critical due to the advances of genetic manipulation techniques. The von Frey hairs/Semmes-Weinstein monofilaments test (von Frey test) has long been applied to examine mechanical nociception in mice. Though the von Frey test is a well-established and standardized method, it is inappropriate to assess a rapid change in the nociceptive threshold because voluntary resting/sleeping states are necessary to examine the response. In this study, we assessed the effectiveness of calibrated forceps to determine the mechanical nociceptive threshold in mice. Repeated daily measurements of the threshold over 5 days indicated that the device obtained stable and reliable values. Furthermore, repeated measurements with 5 minute intervals revealed that the device detected the rapid change of the threshold induced by remifentanil, a short-acting μ-receptor agonist. These results indicate that the calibrated forceps are well-suited for measuring the mechanical nociceptive threshold in mice, and are useful in assessing the effects of short-acting analgesics on mechanical nociception. PMID:28212389

  13. [Postsynaptic reactions of cerebral cortex neurons, activated by nociceptive afferents during stimulation of the Raphe nuclei].

    PubMed

    Labakhua, T Sh; Dzhanashiia, T K; Gedevanishvili, G I; Dzhokhadze, L D; Tkemaladze, T T; Abzianidze, I V

    2012-01-01

    On cats, we studied the influence of stimulation of the Raphe nuclei (RN) on postsynaptic processes evoked in neurons of the somatosensory cortex by stimulation of nociceptive (intensive stimulation of the tooth pulp) and non-nociceptive (moderate stimulation of the ventroposteromedial--VPN--nucleus of the thalamus) afferent inputs. 6 cells, selectively excited by stimulation of nocciceptors and 9 cells, activated by both the above nociceptive and non-nociceptive influences (nociceptive and convergent neurons, respectively) were recorded intracellular. In neurons of both groups, responses to nociceptive stimulation (of sufficient intensity) looked like an EPSP-spike-IPSP (the letter of significant duration, up to 200-300 ms) compleх. Conditioning stimulation of the RN which preceded test stimulus applied to the tooth pulp or VPM nucleus by 100 to 800 ms, induced 40-60 % decrease of the IPSP amplitude only, while maхimal effect of influence, in both cases, was noted within intervals of 300-800 ms between conditioning and test stimulus. During stimulation of the RN, serotonin released via receptor and second messengers, provides postsynaptic modulation of GABAergic system, decreasing the IPSP amplitude which occurs after stimulation of both the tooth pulp and VPM thalamic nucleus. This process may be realized trough either pre- or postsynaptic mechanisms.

  14. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain

    PubMed Central

    Zambelli, Vanessa O.; Gross, Eric R.; Chen, Che-Hong; Gutierrez, Vanessa P.; Cury, Yara; Mochly-Rosen, Daria

    2014-01-01

    Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase 2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2*2), which is also present in human ALDH2 of ~540 million East Asians. The ALDH2*1/*2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R2=0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde and formalin-induced nociceptive behavior was greater in the ALDH2*1/*2 mice than wild-type mice. Finally, Alda-1 treatment was also beneficial when given even after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians’ apparent lower pain tolerance. PMID:25163478

  15. The dolognawmeter: a novel instrument and assay to quantify nociception in rodent models of orofacial pain.

    PubMed

    Dolan, John C; Lam, David K; Achdjian, Stacy H; Schmidt, Brian L

    2010-03-30

    Rodent pain models play an important role in understanding the mechanisms of nociception and have accelerated the search for new treatment approaches for pain. Creating an objective metric for orofacial nociception in these models presents significant technical obstacles. No animal assay accurately measures pain-induced orofacial dysfunction that is directly comparable to human orofacial dysfunction. We developed and validated a high throughput, objective, operant, nociceptive animal assay, and an instrument to perform the assay termed the dolognawmeter, for evaluation of conditions known to elicit orofacial pain in humans. Using the device our assay quantifies gnawing function in the mouse. We quantified a behavioral index of nociception and demonstrated blockade of nociception in three models of orofacial pain: (1) TMJ inflammation, (2) masticatory myositis, and (3) head and neck cancer. This assay will be useful in the study of nociceptive mediators involved in the development and progression of orofacial pain conditions and it will also provide a unique tool for development and assessment of new therapeutic approaches.

  16. Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin.

    PubMed

    Entrena, J M; Sánchez-Fernández, C; Nieto, F R; González-Cano, R; Yeste, S; Cobos, E J; Baeyens, J M

    2016-11-25

    Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception.

  17. Age-Dependent Changes in the Inflammatory Nociceptive Behavior of Mice

    PubMed Central

    King-Himmelreich, Tanya S.; Möser, Christine V.; Wolters, Miriam C.; Olbrich, Katrin; Geisslinger, Gerd; Niederberger, Ellen

    2015-01-01

    The processing of pain undergoes several changes in aging that affect sensory nociceptive fibers and the endogenous neuronal inhibitory systems. So far, it is not completely clear whether age-induced modifications are associated with an increase or decrease in pain perception. In this study, we assessed the impact of age on inflammatory nociception in mice and the role of the hormonal inhibitory systems in this context. We investigated the nociceptive behavior of 12-month-old versus 6–8-week-old mice in two behavioral models of inflammatory nociception. Levels of TRP channels, and cortisol as well as cortisol targets, were measured by qPCR, ELISA, and Western blot in the differently aged mice. We observed an age-related reduction in nociceptive behavior during inflammation as well as a higher level of cortisol in the spinal cord of aged mice compared to young mice, while TRP channels were not reduced. Among potential cortisol targets, the NF-κB inhibitor protein alpha (IκBα) was increased, which might contribute to inhibition of NF-κB and a decreased expression and activity of the inducible nitric oxide synthase (iNOS). In conclusion, our results reveal a reduced nociceptive response in aged mice, which might be at least partially mediated by an augmented inflammation-induced increase in the hormonal inhibitory system involving cortisol. PMID:26593904

  18. Dopamine and NMDA systems modulate long-term nociception in the rat anterior cingulate cortex.

    PubMed

    López-Avila, Alberto; Coffeen, Ulises; Ortega-Legaspi, J Manuel; del Angel, Rosendo; Pellicer, Francisco

    2004-09-01

    The anterior cingulate cortex (ACC) plays a key role in pain processing. It has been reported that increased activity of glutamatergic projections into the ACC intensifies nociception; whereas dopaminergic projections inhibit it. The aim of this study was to evaluate the role of dopaminergic and NMDA systems of the ACC in the modulation of long-term nociception elicited by sciatic denervation in the rat. Score, onset and incidence of long-term nociception were measured by the autotomy behavior. The effects of a single microinjection into the ACC of different doses of dopamine (100 nM, 100 microM and 100 mM), a NMDA receptor antagonist (MK801 200 nM and 9.34 mM) and amantadine, a dopamine agonist and NMDA receptor antagonist (10, 100 and 1000 microM) were tested on long-term nociception. Dopamine diminished autotomy behavior in an inverse dose-dependent manner, with dopamine 100 nM as most effective concentration. MK801 and amantadine elicited a significant reduction on autotomy score. Prior injections of D1 and D2 receptor antagonists blocked the antinociceptive effects of amantadine on long-term nociceptive behavior. The present study suggests an interaction between dopaminergic and glutamatergic systems within the ACC in the genesis and maintenance of long-term nociception.

  19. Involvement of spinal glutamate in nociceptive behavior induced by intrathecal administration of hemokinin-1 in mice.

    PubMed

    Watanabe, Chizuko; Mizoguchi, Hirokazu; Bagetta, Giacinto; Sakurada, Shinobu

    2016-03-23

    The most recently identified tachykinin, hemokinin-1, was cloned from mouse bone marrow. While several studies indicated that hemokinin-1 is involved in pain and inflammation, the physiological functions of hemokinin-1 are not fully understood. Our previous research demonstrated that the intrathecal (i.t.) administration of hemokinin-1 (0.00625-1.6 nmol) dose-dependently induced nociceptive behaviors, consisting of scratching, biting and licking in mice, which are very similar with the nociceptive behaviors induced by the i.t. administration of substance P. Low-dose (0.0125 nmol) hemokinin-1-induced nociceptive behavior was inhibited by a specific NK1 receptor antagonist; however, high-dose (0.1 nmol) hemokinin-1-induced nociceptive behavior was not affected. In the present study, we found that the nociceptive behaviors induced by hemokinin-1 (0.1 nmol) were inhibited by the i.t. co-administration of MK-801 or D-APV, which are NMDA receptor antagonists. Moreover, we measured glutamate in the extracellular fluid of the mouse spinal cord using microdialysis. The i.t. administration of hemokinin-1 produced a significant increase in glutamate in the spinal cord, which was significantly reduced by co-administration with NMDA receptor antagonists. These results suggest that hemokinin-1-induced nociceptive behaviors may be mediated by the NMDA receptor in the spinal cord.

  20. Differential magnetic field effects on heart rate and nociception in anosmic pigeons.

    PubMed

    Del Seppia, Cristina; Mencacci, Resi; Luschi, Paolo; Varanini, Maurizio; Ghione, Sergio

    2012-05-01

    Several studies have shown that exposure to altered magnetic fields affects nociception by suppressing stress-induced hypoalgesia, and that this effect is reduced or abolished if the treatment is performed in the absence of light. This raises the question as to whether other sources of sensory stimuli may also modulate these magnetic effects. We investigated the possible role of olfaction in the magnetically induced effects on sensitivity to nociceptive stimuli and heart rate (HR) in restraint-stressed homing pigeons exposed to an Earth-strength, irregularly varying (<1 Hz) magnetic field. The magnetic treatment decreased the nociceptive threshold in normally smelling birds and an opposite effect was observed in birds made anosmic by nostril plugging. Conversely, no differential effect of olfactory deprivation was observed on HR, which was reduced by the magnetic treatment both in smelling and anosmic pigeons. The findings highlight an important role of olfactory environmental information in the mediation of magnetic effects on nociception, although the data cannot be interpreted unambiguously because of the lack of an additional control group of olfactory-deprived, non-magnetically exposed pigeons. The differential effects on a pigeon's sensitivity to nociceptive stimulus and HR additionally indicate that the magnetic stimuli affect nociception and the cardiovascular system in different ways.

  1. The inhibitory effect of locally injected dexmedetomidine on carrageenan-induced nociception in rats.

    PubMed

    Honda, Yuka; Higuchi, Hitoshi; Matsuoka, Yoshikazu; Yabuki-Kawase, Akiko; Ishii-Maruhama, Minako; Tomoyasu, Yumiko; Maeda, Shigeru; Morimatsu, Hiroshi; Miyawaki, Takuya

    2015-10-05

    Recent studies showed that the administration of dexmedetomidine relieved hyperalgesia in the presence of neuropathic pain. These findings have led to the hypothesis that the local administration of dexmedetomidine is useful for relieving acute inflammatory nociception, such as postoperative pain. Thus, we evaluated the inhibitory effect of locally injected dexmedetomidine on acute inflammatory nociception. Acute inflammatory nociception was induced by an intraplantar injection of 1% carrageenan into the hindpaws of rats, and dexmedetomidine was also injected combined with carrageenan. The paw withdrawal threshold based on von Frey filament stimulation was measured until 12 h after injection. We compared the area under the time-curve (AUC) between carrageenan and carrageenan with dexmedetomidine. To clarify that the action of dexmedetomidine was via α2-adrenoceptors, we evaluated the effect of yohimbine, a selective antagonist of α2-adrenoceptors, on the anti-nociception of dexmedetomidine. As the results, the intraplantar injection of carrageenan with over 10 μM dexmedetomidine significantly increased AUC, compared to that with only carrageenan injection. This effect of dexmedetomidine was reversed by the addition of yohimbine to carrageenan and dexmedetomidine. These results demonstrated that the locally injected dexmedetomidine was effective against carrageenan-induced inflammatory nociception via α2-adrenoceptors. The findings suggest that the local injection of dexmedetomidine is useful for relieving local acute inflammatory nociception.

  2. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain.

    PubMed

    Zambelli, Vanessa O; Gross, Eric R; Chen, Che-Hong; Gutierrez, Vanessa P; Cury, Yara; Mochly-Rosen, Daria

    2014-08-27

    Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase-2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2*2), which is also present in human ALDH2 of ~540 million East Asians. The ALDH2*1/*2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R(2) = 0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde- and formalin-induced nociceptive behavior was greater in the ALDH2*1/*2 mice than in the wild-type mice. Finally, Alda-1 treatment was even beneficial when given after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic, cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians' apparent lower pain tolerance.

  3. The relationship between nociceptive brain activity, spinal reflex withdrawal and behaviour in newborn infants.

    PubMed

    Hartley, Caroline; Goksan, Sezgi; Poorun, Ravi; Brotherhood, Kelly; Mellado, Gabriela Schmidt; Moultrie, Fiona; Rogers, Richard; Adams, Eleri; Slater, Rebeccah

    2015-07-31

    Measuring infant pain is complicated by their inability to describe the experience. While nociceptive brain activity, reflex withdrawal and facial grimacing have been characterised, the relationship between these activity patterns has not been examined. As cortical and spinally mediated activity is developmentally regulated, it cannot be assumed that they are predictive of one another in the immature nervous system. Here, using a new experimental paradigm, we characterise the nociceptive-specific brain activity, spinal reflex withdrawal and behavioural activity following graded intensity noxious stimulation and clinical heel lancing in 30 term infants. We show that nociceptive-specific brain activity and nociceptive reflex withdrawal are graded with stimulus intensity (p < 0.001), significantly correlated (r = 0.53, p = 0.001) and elicited at an intensity that does not evoke changes in clinical pain scores (p = 0.55). The strong correlation between reflex withdrawal and nociceptive brain activity suggests that movement of the limb away from a noxious stimulus is a sensitive indication of nociceptive brain activity in term infants. This could underpin the development of new clinical pain assessment measures.

  4. Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin

    PubMed Central

    Entrena, J. M.; Sánchez-Fernández, C.; Nieto, F. R.; González-Cano, R.; Yeste, S.; Cobos, E. J.; Baeyens, J. M.

    2016-01-01

    Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception. PMID:27886264

  5. Antinociceptive Effects of Prim-O-Glucosylcimifugin in Inflammatory Nociception via Reducing Spinal COX-2.

    PubMed

    Wu, Liu-Qing; Li, Yu; Li, Yuan-Yan; Xu, Shi-Hao; Yang, Zong-Yong; Lin, Zheng; Li, Jun

    2016-07-01

    We measured anti-nociceptive activity of prim-o-glucosylcimifugin (POG), a molecule from Saposhnikovia divaricate (Turcz) Schischk. Anti-nociceptive or anti-inflammatory effects of POG on a formalin-induced tonic nociceptive response and a complete Freund's adjuvant (CFA) inoculation-induced rat arthritis pain model were studied. Single subcutaneous injections of POG produced potent anti-nociception in both models that was comparable to indomethacin analgesia. Anti-nociceptive activity of POG was dose-dependent, maximally reducing pain 56.6% with an ED50 of 1.6 mg. Rats given POG over time did not develop tolerance. POG also time-dependently reduced serum TNFα, IL-1β and IL-6 in arthritic rats and both POG and indomethacin reduced spinal prostaglandin E2 (PGE2). Like indomethacin which inhibits cyclooxygenase-2 (COX-2) activity, POG dose-dependently decreased spinal COX-2 content in arthritic rats. Additionally, POG, and its metabolite cimifugin, downregulated COX-2 expression in vitro. Thus, POG produced potent anti-nociception by downregulating spinal COX-2 expression.

  6. Pickpocket is a DEG/ENaC protein required for mechanical nociception in Drosophila larvae

    PubMed Central

    Zhong, Lixian; Hwang, Richard Y.; Tracey, W. Daniel

    2010-01-01

    Summary Highly branched Class IV multidendritic sensory neurons of the Drosophila larva function as polymodal nociceptors that are necessary for behavioral responses to noxious heat (>39°C) or noxious mechanical (>30 mN) stimuli. However, the molecular mechanisms that allow these cells to detect both heat and force are unknown. Here, we report that the pickpocket(ppk) gene, which encodes a Degenerin/ Epithelial Sodium Channel (DEG/ENaC) subunit, is required for mechanical nociception but not thermal nociception in these sensory cells. Larvae mutant for pickpocket show greatly reduced nociception behaviors in response to harsh mechanical stimuli. However, pickpocket mutants display normal behavioral responses to gentle touch. Tissue specific knockdown of pickpocket in nociceptors phenocopies the mechanical nociception impairment without causing defects in thermal nociception behavior. Finally, optogenetically-triggered nociception behavior is unaffected by pickpocket RNAi which indicates that ppk is not generally required for the excitability of the nociceptors. Interestingly, DEG/ENaCs are known to play a critical role in detecting gentle touch stimuli in C. elegans and have also been implicated in some aspects of harsh touch sensation in mammals. Our results suggest that neurons which detect harsh touch in Drosophila utilize similar mechanosensory molecules. PMID:20171104

  7. Painful engrams: Oscillatory correlates of working memory for phasic nociceptive laser stimuli.

    PubMed

    Valentini, Elia; Nicolardi, Valentina; Aglioti, Salvatore Maria

    2017-04-05

    Research suggests that working memory (WM) is impaired in chronic pain. Yet, information on how potentially noxious stimuli are maintained in memory is limited in patients as well as in healthy people. We recorded electroencephalography (EEG) in healthy volunteers during a modified delayed match-to-sample task where maintenance in memory of relevant attributes of nociceptive laser stimuli was essential for subsequent cued-discrimination. Participants performed in high and low load conditions (i.e. three vs. two stimuli to keep in WM). Modulation of EEG oscillations in the beta band during the retention interval and in the alpha band during the pre-retention interval reflected performance in the WM task. Importantly, both a non-verbal and a verbal neuropsychological WM test predicted oscillatory modulations. Moreover, these two neuropsychological tests and self-reported personality measures predicted the performance in the nociceptive WM task. Results demonstrate (i) that beta and alpha EEG oscillations can represent WM for nociceptive stimuli; (ii) the association between neuropsychological measures of WM and the brain representation of phasic nociceptive painful stimuli; and (iii) that personality factors can predict memory for nociceptive stimuli at the behavioural level. Altogether, our findings offer a promising approach for investigating cortical correlates of nociceptive memory in clinical pain conditions.

  8. Pallidol hexa­acetate ethyl acetate monosolvate

    PubMed Central

    Mao, Qinyong; Taylor, Dennis K.; Ng, Seik Weng; Tiekink, Edward R. T.

    2013-01-01

    The entire mol­ecule of pallidol hexa­acetate {systematic name: (±)-(4bR,5R,9bR,10R)-5,10-bis­[4-(acet­yloxy)phen­yl]-4b,5,9b,10-tetra­hydro­indeno­[2,1-a]indene-1,3,6,8-tetrayl tetra­acetate} is completed by the application of twofold rotational symmetry in the title ethyl acetate solvate, C40H34O12·C4H8O2. The ethyl acetate mol­ecule was highly disordered and was treated with the SQUEEZE routine [Spek (2009 ▶). Acta Cryst. D65, 148–155]; the crystallographic data take into account the presence of the solvent. In pallidol hexa­acetate, the dihedral angle between the fused five-membered rings (r.m.s. deviation = 0.100 Å) is 54.73 (6)°, indicating a significant fold in the mol­ecule. Significant twists between residues are also evident as seen in the dihedral angle of 80.70 (5)° between the five-membered ring and the pendent benzene ring to which it is attached. Similarly, the acetate residues are twisted with respect to the benzene ring to which they are attached [C—O(carb­oxy)—C—C torsion angles = −70.24 (14), −114.43 (10) and −72.54 (13)°]. In the crystal, a three-dimensional architecture is sustained by C—H⋯O inter­actions which encompass channels in which the disordered ethyl acetate mol­ecules reside. PMID:24046702

  9. Sphingolipid biosynthesis upregulation by TOR complex 2-Ypk1 signaling during yeast adaptive response to acetic acid stress.

    PubMed

    Guerreiro, Joana F; Muir, Alexander; Ramachandran, Subramaniam; Thorner, Jeremy; Sá-Correia, Isabel

    2016-12-01

    Acetic acid-induced inhibition of yeast growth and metabolism limits the productivity of industrial fermentation processes, especially when lignocellulosic hydrolysates are used as feedstock in industrial biotechnology. Tolerance to acetic acid of food spoilage yeasts is also a problem in the preservation of acidic foods and beverages. Thus understanding the molecular mechanisms underlying adaptation and tolerance to acetic acid stress is increasingly important in industrial biotechnology and the food industry. Prior genetic screens for Saccharomyces cerevisiae mutants with increased sensitivity to acetic acid identified loss-of-function mutations in the YPK1 gene, which encodes a protein kinase activated by the target of rapamycin (TOR) complex 2 (TORC2). We show in the present study by several independent criteria that TORC2-Ypk1 signaling is stimulated in response to acetic acid stress. Moreover, we demonstrate that TORC2-mediated Ypk1 phosphorylation and activation is necessary for acetic acid tolerance, and occurs independently of Hrk1, a protein kinase previously implicated in the cellular response to acetic acid. In addition, we show that TORC2-Ypk1-mediated activation of l-serine:palmitoyl-CoA acyltransferase, the enzyme complex that catalyzes the first committed step of sphingolipid biosynthesis, is required for acetic acid tolerance. Furthermore, analysis of the sphingolipid pathway using inhibitors and mutants indicates that it is production of certain complex sphingolipids that contributes to conferring acetic acid tolerance. Consistent with that conclusion, promoting sphingolipid synthesis by adding exogenous long-chain base precursor phytosphingosine to the growth medium enhanced acetic acid tolerance. Thus appropriate modulation of the TORC2-Ypk1-sphingolipid axis in industrial yeast strains may have utility in improving fermentations of acetic acid-containing feedstocks.

  10. MICROARRAY ANALYSIS OF DICHLOROACETIC ACID-INDUCED CHANGES IN GENE EXPRESSION

    EPA Science Inventory


    MICROARRAY ANALYSIS OF DICHLOROACETIC ACID-INDUCED CHANGES IN GENE EXPRESSION

    Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated the hepatocarcinogenicity of DCA in rodents when administered in dri...

  11. Primidone inhibits TRPM3 and attenuates thermal nociception in vivo.

    PubMed

    Krügel, Ute; Straub, Isabelle; Beckmann, Holger; Schaefer, Michael

    2017-01-12

    The melastatin-related transient receptor potential channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Since TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline and the anticonvulsant primidone were identified as highly efficient TRPM3 blockers with half-maximal inhibition at 0.6-6 µM and marked specificity for TRPM3. Most prominently, primidone was biologically active to suppress TRPM3 activation by pregnenolone sulfate (PregS) and heat at concentrations markedly lower than plasma concentrations commonly used in antiepileptic therapy. Primidone blocked PregS-induced [Ca]i influx through TRPM3 by allosteric modulation, and reversibly inhibited atypical inwardly rectifying TRPM3 currents induced by co-application of PregS and clotrimazole. In vivo, analgesic effects of low doses of primidone were demonstrated in mice, applying PregS- and heat-induced pain models, including inflammatory hyperalgesia. Thus, applying the approved drug at concentrations that are lower than those needed to induce anticonvulsive effects offers a shortcut for studying physiological and pathophysiological roles of TRPM3 in vivo.

  12. Keratinocytes can modulate and directly initiate nociceptive responses

    PubMed Central

    Baumbauer, Kyle M; DeBerry, Jennifer J; Adelman, Peter C; Miller, Richard H; Hachisuka, Junichi; Lee, Kuan Hsien; Ross, Sarah E; Koerber, H Richard; Davis, Brian M; Albers, Kathryn M

    2015-01-01

    How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can directly elicit AP firing in nociceptive as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory processing. DOI: http://dx.doi.org/10.7554/eLife.09674.001 PMID:26329459

  13. Annexin A2 Regulates TRPA1-Dependent Nociception

    PubMed Central

    Avenali, Luca; Narayanan, Pratibha; Rouwette, Tom; Cervellini, Ilaria; Sereda, Michael

    2014-01-01

    The transient receptor potential A1 (TRPA1) channel is essential for vertebrate pain. Even though TRPA1 activation by ligands has been studied extensively, the molecular machinery regulating TRPA1 is only poorly understood. Using an unbiased proteomics-based approach we uncovered the physical association of Annexin A2 (AnxA2) with native TRPA1 in mouse sensory neurons. AnxA2 is enriched in a subpopulation of sensory neurons and coexpressed with TRPA1. Furthermore, we observe an increase of TRPA1 membrane levels in cultured sensory neurons from AnxA2-deficient mice. This is reflected by our calcium imaging experiments revealing higher responsiveness upon TRPA1 activation in AnxA2-deficient neurons. In vivo these findings are associated with enhanced nocifensive behaviors specifically in TRPA1-dependent paradigms of acute and inflammatory pain, while heat and mechanical sensitivity as well as TRPV1-mediated pain are preserved in AnxA2-deficient mice. Our results support a model whereby AnxA2 limits the availability of TRPA1 channels to regulate nociceptive signaling in vertebrates. PMID:25355205

  14. Annexin A2 regulates TRPA1-dependent nociception.

    PubMed

    Avenali, Luca; Narayanan, Pratibha; Rouwette, Tom; Cervellini, Ilaria; Sereda, Michael; Gomez-Varela, David; Schmidt, Manuela

    2014-10-29

    The transient receptor potential A1 (TRPA1) channel is essential for vertebrate pain. Even though TRPA1 activation by ligands has been studied extensively, the molecular machinery regulating TRPA1 is only poorly understood. Using an unbiased proteomics-based approach we uncovered the physical association of Annexin A2 (AnxA2) with native TRPA1 in mouse sensory neurons. AnxA2 is enriched in a subpopulation of sensory neurons and coexpressed with TRPA1. Furthermore, we observe an increase of TRPA1 membrane levels in cultured sensory neurons from AnxA2-deficient mice. This is reflected by our calcium imaging experiments revealing higher responsiveness upon TRPA1 activation in AnxA2-deficient neurons. In vivo these findings are associated with enhanced nocifensive behaviors specifically in TRPA1-dependent paradigms of acute and inflammatory pain, while heat and mechanical sensitivity as well as TRPV1-mediated pain are preserved in AnxA2-deficient mice. Our results support a model whereby AnxA2 limits the availability of TRPA1 channels to regulate nociceptive signaling in vertebrates.

  15. Trait anxiety affects the orofacial nociceptive response in rats.

    PubMed

    Matos, Anne Caroline C; Teixeira-Silva, Flavia; Goes, Tiago C; Quintans, Lucindo J; Albuquerque, Ricardo Luiz C; Bonjardim, Leonardo R

    2011-01-01

    The aims of the present study were to assess the influence of: a) trait anxiety on orofacial pain; and b) orofacial pain on state anxiety. Forty-four rats were initially exposed to the free-exploratory paradigm for the evaluation of their anxiety profiles. In accordance to the parameter "Percentage of time in the novel side", the animals were considered as presenting high or low levels of trait anxiety when presenting values below the 1st quartile, or above the 3rd quartile, respectively. A week later, formalin-1.5% was injected into the upper lip of each animal. The behavioural nociceptive response, characterized by increased orofacial rubbing (OR), was quantified for 30 minutes, as follows: Total time OR (0-30 minutes: total pain), 1st phase OR (0-6 minutes: neurogenic pain), and 2nd phase OR (12-30 minutes: inflammatory pain). Immediately after this test, but still under the effect of formalin, the rats were submitted to the Elevated Plus-maze test (EPM). The results showed that the high trait anxiety individuals presented higher frequency of OR than the low trait anxiety ones, except during the neurogenic pain period. However, no correlation was found between OR frequency and levels of state anxiety presented on the EPM. In conclusion, the animals presenting higher anxiety profiles were the most susceptible to orofacial pain, nevertheless, orofacial pain did not influence state anxiety.

  16. Mechanisms Involved in the Nociception Triggered by the Venom of the Armed Spider Phoneutria nigriventer

    PubMed Central

    Gewehr, Camila; Oliveira, Sara Marchesan; Rossato, Mateus Fortes; Trevisan, Gabriela; Dalmolin, Gerusa Duarte; Rigo, Flávia Karine; de Castro Júnior, Célio José; Cordeiro, Marta Nascimento; Ferreira, Juliano; Gomez, Marcus V.

    2013-01-01

    Background The frequency of accidental spider bites in Brazil is growing, and poisoning due to bites from the spider genus Phoneutria nigriventer is the second most frequent source of such accidents. Intense local pain is the major symptom reported after bites of P. nigriventer, although the mechanisms involved are still poorly understood. Therefore, the aim of this study was to identify the mechanisms involved in nociception triggered by the venom of Phoneutria nigriventer (PNV). Methodology/Principal Findings Twenty microliters of PNV or PBS was injected into the mouse paw (intraplantar, i.pl.). The time spent licking the injected paw was considered indicative of the level of nociception. I.pl. injection of PNV produced spontaneous nociception, which was reduced by arachnid antivenin (ArAv), local anaesthetics, opioids, acetaminophen and dipyrone, but not indomethacin. Boiling or dialysing the venom reduced the nociception induced by the venom. PNV-induced nociception is not dependent on glutamate or histamine receptors or on mast cell degranulation, but it is mediated by the stimulation of sensory fibres that contain serotonin 4 (5-HT4) and vanilloid receptors (TRPV1). We detected a kallikrein-like kinin-generating enzyme activity in tissue treated with PNV, which also contributes to nociception. Inhibition of enzymatic activity or administration of a receptor antagonist for kinin B2 was able to inhibit the nociception induced by PNV. PNV nociception was also reduced by the blockade of tetrodotoxin-sensitive Na+ channels, acid-sensitive ion channels (ASIC) and TRPV1 receptors. Conclusion/Significance Results suggest that both low- and high-molecular-weight toxins of PNV produce spontaneous nociception through direct or indirect action of kinin B2, TRPV1, 5-HT4 or ASIC receptors and voltage-dependent sodium channels present in sensory neurons but not in mast cells. Understanding the mechanisms involved in nociception caused by PNV are of interest not only for

  17. Effects of Aging on Current Vocalization Threshold in Mice Measured by a Novel Nociception Assay

    PubMed Central

    Finkel, Julia C.; Besch, Virginia G.; Hergen, Adrienne; Kakareka, John; Pohida, Thomas; Melzer, Jonathan M.; Koziol, Deloris; Wesley, Robert; Quezado, Zenaide M. N.

    2016-01-01

    Background Age-related changes in nociception have been extensively studied in the past decades. However, it remains unclear whether in addition to the increased incidence of chronic illness, age-related changes in nociception contribute to increased prevalence of pain in the elderly. Although a great deal of evidence suggests that nociception thresholds increase with aging, other studies yield disparate results. The aim of this investigation was to longitudinally determine the effect of aging on nociception. Methods The authors developed a nociception assay for mice using electrical stimuli at 2,000, 250, and 5 Hz that reportedly stimulate Aβ, Aδ, and C sensory nerve fibers, respectively. A system was designed to automate a method that elicits and detects pain-avoiding behavior in mice. Using a Latin square design, the authors measured current vocalization thresholds serially over the course of mice’s life span. Results For 2,000-Hz (Aβ), 250-Hz (Aδ), and 5-Hz (C) electrical stimuli, current vocalization thresholds first decreases and then increases with aging following a U-shaped pattern (P < 0.001). In addition, average current vocalization thresholds at youth and senescence are significantly higher than those at middle age for the 250-Hz (Aδ) and 5-Hz (C fiber) electrical stimulus (P < 0.05). Conclusions Using a novel and noninjurious nociception assay, the authors showed that over the life span of mice, current vocalization threshold to electrical stimuli changes in a U-shaped pattern. The findings support the notion that age-related changes in nociception are curvilinear, and to properly study and treat pain, the age of subjects should be considered. PMID:16871071

  18. Nociception- and anxiety-like behavior in rats submitted to different periods of restraint stress.

    PubMed

    Gameiro, Gustavo Hauber; Gameiro, Paula Hauber; Andrade, Annicele da Silva; Pereira, Lígia Ferrinho; Arthuri, Mariana Trevisani; Marcondes, Fernanda Klein; Veiga, Maria Cecília Ferraz de Arruda

    2006-04-15

    The aim of this study was to evaluate the effect of acute, sub-chronic and chronic stress on nociception induced by formalin injection in rats' temporomandibular joint (TMJ). It was evaluated the relation between blood levels of adrenocorticotropin, corticosterone, the levels of anxiety and nociceptive responses recorded after different stress protocols. Animals were initially submitted to acute restraint stress (15; 30 min and 1 h), or exposed to sub-chronic (3 days-1 h/day) or chronic stress (40 days-1 h/day). Then, animals were (1) killed immediately to collect blood for hormonal determinations; or (2) submitted to the elevated plus-maze to evaluate anxiety; or (3) submitted to the TMJ formalin test to evaluate nociception. It was also evaluated the role of serotoninergic and opioid systems in nociceptive changes induced by stress. For this, the serotonin-selective reuptake inhibitor (fluoxetine 10 mg/kg) and the opioid agonist (morphine 1-5 mg/kg) were administered before the nociception test. All stress protocols significantly raised the levels of ACTH or corticosterone, as well as the anxiety behavior. In relation to nociception, the chronic stressed animals showed an increase in nociceptive responses (hyperalgesia). In this group, there was a reduction in the morphine analgesic effects, suggesting dysfunction in the endogenous opioid system. Fluoxetine had an analgesic effect in both stressed and control groups, although this effect was more evident in the stressed group. It was concluded that stress-induced hyperalgesia may result from changes in the serotoninergic and opioid systems, which can explain, at least in part, the important link between stress and orofacial pain.

  19. Alfaxalone Anaesthesia Facilitates Electrophysiological Recordings of Nociceptive Withdrawal Reflexes in Dogs (Canis familiaris)

    PubMed Central

    Hunt, James; Murrell, Jo; Knazovicky, David; Harris, John; Kelly, Sara; Knowles, Toby G.; Lascelles, B. Duncan X.

    2016-01-01

    Naturally occurring canine osteoarthritis represents a welfare issue for affected dogs (Canis familiaris), but is also considered very similar to human osteoarthritis and has therefore been proposed as a model of disease in humans. Central sensitisation is recognized in human osteoarthritis sufferers but identification in dogs is challenging. Electromyographic measurement of responses to nociceptive stimulation represents a potential means of investigating alterations in central nociceptive processing, and has been evaluated in conscious experimental dogs, but is likely to be aversive. Development of a suitable anaesthetic protocol in experimental dogs, which facilitated electrophysiological nociceptive withdrawal reflex assessment, may increase the acceptability of using the technique in owned dogs with naturally occurring osteoarthritis. Seven purpose bred male hound dogs underwent electromyographic recording sessions in each of three states: acepromazine sedation, alfaxalone sedation, and alfaxalone anaesthesia. Electromyographic responses to escalating mechanical and electrical, and repeated electrical, stimuli were recorded. Subsequently the integral of both early and late rectified responses was calculated. Natural logarithms of the integral values were analysed within and between the three states using multi level modeling. Alfaxalone increased nociceptive thresholds and decreased the magnitude of recorded responses, but characteristics of increasing responses with increasing stimulus magnitude were preserved. Behavioural signs of anxiety were noted in two out of seven dogs during recordings in the acepromazine sedated state. There were few significant differences in response magnitude or nociceptive threshold between the two alfaxalone states. Following acepromazine premedication, induction of anaesthesia with 1–2 mg kg-1 alfaxalone, followed by a continuous rate infusion in the range 0.075–0.1 mg kg-1 min-1 produced suitable conditions to enable

  20. Brain measures of nociception using near-infrared spectroscopy in patients undergoing routine screening colonoscopy.

    PubMed

    Becerra, Lino; Aasted, Christopher M; Boas, David A; George, Edward; Yücel, Meryem A; Kussman, Barry D; Kelsey, Peter; Borsook, David

    2016-04-01

    Colonoscopy is an invaluable tool for the screening and diagnosis of many colonic diseases. For most colonoscopies, moderate sedation is used during the procedure. However, insufflation of the colon produces a nociceptive stimulus that is usually accompanied by facial grimacing/groaning while under sedation. The objective of this study was to evaluate whether a nociceptive signal elicited by colonic insufflation could be measured from the brain. Seventeen otherwise healthy patients (age 54.8 ± 9.1; 6 female) undergoing routine colonoscopy (ie, no history of significant medical conditions) were monitored using near-infrared spectroscopy (NIRS). Moderate sedation was produced using standard clinical protocols for midazolam and meperidine, titrated to effect. Near-infrared spectroscopy data captured during the procedure was analyzed offline to evaluate the brains' responses to nociceptive stimuli evoked by the insufflation events (defined by physician or observing patients' facial responses). Analysis of NIRS data revealed a specific, reproducible prefrontal cortex activity corresponding to times when patients grimaced. The pattern of the activation is similar to that previously observed during nociceptive stimuli in awake healthy individuals, suggesting that this approach may be used to evaluate brain activity evoked by nociceptive stimuli under sedation, when there is incomplete analgesia. Although some patients report recollection of procedural pain after the procedure, the effects of repeated nociceptive stimuli in surgical patients may contribute to postoperative changes including chronic pain. The results from this study indicate that NIRS may be a suitable technology for continuous nociceptive afferent monitoring in patients undergoing sedation and could have applications under sedation or anesthesia.

  1. Tuberoinfundibular peptide of 39 residues (TIP39) signaling modulates acute and tonic nociception

    PubMed Central

    Dimitrov, Eugene L.; Petrus, Emily; Usdin, Ted B.

    2010-01-01

    Tuberoinfundibular peptide of 39 residues (TIP39) synthesizing neurons at the caudal border of the thalamus and in the lateral pons project to areas rich in its receptor, the parathyroid hormone 2 receptor (PTH2R). These areas include many involved in processing nociceptive information. Here we examined the potential role of TIP39 signaling in nociception using a PTH2R antagonist (HYWH) and mice with deletion of TIP39's coding sequence or PTH2R null mutation. Intracerebroventricular (icv) infusion of HYWH significantly inhibited nociceptive responses in tail-flick and hot-plate tests and attenuated the nociceptive response to hindpaw formalin injection. TIP39-KO and PTH2R-KO had increased response latency in the 55 °C hot-plate test and reduced responses in the hindpaw formalin test. The tail-flick test was not affected in either KO line. Thermal hypoalgesia in KO mice was dose-dependently reversed by systemic administration of the cannabinoid receptor 1 (CB1) antagonist rimonabant, which did not affect nociception in wild-type (WT). Systemic administration of the cannabinoid agonist CP 55,940 did not affect nociception in KO mice at a dose effective in WT. WT mice administered HYWH icv, and both KOs, had significantly increased stress-induced analgesia (SIA). Rimonabant blocked the increased SIA in TIP39-KO, PTH2R-KO or after HYWH infusion. CB1 and FAAH mRNA were decreased and increased, respectively, in the basolateral amygdala of TIP39-KO mice. These data suggest that TIP39 signaling modulates nociception, very likely by inhibiting endocannabinoid circuitry at a supraspinal level. We infer a new central mechanism for endocannabinoid regulation, via TIP39 acting on the PTH2R in discrete brain regions. PMID:20696160

  2. The nociceptive and anti-nociceptive effects of bee venom injection and therapy: A double-edged sword

    PubMed Central

    Chen, Jun; Lariviere, William R.

    2010-01-01

    Bee venom injection as a therapy, like many other complementary and alternative medicine approaches, has been used for thousands of years to attempt to alleviate a range of diseases including arthritis. More recently, additional theraupeutic goals have been added to the list of diseases making this a critical time to evaluate the evidence for the beneficial and adverse effects of bee venom injection. Although reports of pain reduction (analgesic and antinociceptive) and anti-inflammatory effects of bee venom injection are accumulating in the literature, it is common knowledge that bee venom stings are painful and produce inflammation. In addition, a significant number of studies have been performed in the past decade highlighting that injection of bee venom and components of bee venom produce significant signs of pain or nociception, inflammation and many effects at multiple levels of immediate, acute and prolonged pain processes. This report reviews the extensive new data regarding the deleterious effects of bee venom injection in people and animals, our current understanding of the responsible underlying mechanisms and critical venom components, and provides a critical evaluation of reports of the beneficial effects of bee venom injection in people and animals and the proposed underlying mechanisms. Although further studies are required to make firm conclusions, therapeutic bee venom injection may be beneficial for some patients, but may also be harmful. This report highlights key patterns of results, critical shortcomings, and essential areas requiring further study. PMID:20558236

  3. Teleantagonism: A pharmacodynamic property of the primary nociceptive neuron

    PubMed Central

    Funez, Mani I.; Ferrari, Luiz F.; Duarte, Djane B.; Sachs, Daniela; Cunha, Fernando Q.; Lorenzetti, Berenice B.; Parada, Carlos A.; Ferreira, Sérgio H.

    2008-01-01

    Previous work from our group showed that intrathecal (i.t.) administration of substances such as glutamate, NMDA, or PGE2 induced sensitization of the primary nociceptive neuron (PNN hypernociception) that was inhibited by a distal intraplantar (i.pl.) injection of either morphine or dipyrone. This pharmacodynamic phenomenon is referred to in the present work as “teleantagonism”. We previously observed that the antinociceptive effect of i.t. morphine could be blocked by injecting inhibitors of the NO signaling pathway in the paw (i.pl.), and this effect was used to explain the mechanism of opioid-induced peripheral analgesia by i.t. administration. The objective of the present investigation was to determine whether this teleantagonism phenomenon was specific to this biochemical pathway (NO) or was a general property of the PNNs. Teleantagonism was investigated by administering test substances to the two ends of the PNN (i.e., to distal and proximal terminals; i.pl. plus i.t. or i.t. plus i.pl. injections). We found teleantagonism when: (i) inhibitors of the NO signaling pathway were injected distally during the antinociception induced by opioid agonists; (ii) a nonselective COX inhibitor was tested against PNN sensitization by IL-1β; (iii) selective opioid-receptor antagonists tested against antinociception induced by corresponding selective agonists. Although the dorsal root ganglion seems to be an important site for drug interactions, the teleantagonism phenomenon suggests that, in PNNs, a local sensitization spreads to the entire cell and constitutes an intriguing and not yet completely understood pharmacodynamic property of this group of neurons. PMID:18799742

  4. Inhibition of nociceptive responses after systemic administration of amidated kyotorphin

    PubMed Central

    Ribeiro, MMB; Pinto, A; Pinto, M; Heras, M; Martins, I; Correia, A; Bardaji, E; Tavares, I; Castanho, M

    2011-01-01

    BACKGROUND AND PURPOSE Kyotorphin (KTP; L-Tyr-L-Arg), an endogenous neuropeptide, is potently analgesic when delivered directly to the central nervous system. Its weak analgesic effects after systemic administration have been explained by inability to cross the blood–brain barrier (BBB) and detract from the possible clinical use of KTP as an analgesic. In this study, we aimed to increase the lipophilicity of KTP by amidation and to evaluate the analgesic efficacy of a new KTP derivative (KTP-amide – KTP-NH2). EXPERIMENTAL APPROACH We synthesized KTP-NH2. This peptide was given systemically to assess its ability to cross the BBB. A wide range of pain models, including acute, sustained and chronic inflammatory and neuropathic pain, were used to characterize analgesic efficacies of KTP-NH2. Binding to opioid receptors and toxicity were also measured. KEY RESULTS KTP-NH2, unlike its precursor KTP, was lipophilic and highly analgesic following systemic administration in several acute and chronic pain models, without inducing toxic effects or affecting motor responses and blood pressure. Binding to opioid receptors was minimal. KTP-NH2 inhibited nociceptive responses of spinal neurons. Its analgesic effects were prevented by intrathecal or i.p. administration of naloxone. CONCLUSIONS AND IMPLICATIONS Amidation allowed KTP to show good analgesic ability after systemic delivery in acute and chronic pain models. The indirect opioid-mediated actions of KTP-NH2 may explain why this compound retained its analgesic effects although the usual side effects of opioids were absent, which is a desired feature in next-generation pain medications. PMID:21366550

  5. Spinal nociceptive transmission by mechanical stimulation of bone marrow

    PubMed Central

    Tanaka, Satoshi; Sekiguchi, Takemi; Sugiyama, Daisuke; Kawamata, Mikito

    2016-01-01

    Background Since bone marrow receives innervation from A-delta and C-fibers and since an increase in intramedullary pressure in bone marrow may induce acute pain in orthopedic patients during surgery and chronic pain in patients with bone marrow edema, skeletal pain may partly originate from bone marrow. Intraosseous lesions, such as osteomyelitis and bone cancer, are also known to produce cutaneous hypersensitivity, which might be referred pain from bone. However, little is known about pain perception in bone marrow and referred pain induced by bone disease. Thus, we carried out an in vivo electrophysiological study and behavioral study to determine whether increased intraosseous pressure of the femur induces acute pain and whether increased intraosseous pressure induces referred pain in the corresponding receptive fields of the skin. Results Intraosseous balloon inflation caused spontaneous pain-related behavior and mechanical hyperalgesia and allodynia in the lumbosacral region. Single neuronal activities of spinal dorsal horn neurons were extracellularly isolated, and then evoked responses to non-noxious and noxious cutaneous stimuli and intraosseous balloon inflation were recorded. Ninety-four spinal dorsal horn neurons, which had somatic receptive fields at the lower back and thigh, were obtained. Sixty-two percent of the wide-dynamic-range neurons (24/39) and 86% of the high-threshold neurons (12/14) responded to intraosseous balloon inflation, while none of the low-threshold neurons (0/41) responded to intraosseous balloon inflation. Spinally administered morphine (1 µg) abolished balloon inflation-induced spontaneous pain-related behavior and mechanical hyperalgesia in awake rats and also suppressed evoked activities of wide-dynamic-range neurons to noxious cutaneous stimulation and intraosseous balloon inflation. Conclusions The results suggest that mechanical stimulation to bone marrow produces nociception, concomitantly producing its referred pain

  6. Sensitization of the Nociceptive System in Complex Regional Pain Syndrome

    PubMed Central

    Diedrichs, Carolina; Baron, Ralf; Gierthmühlen, Janne

    2016-01-01

    Background Complex regional pain syndrome type I (CRPS-I) is characterized by sensory, motor and autonomic abnormalities without electrophysiological evidence of a nerve lesion. Objective Aims were to investigate how sensory, autonomic and motor function change in the course of the disease. Methods 19 CRPS-I patients (17 with acute, 2 with chronic CRPS, mean duration of disease 5.7±8.3, range 1–33 months) were examined with questionnaires (LANSS, NPS, MPI, Quick DASH, multiple choice list of descriptors for sensory, motor, autonomic symptoms), motor and autonomic tests as well as quantitative sensory testing according to the German Research Network on Neuropathic Pain at two visits (baseline and 36±10.6, range 16–53 months later). Results CRPS-I patients had an improvement of sudomotor and vasomotor function, but still a great impairment of sensory and motor function upon follow-up. Although pain and mechanical detection improved upon follow-up, thermal and mechanical pain sensitivity increased, including the contralateral side. Increase in mechanical pain sensitivity and loss of mechanical detection were associated with presence of ongoing pain. Conclusions The results demonstrate that patients with CRPS-I show a sensitization of the nociceptive system in the course of the disease, for which ongoing pain seems to be the most important trigger. They further suggest that measured loss of function in CRPS-I is due to pain-induced hypoesthesia rather than a minimal nerve lesion. In conclusion, this article gives evidence for a pronociceptive pain modulation profile developing in the course of CRPS and thus helps to assess underlying mechanisms of CRPS that contribute to the maintenance of patients’ pain and disability. PMID:27149519

  7. Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies

    PubMed Central

    Mickle, Aaron D.; Shepherd, Andrew J.; Mohapatra, Durga P.

    2016-01-01

    Specialized receptors belonging to the transient receptor potential (TRP) family of ligand-gated ion channels constitute the critical detectors and transducers of pain-causing stimuli. Nociceptive TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system. Several of these TRP channels are also expressed in neurons of the central nervous system, and in non-neuronal cells that communicate with sensory nerves. Nociceptive TRPs are activated by specific physico-chemical stimuli to provide the excitatory trigger in neurons. In addition, decades of research has identified a large number of immune and neuromodulators as mediators of nociceptive TRP channel activation during injury, inflammatory and other pathological conditions. These findings have led to aggressive targeting of TRP channels for the development of new-generation analgesics. This review summarizes the complex activation and/or modulation of nociceptive TRP channels under pathophysiological conditions, and how these changes underlie acute and chronic pain conditions. Furthermore, development of small-molecule antagonists for several TRP channels as analgesics, and the positive and negative outcomes of these drugs in clinical trials are discussed. Understanding the diverse functional and modulatory properties of nociceptive TRP channels is critical to function-based drug targeting for the development of evidence-based and efficacious new generation analgesics. PMID:27854251

  8. Identification of oxytocin receptor in the dorsal horn and nociceptive dorsal root ganglion neurons.

    PubMed

    Moreno-López, Y; Martínez-Lorenzana, G; Condés-Lara, M; Rojas-Piloni, G

    2013-04-01

    Oxytocin (OT) secreted by the hypothalamo-spinal projection exerts antinociceptive effects in the dorsal horn. Electrophysiological evidence indicates that OT could exert these effects by activating OT receptors (OTR) directly on dorsal horn neurons and/or primary nociceptive afferents in the dorsal root ganglia (DRG). However, little is known about the identity of the dorsal horn and DRG neurons that express the OTR. In the dorsal horn, we found that the OTR is expressed principally in neurons cell bodies. However, neither spino-thalamic dorsal horn neurons projecting to the contralateral thalamic ventral posterolateral nucleus (VPL) and posterior nuclear group (Po) nor GABaergic dorsal horn neurons express the OTR. The OTR is not expressed in skin nociceptive terminals or in dorsal horn nociceptive fibers. In the DRG, however, the OTR is expressed predominantly in non-peptidergic C-fiber cell bodies, but not in peptidergic or mechanoreceptor afferents or in skin nociceptive terminals. Our results suggest that the antinociceptive effects of OT are mediated by direct activation of dorsal horn neurons and peripheral actions on nociceptive, non-peptidergic C-afferents in the DRG.

  9. FGF13 Selectively Regulates Heat Nociception by Interacting with Nav1.7.

    PubMed

    Yang, Liu; Dong, Fei; Yang, Qing; Yang, Pai-Feng; Wu, Ruiqi; Wu, Qing-Feng; Wu, Dan; Li, Chang-Lin; Zhong, Yan-Qing; Lu, Ying-Jin; Cheng, Xiaoyang; Xu, Fu-Qiang; Chen, Limin; Bao, Lan; Zhang, Xu

    2017-02-22

    The current knowledge about heat nociception is mainly confined to the thermosensors, including the transient receptor potential cation channel V1 expressed in the nociceptive neurons of dorsal root ganglion (DRG). However, the loss of thermosensors only partially impairs heat nociception, suggesting the existence of undiscovered mechanisms. We found that the loss of an intracellular fibroblast growth factor (FGF), FGF13, in the mouse DRG neurons selectively abolished heat nociception. The noxious heat stimuli could not evoke the sustained action potential firing in FGF13-deficient DRG neurons. Furthermore, FGF13 interacted with the sodium channel Nav1.7 in a heat-facilitated manner. FGF13 increased Nav1.7 sodium currents and maintained the membrane localization of Nav1.7 during noxious heat stimulation, enabling the sustained firing of action potentials. Disrupting the FGF13/Nav1.7 interaction reduced the heat-evoked action potential firing and nociceptive behavior. Thus, beyond the thermosensors, the FGF13/Nav1.7 complex is essential for sustaining the transmission of noxious heat signals.

  10. Influence of early neonatal experience on nociceptive responses and analgesic effects in rats.

    PubMed

    Dickinson, Amy L; Leach, Matthew C; Flecknell, Paul A

    2009-01-01

    Early maternal separation has profound effects on nociception in rats. Cross-fostering is a standard husbandry procedure used by some commercial breeders. This study aimed to determine if cross-fostering altered nociception and the analgesic efficacy of buprenorphine and morphine. At seven and nine weeks of age, an elevated plus maze was used to assess anxiety and Hargreaves apparatus was used to measure thermal nociception at two intensities in cross-fostered and naturally-reared rats. At 10 weeks of age these rats were assigned to one of three treatment groups: saline, buprenorphine or morphine. The Hargreaves apparatus was used to evaluate the effect of analgesics on nociception. Differences were observed in nociception between the cross-fostered and naturally-reared rats at both intensities. At the lower intensity no significant differences were seen between the cross-fostered and naturally-reared rats post-administration of an analgesic. At the higher intensity significant differences were apparent. Morphine was less effective in inducing analgesia to thermal stimuli in cross-fostered rats compared with naturally-reared rats, whereas the opposite was found with buprenorphine which had a more pronounced analgesic effect in the cross-fostered rats. No significant differences in performance on an elevated plus maze were demonstrated between the cross-fostered and naturally-reared rats.

  11. Oral manganese as an MRI contrast agent for the detection of nociceptive activity.

    PubMed

    Jacobs, Kathleen E; Behera, Deepak; Rosenberg, Jarrett; Gold, Garry; Moseley, Michael; Yeomans, David; Biswal, Sandip

    2012-04-01

    The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T(1)-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D(3) by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T(1)-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity.

  12. Neuronal NTPDase3 Mediates Extracellular ATP Degradation in Trigeminal Nociceptive Pathway

    PubMed Central

    Ma, Lihua; Trinh, Thu; Ren, Yanfang; Dirksen, Robert T.; Liu, Xiuxin

    2016-01-01

    ATP induces pain via activation of purinergic receptors in nociceptive sensory nerves. ATP signaling is terminated by ATP hydrolysis mediated by cell surface-localized ecto-nucleotidases. Using enzymatic histochemical staining, we show that ecto-ATPase activity is present in mouse trigeminal nerves. Using immunofluorescence staining, we found that ecto-NTPDase3 is expressed in trigeminal nociceptive neurons and their projections to the brainstem. In addition, ecto-ATPase activity and ecto-NTPDase3 are also detected in the nociceptive outermost layer of the trigeminal subnucleus caudalis. Furthermore, we demonstrate that incubation with anti-NTPDase3 serum reduces extracellular ATP degradation in the nociceptive lamina of both the trigeminal subnucleus caudalis and the spinal cord dorsal horn. These results are consistent with neuronal NTPDase3 activity modulating pain signal transduction and transmission by affecting extracellular ATP hydrolysis within the trigeminal nociceptive pathway. Thus, disruption of trigeminal neuronal NTPDase3 expression and localization to presynaptic terminals during chronic inflammation, local constriction and injury may contribute to the pathogenesis of orofacial neuropathic pain. PMID:27706204

  13. Nociceptive-Evoked Potentials Are Sensitive to Behaviorally Relevant Stimulus Displacements in Egocentric Coordinates

    PubMed Central

    Di Stefano, G.; Stubbs, M. T.; Djeugam, B.; Liang, M.

    2016-01-01

    Abstract Feature selection has been extensively studied in the context of goal-directed behavior, where it is heavily driven by top-down factors. A more primitive version of this function is the detection of bottom-up changes in stimulus features in the environment. Indeed, the nervous system is tuned to detect fast-rising, intense stimuli that are likely to reflect threats, such as nociceptive somatosensory stimuli. These stimuli elicit large brain potentials maximal at the scalp vertex. When elicited by nociceptive laser stimuli, these responses are labeled laser-evoked potentials (LEPs). Although it has been shown that changes in stimulus modality and increases in stimulus intensity evoke large LEPs, it has yet to be determined whether stimulus displacements affect the amplitude of the main LEP waves (N1, N2, and P2). Here, in three experiments, we identified a set of rules that the human nervous system obeys to identify changes in the spatial location of a nociceptive stimulus. We showed that the N2 wave is sensitive to: (1) large displacements between consecutive stimuli in egocentric, but not somatotopic coordinates; and (2) displacements that entail a behaviorally relevant change in the stimulus location. These findings indicate that nociceptive-evoked vertex potentials are sensitive to behaviorally relevant changes in the location of a nociceptive stimulus with respect to the body, and that the hand is a particularly behaviorally important site. PMID:27419217

  14. What’s Coming Near? The Influence of Dynamical Visual Stimuli on Nociceptive Processing

    PubMed Central

    De Paepe, Annick L.; Crombez, Geert; Legrain, Valéry

    2016-01-01

    Objects approaching us may pose a threat, and signal the need to initiate defensive behavior. Detecting these objects early is crucial to either avoid the object or prepare for contact most efficiently. This requires the construction of a coherent representation of our body, and the space closely surrounding our body, i.e. the peripersonal space. This study, with 27 healthy volunteers, investigated how the processing of nociceptive stimuli applied to the hand is influenced by dynamical visual stimuli either approaching or receding from the hand. On each trial a visual stimulus was either approaching or receding the participant’s left or right hand. At different temporal delays from the onset of the visual stimulus, a nociceptive stimulus was applied either at the same or the opposite hand, so that it was presented when the visual stimulus was perceived at varying distances from the hand. Participants were asked to respond as fast as possible at which side they perceived a nociceptive stimulus. We found that reaction times were fastest when the visual stimulus appeared near the stimulated hand. Moreover, investigating the influence of the visual stimuli along the continuous spatial range (from near to far) showed that approaching lights had a stronger spatially dependent effect on nociceptive processing, compared to receding lights. These results suggest that the coding of nociceptive information in a peripersonal frame of reference may constitute a safety margin around the body that is designed to protect it from potential physical threat. PMID:27224421

  15. Roles of prefrontal cortex and paraventricular thalamus in affective and mechanical components of visceral nociception.

    PubMed

    Jurik, Angela; Auffenberg, Eva; Klein, Sabine; Deussing, Jan M; Schmid, Roland M; Wotjak, Carsten T; Thoeringer, Christoph K

    2015-12-01

    Visceral pain represents a major clinical challenge in the management of many gastrointestinal disorders, eg, pancreatitis. However, cerebral neurobiological mechanisms underlying visceral nociception are poorly understood. As a representative model of visceral nociception, we applied cerulein hyperstimulation in C57BL6 mice to induce acute pancreatitis and performed a behavioral test battery and c-Fos staining of brains. We observed a specific pain phenotype and a significant increase in c-Fos immunoreactivity in the paraventricular nucleus of the thalamus (PVT), the periaqueductal gray, and the medial prefrontal cortex (mPFC). Using neuronal tracing, we observed projections of the PVT to cortical layers of the mPFC with contacts to inhibitory GABAergic neurons. These inhibitory neurons showed more activation after cerulein treatment suggesting thalamocortical "feedforward inhibition" in visceral nociception. The activity of neurons in pancreatitis-related pain centers was pharmacogenetically modulated by designer receptors exclusively activated by designer drugs, selectively and cell type specifically expressed in target neurons using adeno-associated virus-mediated gene transfer. Pharmacogenetic inhibition of PVT but not periaqueductal gray neurons attenuated visceral pain and induced an activation of the descending inhibitory pain pathway. Activation of glutamatergic principle neurons in the mPFC, but not inhibitory neurons, also reversed visceral nociception. These data reveal novel insights into central pain processing that underlies visceral nociception and may trigger the development of novel, potent centrally acting analgesic drugs.

  16. Long-term gender behavioral vulnerability after nociceptive neonatal formalin stimulation in rats.

    PubMed

    Negrigo, Aline; Medeiros, Magda; Guinsburg, Ruth; Covolan, Luciene

    2011-03-03

    The role of sex and gender in accounting for individual pain behaviors is poorly understood. The present study was conducted to determine whether neonatal nociceptive stimuli at postnatal day 1 (PD1) in rats would lead to a differential behavioral impact based on gender. Animals were divided in 4 groups according to treatment (two injections of 4% formalin into the pad of right paws at PD1 or control) and gender. The sensory threshold and cognition tests were performed in adult rats using the hot plate, open field, elevated plus maze and forced swim tests. The number of paw licks was higher in females and in formalin-treated rats (P=0.02), but without interaction between gender and treatment. Exploratory activity was reduced in males (P<0.01), especially in the nociceptive group (P<0.01). Anxiety levels were higher in the female-nociceptive group (P<0.05). Depression-like behavior was more evident among females, independent of treatment. We concluded that a single acute nociceptive stimulation early in development does not affect nociception and depressive behaviors, but is able to alter the exploratory behavior and anxiety levels in adulthood in a gender specific manner.

  17. Sida cordifolia leaf extract reduces the orofacial nociceptive response in mice.

    PubMed

    Bonjardim, L R; Silva, A M; Oliveira, M G B; Guimarães, A G; Antoniolli, A R; Santana, M F; Serafini, M R; Santos, R C; Araújo, A A S; Estevam, C S; Santos, M R V; Lyra, A; Carvalho, R; Quintans-Júnior, L J; Azevedo, E G; Botelho, M A

    2011-08-01

    In this study, we describe the antinociceptive activity of the ethanol extract (EE), chloroform (CF) and methanol (MF) fractions obtained from Sida cordifolia, popularly known in Brazil as "malva branca" or "malva branca sedosa". Leaves of S. cordifolia were used to produce the crude ethanol extract and after CF and MF. Experiments were conducted on Swiss mice using the glutamate and formalin-induced orofacial nociception. In the formalin test, all doses of EE, CF and MF significantly reduced the orofacial nociception in the first (p < 0.001) and second phase (p < 0.001), which was also naloxone-sensitive. In the glutamate-induced nociception test, only CF and MF significantly reduced the orofacial nociceptive behavior with inhibition percentage values of 48.1% (100 mg/kg, CF), 56.1% (200 mg/kg, CF), 66.4% (400 mg/kg, CF), 48.2 (200 mg/kg, MF) and 60.1 (400 mg/kg, MF). Furthermore, treatment of the animals with EE, CF and MF was not able to promote motor activity changes. These data demonstrate that S. cordifolia has a pronounced antinociceptive activity on orofacial nociception. However, pharmacological and chemical studies are necessary in order to characterize the responsible mechanisms for this antinociceptive action and also to identify other bioactive compounds present in S. cordifolia.

  18. SCH 58261 differentially influences quinolinic acid-induced effects in striatal and in hippocampal slices.

    PubMed

    Tebano, Maria Teresa; Domenici, Maria Rosaria; Popoli, Patrizia

    2002-08-30

    The influence of the adenosine A(2A) receptor antagonist SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-trizolo[1,5-c] pyrimidine) (50, 200 nM, 1 microM) on quinolinic acid effects has been studied in rat striatal and hippocampal slices. Quinolinic acid induced disappearance of field potentials at concentrations of 500 microM and 2 mM in hippocampal and corticostriatal slices, respectively. We found that 1 microM SCH 58261 prevented quinolinic acid-induced field potential disappearance in corticostriatal but not in hippocampal slices. This finding demonstrates that the peculiar binding profile of SCH 58261 and the predominance in the hippocampus of "atypical" adenosine A(2A) receptor population (not recognized by SCH 58261) could have a functional relevance in the occurrence of region-specific neuroprotective effects.

  19. Effects of sodium bicarbonate on butyric acid-induced epithelial cell damage in vitro.

    PubMed

    Takigawa, Satoko; Sugano, Naoyuki; Ochiai, Kuniyasu; Arai, Noriyuki; Ota, Noriko; Ito, Koichi

    2008-12-01

    Butyric acid is detected in periodontal pockets and is thought to be involved in the initiation and progression of periodontal disease. We examined the effects of sodium bicarbonate on the butyric acid-induced epithelial cell damage. The human gingival carcinoma cell line Ca9-22 was cultured in medium that contained butyric acid with or without sodium bicarbonate. The viability of cells treated with sodium bicarbonate was significantly higher than that of cells treated with butyric acid alone. The effects of butyric acid on ICAM-1 expression were significantly improved by sodium bicarbonate. Within the limitations of this in vitro study, sodium bicarbonate was indicated to be a useful therapeutic agent to reduce the butyric acid-induced periodontal tissue damage.

  20. Acid-inducible proton influx currents in the plasma membrane of murine osteoclast-like cells.

    PubMed

    Kuno, Miyuki; Li, Guangshuai; Moriura, Yoshie; Hino, Yoshiko; Kawawaki, Junko; Sakai, Hiromu

    2016-05-01

    Acidification of the resorption pits, which is essential for dissolving bone, is produced by secretion of protons through vacuolar H(+)-ATPases in the plasma membrane of bone-resorbing cells, osteoclasts. Consequently, osteoclasts face highly acidic extracellular environments, where the pH gradient across the plasma membrane could generate a force driving protons into the cells. Proton influx mechanisms during the acid exposure are largely unknown, however. In this study, we investigated extracellular-acid-inducible proton influx currents in osteoclast-like cells derived from a macrophage cell line (RAW264). Decreasing extracellular pH to <5.5 induced non-ohmic inward currents. The reversal potentials depended on the pH gradients across the membrane and were independent of concentrations of Na(+), Cl(-), and HCO3 (-), suggesting that they were carried largely by protons. The acid-inducible proton influx currents were not inhibited by amiloride, a widely used blocker for cation channels/transporters, or by 4,4'-diisothiocyanato-2,2'-stilbenesulfonate(DIDS) which blocks anion channels/transporters. Additionally, the currents were not significantly affected by V-ATPase inhibitors, bafilomycin A1 and N,N'-dicyclohexylcarbodiimide. Extracellular Ca(2+) (10 mM) did not affect the currents, but 1 mM ZnCl2 decreased the currents partially. The intracellular pH in the vicinity of the plasma membrane was dropped by the acid-inducible H(+) influx currents, which caused overshoot of the voltage-gated H(+) channels after removal of acids. The H(+) influx currents were smaller in undifferentiated, mononuclear RAW cells and were negligible in COS7 cells. These data suggest that the acid-inducible H(+) influx (H(+) leak) pathway may be an additional mechanism modifying the pH environments of osteoclasts upon exposure to strong acids.

  1. Autophagy Protects against Palmitic Acid-Induced Apoptosis in Podocytes in vitro.

    PubMed

    Jiang, Xu-Shun; Chen, Xue-Mei; Wan, Jiang-Min; Gui, Hai-Bo; Ruan, Xiong-Zhong; Du, Xiao-Gang

    2017-02-22

    Autophagy is a highly conserved degradation process that is involved in the clearance of proteins and damaged organelles to maintain intracellular homeostasis and cell integrity. Type 2 diabetes is often accompanied by dyslipidemia with elevated levels of free fatty acids (FFAs). Podocytes, as an important component of the filtration barrier, are susceptible to lipid disorders. The loss of podocytes causes proteinuria, which is involved in the pathogenesis of diabetic nephropathy. In the present study, we demonstrated that palmitic acid (PA) promoted autophagy in podocytes. We further found that PA increased the production of reactive oxygen species (ROS) in podocytes and that NAC (N-acetyl-cysteine), a potent antioxidant, significantly eliminated the excessive ROS and suppressed autophagy, indicating that the increased generation of ROS was associated with the palmitic acid-induced autophagy in podocytes. Moreover, we also found that PA stimulation decreased the mitochondrial membrane potential in podocytes and induced podocyte apoptosis, while the inhibition of autophagy by chloroquine (CQ) enhanced palmitic acid-induced apoptosis accompanied by increased ROS generation, and the stimulation of autophagy by rapamycin (Rap) remarkably suppressed palmitic acid-induced ROS generation and apoptosis. Taken together, these in vitro findings suggest that PA-induced autophagy in podocytes is mediated by ROS production and that autophagy plays a protective role against PA-induced podocyte apoptosis.

  2. Protective effect of hispidulin on kainic acid-induced seizures and neurotoxicity in rats.

    PubMed

    Lin, Tzu Yu; Lu, Cheng Wei; Wang, Su Jane; Huang, Shu Kuei

    2015-05-15

    Hispidulin is a flavonoid compound which is an active ingredient in a number of traditional Chinese medicinal herbs, and it has been reported to inhibit glutamate release. The purpose of this study was to investigate whether hispidulin protects against seizures induced by kainic acid, a glutamate analog with excitotoxic properties. The results indicated that intraperitoneally administering hispidulin (10 or 50mg/kg) to rats 30 min before intraperitoneally injecting kainic acid (15 mg/kg) increased seizure latency and decreased seizure score. In addition, hispidulin substantially attenuated kainic acid-induced hippocampal neuronal cell death, and this protective effect was accompanied by the suppression of microglial activation and the production of proinflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α in the hippocampus. Moreover, hispidulin reduced kainic acid-induced c-Fos expression and the activation of mitogen-activated protein kinases in the hippocampus. These data suggest that hispidulin has considerable antiepileptic, neuroprotective, and antiinflammatory effects on kainic acid-induced seizures in rats.

  3. Autophagy Protects against Palmitic Acid-Induced Apoptosis in Podocytes in vitro

    PubMed Central

    Jiang, Xu-shun; Chen, Xue-mei; Wan, Jiang-min; Gui, Hai-bo; Ruan, Xiong-zhong; Du, Xiao-gang

    2017-01-01

    Autophagy is a highly conserved degradation process that is involved in the clearance of proteins and damaged organelles to maintain intracellular homeostasis and cell integrity. Type 2 diabetes is often accompanied by dyslipidemia with elevated levels of free fatty acids (FFAs). Podocytes, as an important component of the filtration barrier, are susceptible to lipid disorders. The loss of podocytes causes proteinuria, which is involved in the pathogenesis of diabetic nephropathy. In the present study, we demonstrated that palmitic acid (PA) promoted autophagy in podocytes. We further found that PA increased the production of reactive oxygen species (ROS) in podocytes and that NAC (N-acetyl-cysteine), a potent antioxidant, significantly eliminated the excessive ROS and suppressed autophagy, indicating that the increased generation of ROS was associated with the palmitic acid-induced autophagy in podocytes. Moreover, we also found that PA stimulation decreased the mitochondrial membrane potential in podocytes and induced podocyte apoptosis, while the inhibition of autophagy by chloroquine (CQ) enhanced palmitic acid-induced apoptosis accompanied by increased ROS generation, and the stimulation of autophagy by rapamycin (Rap) remarkably suppressed palmitic acid-induced ROS generation and apoptosis. Taken together, these in vitro findings suggest that PA-induced autophagy in podocytes is mediated by ROS production and that autophagy plays a protective role against PA-induced podocyte apoptosis. PMID:28225005

  4. Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats.

    PubMed

    Kumar, Hariom; Sharma, Bhupesh

    2016-01-01

    Autism is a neurodevelopment disorder. One percent worldwide population suffers with autism and males suffer more than females. Microglia plays an important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. The present study has been designed to investigate the role of minocycline in prenatal valproic acid induced autism in rats. Animals with prenatal valproic acid have reduced social interaction (three chamber social behaviour apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complexes I, II, IV). Furthermore, prenatal valproic acid treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood brain barrier permeability. Treatment with minocycline significantly attenuated prenatal valproic acid induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, minocycline has also attenuated prenatal valproic acid induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behaviour, biochemistry and blood brain barrier impairment in animals, which were significantly attenuated by minocycline. Minocycline should be explored further for its therapeutic benefits in autism.

  5. Application of bifurcation analysis for determining the mechanism of coding of nociceptive signals

    NASA Astrophysics Data System (ADS)

    Dik, O. E.; Shelykh, T. N.; Plakhova, V. B.; Nozdrachev, A. D.; Podzorova, S. A.; Krylov, B. V.

    2015-10-01

    The patch clamp method is used for studying the characteristics of slow sodium channels responsible for coding of nociceptive signals. Quantitative estimates of rate constants of transitions of "normal" and pharmacologically modified activation gating mechanisms of these channels are obtained. A mathematical model of the type of Hogdkin-Huxley nociceptive neuron membrane is constructed. Cometic acid, which is a drug substance of a new nonopioid analgesic, is used as a pharmacological agent. The application of bifurcation analysis makes it possible to outline the boundaries of the region in which a periodic impulse activity is generated. This boundary separates the set of values of the model parameter for which periodic pulsation is observed from the values for which such pulsations are absent or damped. The results show that the finest effect of modulation of physical characteristic of a part of a protein molecule and its effective charge suppresses the excitability of the nociceptive neuron membrane and, hence, leads to rapid reduction of pain.

  6. Emotional modulation of pain and spinal nociception in persons with severe insomnia symptoms

    PubMed Central

    DelVentura, Jennifer L.; Terry, Ellen L.; Bartley, Emily J.; Rhudy, Jamie L.

    2013-01-01

    Background Impaired sleep enhances pain, perhaps by disrupting pain modulation. Purpose Given that emotion modulates pain, the present study examined whether emotional modulation of pain and nociception is impaired in persons with severe insomnia symptoms relative to controls. Methods Insomnia group (n=12) met ICD-10 symptoms for primary insomnia and controls (n=13) reported no sleep impairment. Participants were shown emotionally-evocative pictures (mutilation, neutral, erotica) during which suprathreshold pain stimuli were delivered to evoke pain and the nociceptive flexion reflex (NFR; physiological correlate of spinal nociception). Results Emotional responses to pictures were similar in both groups, except that subjective valence/pleasure ratings were blunted in insomnia. Emotional modulation of pain and NFR was observed in controls, but only emotional modulation of NFR was observed in insomnia. Conclusions Consistent with previous findings, pain modulation is disrupted in insomnia which might promote pain. This may stem from disrupted supraspinal circuits not disrupted brain-to-spinal cord circuits. PMID:24101292

  7. Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice.

    PubMed

    Neelakantan, Harshini; Ward, Sara Jane; Walker, Ellen Ann

    2015-08-01

    The use of prescription opioids for clinical management of pain remains problematic because of concerns about addiction associated with opioid use. Another difficulty in pain management is the increasing evidence for sex differences in pain behavior and opioid-induced behavioral effects. However, few studies have documented the abuse potential of prescription opioids as a function of pain in rodents, with significant gaps in the literature pertaining to sex differences in the interaction between pain and opioid effects. The present study evaluated the effects of an experimentally induced acute pain state (acetic acid injections) on the potency of morphine and oxycodone to produce discriminative stimulus effects in male and female C57Bl/6 mice trained to discriminate 3.2 mg/kg morphine from saline. Acetic acid injections attenuated the stimulus potency of morphine by 2.2-fold but not the stimulus potency of oxycodone in male mice. Acetic acid injections did not alter the discriminative stimulus effects of either morphine or oxycodone in female mice. The antinociceptive effects of the 2 opioids were evaluated using the acetic acid-induced stretching test. For antinociceptive effects, morphine was 2.0-fold less potent relative to oxycodone in male mice, whereas morphine and oxycodone were equipotent in female mice. Taken together, these results indicate that acetic acid-induced acute pain differentially modulates the discriminative stimulus effects of morphine in male and female mice and that this change may be related to the variable antinociceptive effectiveness of these opioids across sexes.

  8. Adaptive response to acetic acid in the highly resistant yeast species Zygosaccharomyces bailii revealed by quantitative proteomics.

    PubMed

    Guerreiro, Joana F; Mira, Nuno P; Sá-Correia, Isabel

    2012-08-01

    Zygosaccharomyces bailii is the most tolerant yeast species to acetic acid-induced toxicity, being able to grow in the presence of concentrations of this food preservative close to the legal limits. For this reason, Z. bailii is the most important microbial contaminant of acidic food products but the mechanisms behind this intrinsic resistance to acetic acid are very poorly characterized. To gain insights into the adaptive response and tolerance to acetic acid in Z. bailii, we explored an expression proteomics approach, based on quantitative 2DE, to identify alterations occurring in the protein content in response to sudden exposure or balanced growth in the presence of an inhibitory but nonlethal concentration of this weak acid. A coordinate increase in the content of proteins involved in cellular metabolism, in particular, in carbohydrate metabolism (Mdh1p, Aco1p, Cit1p, Idh2p, and Lpd1p) and energy generation (Atp1p and Atp2p), as well as in general and oxidative stress response (Sod2p, Dak2p, Omp2p) was registered. Results reinforce the concept that glucose and acetic acid are coconsumed in Z. bailii, with acetate being channeled into the tricarboxylic acid cycle. When acetic acid is the sole carbon source, results suggest the activation of gluconeogenic and pentose phosphate pathways, based on the increased content of several proteins of these pathways after glucose exhaustion.

  9. Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats

    PubMed Central

    Dimov, Luiz Fabio; Franciosi, Adriano Cardozo; Campos, Ana Carolina Pinheiro; Brunoni, André Russowsky

    2016-01-01

    Transcranial direct current stimulation (tDCS) is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS) on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG) and the dorsal horn of the spinal cord (DHSC) in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1), which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment. PMID:27071073

  10. Acute estrogen surge enhances inflammatory nociception without altering spinal Fos expression.

    PubMed

    Ralya, Andrew; McCarson, Kenneth E

    2014-07-11

    Chronic pain is a major neurological disorder that can manifest differently between genders or sexes. The complex actions of sex hormones may underlie these differences; previous studies have suggested that elevated estrogen levels can enhance pain perception. The purpose of this study was to investigate the hypothesis that acute, activational effects of estradiol (E2) increase persistent inflammatory nociception, and anatomically where this modulation occurs. Spinal expression of Fos is widely used as a marker of nociceptive activation. This study used formalin-evoked nociception in ovariectomized (OVX) adult female rats and measured late-phase hindlimb flinching and Fos expression in the spinal cord, and their modification by acute estrogen supplementation similar to a proestrus surge. Six days after ovariectomy, female rats were injected subcutaneously (s.c.) with 10μg/kg E2 or vehicle. Twenty-four hours later, 50μL of 1.25% or 100μL of 5% formalin was injected into the right hindpaw; hindlimb flinches were counted, and spinal cords removed 2h after formalin injection. The numbers of Fos-expressing neurons in sections of the lumbar spinal cord were analyzed using immunohistochemistry. Formalin-induced inflammation produced a dose-dependent increase in late-phase hindlimb flinching, and E2 pretreatment increased flinching following 5%, but not 1.25% formalin injection. Despite the modification of behavior by E2, the number of spinal Fos-positive neurons was not altered by E2 pretreatment. These findings demonstrate that an acute proestrus-like surge in serum estrogen can produce a stimulus-intensity-dependent increase in inflammation-evoked nociceptive behavior. However, the lack of effect on spinal Fos expression suggests that this enhancement of nociceptive signaling by estrogen is independent of changes in peripheral activation of, expression of the immediate early gene Fos by, or signal throughput of spinal nociceptive neurons.

  11. Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex-different manner.

    PubMed

    Liu, Peng; Xing, Bo; Chu, Zheng; Liu, Fei; Lei, Gang; Zhu, Li; Gao, Ya; Chen, Teng; Dang, Yong-Hui

    2016-09-26

    Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor (D3RKO) exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice. In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. This test was performed at different temperatures including 52°C, 55°C, and 58°C. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test. In the hot-plate test, compared with wild-type (WT) mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. Specially, male D3RKO mice showed hypoalgesia compared with male WT mice when the temperature was 55°C, while for the female mice, there was a statistical difference between genotypes when the test condition was 52°C. In the von Frey hair test, both male and female D3RKO mice exhibited hypoalgesia. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants. These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice. © 2016 Wiley Periodicals, Inc.

  12. Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation.

    PubMed

    Pritchard, Rory A; Falk, Lovissa; Larsson, Mathilda; Leinders, Mathias; Sorkin, Linda S

    2016-01-01

    Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P ≤ 0.01). In contrast, pretreatment with PI3K-α, -δ, and-γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P ≤ 0.05), -δ (P ≤ 0.05), and -γ (P ≤ 0.01), early (0-2 hour) edema -α (P ≤ 0.05), -δ (P ≤ 0.001), and -γ (P ≤ 0.05), and neutrophil infiltration (all P ≤ 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P ≤ 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.

  13. Acetate fuels the cancer engine.

    PubMed

    Lyssiotis, Costas A; Cantley, Lewis C

    2014-12-18

    Cancer cells have distinctive nutrient demands to fuel growth and proliferation, including the disproportionate use of glucose, glutamine, and fatty acids. Comerford et al. and Mashimo et al. now demonstrate that several types of cancer are avid consumers of acetate, which facilitates macromolecular biosynthesis and histone modification.

  14. p-Hydroxyacetophenone suppresses nuclear factor-κB-related inflammation in nociceptive and inflammatory animal models.

    PubMed

    Ching-Wen, Chang; Yun-Chieh, Chen; Yu-Chin, Lin; Wen-Huang, Peng

    2017-04-01

    p-Hydroxyacetophenone (HAP) is a crucial chemical compound present in plants of the genus Artemisia, which are used in traditional therapies for treating jaundice, hepatitis, and inflammatory diseases. Nevertheless, the bioactivity of HAP remains to be identified in order to prove its importance in the plants of genus Artemisia. This study investigated the antioxidative, antinociceptive, and anti-inflammatory effects of HAP, and probed its possible molecular mechanisms. Our results revealed that HAP (80 mg/kg, intraperitoneally) in vivo reduced the acetic acid-induced writhing response and formalin-induced licking time. Moreover, in the λ-carrageenan-induced acute-inflammatory paw edema model in mice, HAP significantly improved hind paw swelling and neutrophil infiltration. In a homogenized paw tissue examination, HAP attenuated pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β, and interleukin-6. Simultaneously, HAP also inhibited the production of nuclear factor kappa B, cyclooxygenase-2, and nitric oxide (NO). Another examination revealed that HAP exerted anti-inflammatory activity by decreasing malondialdehyde levels in the edematous paw through increasing the activities of superoxide dismutase, glutathione peroxidase, and glutathione reductase in the liver. These findings may be beneficial in understanding the therapeutic effects of some plants of the genus Artemisia in the pretreatment of inflammation-associated diseases.

  15. A comparison of the anti-inflammatory and anti-nociceptive activity of nitroaspirin and aspirin

    PubMed Central

    al-Swayeh, O A; Clifford, R H; del Soldato, P; Moore, P K

    2000-01-01

    Nitroaspirin (2.5–50 mg kg−1, i.p. or 2.5–100 mg kg−1, p.o.) and aspirin (2.5–100 mg kg−1, i.p. or p.o.) exhibit anti-inflammatory activity in the carrageenan-induced hindpaw oedema model in the rat. When administered i.p., nitroaspirin was a more effective anti-oedema agent than aspirin particularly in the ‘early' phase (i.e. up to 60 min) of the response. The ED50 values for nitroaspirin and aspirin as inhibitors of the ‘late' phase response (measured at 180 min) were 64.3 μmol kg−1 and >555 μmol kg−1, respectively. When administered p.o., neither nitroaspirin nor aspirin exhibited significant anti-inflammatory activity in the ‘early' phase and were of similar potency in the ‘late' phase. Thus, at the highest dose used (100 mg kg−1, 360 min) orally administered nitroaspirin (aspirin in parenthesis) inhibited oedema formation by 46.9±1.6% (47.2±3.8%, both n=6, P<0.05). Nitroaspirin and aspirin (25–200 mg kg−1, p.o.) caused dose-related inhibition of the hyperalgesia to mechanical stimulation following intraplantar injection of carrageenan in the rat. ED50 values were 365 μmol kg−1 and 784 μmol kg−1, respectively. Neither drug influenced the threshold for mechanical stimulation in the contralateral (i.e. untreated) hindpaw. Nitroaspirin and aspirin (2.5–100 mg kg−1, p.o.) caused dose-related inhibition of acetic acid induced abdominal constrictions in the mouse (ED50 values of 154.7 μmol kg−1 and 242.8 μmol kg−1, respectively). Nitroaspirin and aspirin (>200 mg kg−1, p.o.) reduced the ‘late' phase (but not the ‘early' phase) of the formalin-induced hindpaw licking assay in the mouse. Similarly, nitroaspirin and aspirin (>50 mg kg−1, p.o.) prolonged tail withdrawal latency following application of a noxious heat stimulus in the mouse. PMID:10694241

  16. Anti-nociceptive Activity of Ethnomedicinally Important Analgesic Plant Isodon rugosus Wall. ex Benth: Mechanistic Study and Identifications of Bioactive Compounds

    PubMed Central

    Zeb, Anwar; Ahmad, Sajjad; Ullah, Farhat; Ayaz, Muhammad; Sadiq, Abdul

    2016-01-01

    Isodon rugosus Wall. ex Benth. is extensively used as traditional medicine for the management of various types of pain including tooth ache, gastric pain, abdominal pain, ear ache, and generalized body pain. The current study is designed to scientifically verify the purported uses of I. rugosus as analgesic agent and to figure out its possible mechanism of action. Bioactive compounds responsible for analgesic activity were identified using GC and GC-MS analysis. Analgesic potentials were evaluated using acetic acid induced writhing, hot plate test, and formalin induced paw licking test. In acetic acid induced writhing chloroform fraction (Ir.Chf) exhibited 53% analgesia while formalin test displayed 61% inhibition at phase-I and 45% at phase-II respectively at a dose of 100 mg/kg. Similarly, in hot plate test Ir.Chf displayed average reaction time of 7 min at 15, 30, 45, and 60 min intervals. The possible mechanism of action was found to be the central pathway via opioidergic receptors as the mice showed morphine like analgesic activity at pre-administration of naloxone (opioid antagonist) in hot plate and formalin tests. In GC-MS analysis, 83 compounds were identified among which eight compounds including benzyl alcohol, sebacic acid, myristic acid, phytol, sugiol, Tocopherol, α-Amyrin, and stigmasterol were sorted out as previously reported analgesic compounds. Current study revealed that analgesic potential of I. rugosus can attributed to the presence of analgesic compounds. It may also be concluded that opioids receptors are involved in the analgesic mechanism of I. rugosus due to effective antagonism of nalaxone. PMID:27458379

  17. Origins of blood acetate in the rat.

    PubMed Central

    Buckley, B M; Williamson, D H

    1977-01-01

    A novel enzymimc cycling assay for the determination of acetate in biological material is described. Measurements of the acetate concentration in blood and liver samples from rats of various ages and nutritional states with this assay are reported. The contribution of the intestine, the liver and the rest of the body to maintaining the concentration of acetate in the circulation is examined. Evidence is presented that the gut flora constitute the main source of acetate in blood of fed adult rats, though endogenous production of acetate is of significance in other situations. The streptozotocin-diabetic rat has an elevated blood acetate concentration. PMID:597244

  18. The facC Gene of Aspergillus nidulans Encodes an Acetate-Inducible Carnitine Acetyltransferase

    PubMed Central

    Stemple, Christopher J.; Davis, Meryl A.; Hynes, Michael J.

    1998-01-01

    Mutations in the facC gene of Aspergillus nidulans result in an inability to use acetate as a sole carbon source. This gene has been cloned by complementation. The proposed translation product of the facC gene has significant similarity to carnitine acetyltransferases (CAT) from other organisms. Total CAT activity was found to be inducible by acetate and fatty acids and repressed by glucose. Acetate-inducible activity was found to be absent in facC mutants, while fatty acid-inducible activity was absent in an acuJ mutant. Acetate induction of facC expression was dependent on the facB regulatory gene, and an expressed FacB fusion protein was demonstrated to bind to 5′ facC sequences. Carbon catabolite repression of facC expression was affected by mutations in the creA gene and a CreA fusion protein bound to 5′ facC sequences. Mutations in the acuJ gene led to increased acetate induction of facC expression and also of an amdS-lacZ reporter gene, and it is proposed that this results from accumulation of acetate, as well as increased expression of facB. A model is presented in which facC encodes a cytosolic CAT enzyme, while a different CAT enzyme, which is acuJ dependent, is present in peroxisomes and mitochondria, and these activities are required for the movement of acetyl groups between intracellular compartments. PMID:9829933

  19. Carbon-isotopic analysis of dissolved acetate

    NASA Technical Reports Server (NTRS)

    Gelwicks, J. T.; Hayes, J. M.

    1990-01-01

    Heating of dried, acetate-containing solids together with oxalic acid dihydrate conveniently releases acetic acid for purification by gas chromatography. For determination of the carbon-isotopic composition of total acetate, the acetate-containing zone of the chromatographic effluent can be routed directly to a combustion furnace coupled to a vacuum system allowing recovery, purification, and packaging of CO2 for mass-spectrometric analysis. For analysis of methyl carbon, acetic acid can be cryogenically trapped from the chromatographic effluent, then transferred to a tube containing excess NaOH. The tube is evacuated, sealed, and heated to 500 degrees C to produce methane by pyrolysis of sodium acetate. Subsequent combustion of the methane allows determination of the 13C content at the methyl position in the parent acetate. With typical blanks, the standard deviation of single analyses is less than 0.4% for acetate samples larger than 5 micromoles. A full treatment of uncertainties is outlined.

  20. Ozone decomposition in aqueous acetate solutions

    SciTech Connect

    Sehested, K.; Holcman, J.; Bjergbakke, E.; Hart, E.J.

    1987-01-01

    The acetate radical ion reacts with ozone with a rate constant of k = (1.5 +/- 0.5) x 10Z dmT mol s . The products from this reaction are CO2, HCHO, and O2 . By subsequent reaction of the peroxy radical with ozone the acetate radical ion is regenerated through the OH radical. A chain decomposition of ozone takes place. It terminates when the acetate radical ion reacts with oxygen forming the unreactive peroxy acetate radical. The chain is rather short as oxygen is developed, as a result of the ozone consumption. The inhibiting effect of acetate on the ozone decay is rationalized by OH scavenging by acetate and successive reaction of the acetate radical ion with oxygen. Some products from the bimolecular disappearance of the peroxy acetate radicals, however, react further with ozone, reducing the effectiveness of the stabilization.

  1. Carbon-isotopic analysis of dissolved acetate.

    PubMed

    Gelwicks, J T; Hayes, J M

    1990-01-01

    Heating of dried, acetate-containing solids together with oxalic acid dihydrate conveniently releases acetic acid for purification by gas chromatography. For determination of the carbon-isotopic composition of total acetate, the acetate-containing zone of the chromatographic effluent can be routed directly to a combustion furnace coupled to a vacuum system allowing recovery, purification, and packaging of CO2 for mass-spectrometric analysis. For analysis of methyl carbon, acetic acid can be cryogenically trapped from the chromatographic effluent, then transferred to a tube containing excess NaOH. The tube is evacuated, sealed, and heated to 500 degrees C to produce methane by pyrolysis of sodium acetate. Subsequent combustion of the methane allows determination of the 13C content at the methyl position in the parent acetate. With typical blanks, the standard deviation of single analyses is less than 0.4% for acetate samples larger than 5 micromoles. A full treatment of uncertainties is outlined.

  2. 21 CFR 184.1721 - Sodium acetate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Sodium acetate. 184.1721 Section 184.1721 Food and....1721 Sodium acetate. (a) Sodium acetate (C2H3O2Na, CAS Reg. No. 127-09-3 or C2H3O2Na·3H2O, CAS Reg. No. 6131-90-4) is the sodium salt of acetic acid and occurs naturally in plant and animal tissues....

  3. The Development of Nociceptive Network Activity in the Somatosensory Cortex of Freely Moving Rat Pups

    PubMed Central

    Chang, P.; Fabrizi, L.; Olhede, S.; Fitzgerald, M.

    2016-01-01

    Cortical perception of noxious stimulation is an essential component of pain experience but it is not known how cortical nociceptive activity emerges during brain development. Here we use continuous telemetric electrocorticogram (ECoG) recording from the primary somatosensory cortex (S1) of awake active rat pups to map functional nociceptive processing in the developing brain over the first 4 weeks of life. Cross-sectional and longitudinal recordings show that baseline S1 ECoG energy increases steadily with age, with a distinctive beta component replaced by a distinctive theta component in week 3. Event-related potentials were evoked by brief noxious hindpaw skin stimulation at all ages tested, confirming the presence of functional nociceptive spinothalamic inputs in S1. However, hindpaw incision, which increases pain sensitivity at all ages, did not increase S1 ECoG energy until week 3. A significant increase in gamma (20–50 Hz) energy occurred in the presence of skin incision at week 3 accompanied by a longer-lasting increase in theta (4–8 Hz) energy at week 4. Continuous ECoG recording demonstrates specific postnatal functional stages in the maturation of S1 cortical nociception. Somatosensory cortical coding of an ongoing pain “state” in awake rat pups becomes apparent between 2 and 4 weeks of age. PMID:27797835

  4. Activation of TRPV1 and TRPA1 leads to muscle nociception and mechanical hyperalgesia.

    PubMed

    Ro, Jin Y; Lee, Jong-Seok; Zhang, Youping

    2009-08-01

    The involvement of TRPV1 and TRPA1 in mediating craniofacial muscle nociception and mechanical hyperalgesia was investigated in male Sprague-Dawley rats. First, we confirmed the expression of TRPV1 in masseter afferents in rat trigeminal ganglia (TG), and provided new data that TRPA1 is also expressed in primary afferents innervating masticatory muscles in double-labeling immunohistochemistry experiments. We then examined whether the activation of each TRP channel in the masseter muscle evokes acute nocifensive responses and leads to the development of masseter hypersensitivity to mechanical stimulation using the behavioral models that have been specifically designed and validated for the craniofacial system. Intramuscular injections with specific agonists for TRPV1 and TRPA1, capsaicin and mustard oil (MO), respectively, produced immediate nocifensive hindpaw responses followed by prolonged mechanical hyperalgesia in a concentration-dependent manner. Pretreatment of the muscle with a TRPV1 antagonist, capsazepine, effectively attenuated the capsaicin-induced muscle nociception and mechanical hyperalgesia. Similarly, pretreatment of the muscle with a selective TRPA1 antagonist, AP18, significantly blocked the MO-induced muscle nociception and mechanical hyperalgesia. We confirmed these data with another set of selective antagonist for TRPV1 and TRPA1, AMG9810 and HC030031, respectively. Collectively, these results provide compelling evidence that TRPV1 and TRPA1 can functionally contribute to muscle nociception and hyperalgesia, and suggest that TRP channels expressed in muscle afferents can engage in the development of pathologic muscle pain conditions.

  5. Heritability of Nociception IV: Neuropathic pain assays are genetically distinct across methods of peripheral nerve injury

    PubMed Central

    Young, Erin E.; Costigan, Michael; Herbert, Teri A.; Lariviere, William R.

    2013-01-01

    Prior genetic correlation analysis of 22 heritable behavioral measures of nociception and hypersensitivity in the mouse identified five genetically distinct pain types. In the present study, we reanalyzed that dataset and included the results of an additional nine assays of nociception and hypersensitivity to: 1) replicate the previously identified five pain types; 2) test whether any of the newly added pain assays represent novel genetically distinct pain types; 3) test the level of genetic relatedness among nine commonly employed neuropathic pain assays. Multivariate analysis of pairwise correlations between assays shows that the newly added zymosan-induced heat hypersensitivity assay does not conform to the two previously identified groups of heat hypersensitivity assays and cyclophosphamide-induced cystitis, the first organ-specific visceral pain model examined, is genetically distinct from other inflammatory assays. The four included mechanical hypersensitivity assays are genetically distinct, and do not comprise a single pain type as previously reported. Among the nine neuropathic pain assays including autotomy, chemotherapy, nerve ligation and spared nerve injury assays, at least four genetically distinct types of neuropathic sensory abnormalities were identified, corresponding to differences in nerve injury method. In addition, two itch assays and Comt genotype were compared to the expanded set of nociception and hypersensitivity assays. Comt genotype was strongly related only to spontaneous inflammatory nociception assays. These results indicate the priority for continued investigation of genetic mechanisms in several assays newly identified to represent genetically distinct pain types. PMID:24071598

  6. Perceptual learning to discriminate the intensity and spatial location of nociceptive stimuli

    PubMed Central

    Mancini, Flavia; Dolgevica, Karina; Steckelmacher, James; Haggard, Patrick; Friston, Karl; Iannetti, Giandomenico D.

    2016-01-01

    Accurate discrimination of the intensity and spatial location of nociceptive stimuli is essential to guide appropriate behaviour. The ability to discriminate the attributes of sensory stimuli is continuously refined by practice, even throughout adulthood - a phenomenon called perceptual learning. In the visual domain, perceptual learning to discriminate one of the features that define a visual stimulus (e.g., its orientation) can transfer to a different feature of the same stimulus (e.g., its contrast). Here, we performed two experiments on 48 volunteers to characterize perceptual learning in nociception, which has been rarely studied. We investigated whether learning to discriminate either the intensity or the location of nociceptive stimuli (1) occurs during practice and is subsequently maintained, (2) requires feedback on performance, and (3) transfers to the other, unpractised stimulus feature. First, we found clear evidence that perceptual learning in discriminating both the intensity and the location of nociceptive stimuli occurs, and is maintained for at least 3 hours after practice. Second, learning occurs only when feedback is provided during practice. Finally, learning is largely confined to the feature for which feedback was provided. We discuss these effects in a predictive coding framework, and consider implications for future studies. PMID:27996022

  7. Heritability of nociception IV: neuropathic pain assays are genetically distinct across methods of peripheral nerve injury.

    PubMed

    Young, Erin E; Costigan, Michael; Herbert, Teri A; Lariviere, William R

    2014-05-01

    Prior genetic correlation analysis of 22 heritable behavioral measures of nociception and hypersensitivity in the mouse identified 5 genetically distinct pain types. In the present study, we reanalyzed that dataset and included the results of an additional 9 assays of nociception and hypersensitivity, with the following goals: to replicate the previously identified 5 pain types; to test whether any of the newly added pain assays represent novel genetically distinct pain types; and to test the level of genetic relatedness among 9 commonly used neuropathic pain assays. Multivariate analysis of pairwise correlations between assays shows that the newly added zymosan-induced heat hypersensitivity assay does not conform to the 2 previously identified groups of heat hypersensitivity assays and cyclophosphamide-induced cystitis, the first organ-specific visceral pain model examined, is genetically distinct from other inflammatory assays. The 4 included mechanical hypersensitivity assays are genetically distinct and do not comprise a single pain type as previously reported. Among the 9 neuropathic pain assays including autotomy, chemotherapy, nerve ligation and spared nerve injury assays, at least 4 genetically distinct types of neuropathic sensory abnormalities were identified, corresponding to differences in nerve injury method. In addition, 2 itch assays and Comt genotype were compared to the expanded set of nociception and hypersensitivity assays. Comt genotype was strongly related only to spontaneous inflammatory nociception assays. These results indicate the priority for continued investigation of genetic mechanisms in several assays newly identified to represent genetically distinct pain types.

  8. Effects of Visual Cortex Activation on the Nociceptive Blink Reflex in Healthy Subjects

    PubMed Central

    Sava, Simona L.; de Pasqua, Victor; Magis, Delphine; Schoenen, Jean

    2014-01-01

    Bright light can cause excessive visual discomfort, referred to as photophobia. The precise mechanisms linking luminance to the trigeminal nociceptive system supposed to mediate this discomfort are not known. To address this issue in healthy human subjects we modulated differentially visual cortex activity by repetitive transcranial magnetic stimulation (rTMS) or flash light stimulation, and studied the effect on supraorbital pain thresholds and the nociceptive-specific blink reflex (nBR). Low frequency rTMS that inhibits the underlying cortex, significantly decreased pain thresholds, increased the 1st nBR block ipsi- and contralaterally and potentiated habituation contralaterally. After high frequency or sham rTMS over the visual cortex, and rMS over the right greater occipital nerve we found no significant change. By contrast, excitatory flash light stimulation increased pain thresholds, decreased the 1st nBR block of ipsi- and contralaterally and increased habituation contralaterally. Our data demonstrate in healthy subjects a functional relation between the visual cortex and the trigeminal nociceptive system, as assessed by the nociceptive blink reflex. The results argue in favour of a top-down inhibitory pathway from the visual areas to trigemino-cervical nociceptors. We postulate that in normal conditions this visuo-trigeminal inhibitory pathway may avoid disturbance of vision by too frequent blinking and that hypoactivity of the visual cortex for pathological reasons may promote headache and photophobia. PMID:24936654

  9. Fibroblast growth factor 7 is a nociceptive modulator secreted via large dense-core vesicles.

    PubMed

    Liu, Hui; Wu, Qing-Feng; Li, Jia-Yin; Liu, Xing-Jun; Li, Kai-Cheng; Zhong, Yan-Qing; Wu, Dan; Wang, Qiong; Lu, Yin-Jing; Bao, Lan; Zhang, Xu

    2015-10-01

    Fibroblast growth factor (FGF) 7, a member of FGF family, is initially found to be secreted from mesenchymal cells to repair epithelial tissues. However, its functions in the nervous system are largely unknown. The present study showed that FGF7 was a neuromodulator localized in the large dense-core vesicles (LDCVs) in nociceptive neurons. FGF7 was mainly expressed in small-diameter neurons of the dorsal root ganglion and could be transported to the dorsal spinal cord. Interestingly, FGF7 was mostly stored in LDCVs that did not contain neuropeptide substance P. Electrophysiological recordings in the spinal cord slice showed that buffer-applied FGF7 increased the amplitude of excitatory post-synaptic current evoked by stimulating the sensory afferent fibers. Behavior tests showed that intrathecally applied FGF7 potentiated the formalin-induced acute nociceptive response. Moreover, both acute and inflammatory nociceptive responses were significantly reduced in Fgf7-deficient mice. These results suggest that FGF7 exerts an excitatory modulation of nociceptive afferent transmission.

  10. Introduction and validation of a less painful algorithm to estimate the nociceptive flexion reflex threshold.

    PubMed

    Lichtner, Gregor; Golebiewski, Anna; Schneider, Martin H; von Dincklage, Falk

    2015-05-22

    The nociceptive flexion reflex (NFR) is a widely used tool to investigate spinal nociception for scientific and diagnostic purposes, but its clinical use is currently limited due to the painful measurement procedure, especially restricting its applicability for patients suffering from chronic pain disorders. Here we introduce a less painful algorithm to assess the NFR threshold. Application of this new algorithm leads to a reduction of subjective pain ratings by over 30% compared to the standard algorithm. We show that the reflex threshold estimates resulting from application of the new algorithm can be used interchangeably with those of the standard algorithm after adjusting for the constant difference between the algorithms. Furthermore, we show that the new algorithm can be applied at shorter interstimulus intervals than are commonly used with the standard algorithm, since reflex threshold values remain unchanged and no habituation effects occur when reducing the interstimulus interval for the new algorithm down to 3s. Finally we demonstrate the utility of the new algorithm to investigate the modulation of nociception through different states of attention. Taken together, the here presented new algorithm could increase the utility of the NFR for investigation of nociception in subjects who were previously not able to endure the measurement procedure, such as chronic pain patients.

  11. Chronic psychological stress enhances nociceptive processing in the urinary bladder in high-anxiety rats.

    PubMed

    Robbins, M T; DeBerry, J; Ness, T J

    2007-08-15

    This study sought to determine whether acute and/or chronic psychological stress produce changes in urinary bladder nociception. Female Sprague-Dawley (SD; low/moderate anxiety) or Wistar-Kyoto (WK; high-anxiety) rats were exposed to either an acute (1 day) or a chronic (10 days) water avoidance stress paradigm or a sham stress paradigm. Paw withdrawal thresholds to mechanical and thermal stimuli and fecal pellet output, were quantified at baseline and after the final stress or sham stress exposure. Rats were then sedated, and visceromotor responses (VMRs) to urinary bladder distension (UBD) were recorded. While acute stress exposure did not significantly alter bladder nociceptive responses in either strain of rats, WK rats exposed to a chronic stress paradigm exhibited enhanced responses to UBD. These high-anxiety rats also exhibited somatic analgesia following acute, but not chronic, stress. Furthermore, WK rats had greater fecal pellet output than SD rats when stressed. Significant stress-induced changes in nociceptive responses to mechanical stimuli were observed in SD rats. That chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats provides further support for a critical role of genetics, stress and anxiety as exacerbating factors in painful urogenital disorders such as interstitial cystitis (IC).

  12. Effects of silymarin on neuropathic pain and formalin-induced nociception in mice

    PubMed Central

    Hassani, Faezeh Vahdati; Rezaee, Ramin; Sazegara, Hasan; Hashemzaei, Mahmoud; Shirani, Kobra; Karimi, Gholamreza

    2015-01-01

    Objective(s): Based on the previous reports, silymarin can suppress nitric oxide, prostaglandin E2 (PGE2), leukotrienes, cytokines production, and neutrophils infiltration. Regarding the fact that inflammation plays an important role in neuropathic and formalin-induced pain, it was assumed that silymarin could reduce pain. The present study investigates the analgesic effects of silymarin in chemical nociception and a model of neuropathic pain. Materials and Methods: Chemical nociception was produced by injection of 20 µl of formalin (0.5% formaldehyde in saline) into the plantar region of the right hind paw. A sciatic-nerve ligated mouse was applied as the model of neuropathic pain and the antinociceptive response of silymarin was examined 14 days after unilateral nerve-ligation using the hot plate test. Results: The intraperitoneal administration of silymarin (25, 50, and, 100 mg/kg) 2 hr prior to the intraplantar formalin injection suppressed the nociceptive response during the late phase of the formalin test significantly, but it was not in a dose-dependent manner. Different doses of silymarin 14 days after unilateral sciatic nerve ligation in hot plate test did not induce obvious antinociception. Conclusion: Results of the present study indicated that repeated administration of silymarin prevents the formalin-induced nociceptive behavior. However, it is not effective in the treatment of sciatic neuropathic pain. PMID:26351564

  13. A role for sodium and chloride in kainic acid-induced beading of inhibitory interneuron dendrites.

    PubMed

    Al-Noori, S; Swann, J W

    2000-01-01

    Excitotoxic injury of the dendrites of inhibitory interneurons could lead to decreases in their synaptic activation and explain subsequent local circuit hyperexcitability and epilepsy. A hallmark of dendrotoxicity, at least in principal neurons of the hippocampus and cortex, is focal or varicose swellings of dendritic arbors. In experiments reported here, transient (1h) exposure of hippocampal explant cultures to kainic acid produced marked focal swellings of the dendrites of parvalbumin-immunoreactive pyramidal basket cells in a highly reproducible and dose-dependent manner. At 5mM kainic acid, more than half of the immunopositive apical dendrites in area CA(1) had a beaded appearance. However, the somal volumes of these cells were unaltered by the same treatment. The presence of focal swellings was reversible with kainate washout and was not accompanied by interneuronal cell death. In contrast, exposure to much higher concentrations (300mM) of kainic acid resulted in the total loss of parvalbumin-positive interneurons from explants. Surprisingly, kainic acid-induced dendritic beading does not appear to be mediated by extracellular calcium. Beading was unaltered in the presence of N-methyl-D-aspartate receptor antagonists, the L-type calcium channel antagonist, nimodipine, cadmium, or by removing extracellular calcium. However, blockade of voltage-gated sodium channels by either tetrodotoxin or lidocaine abolished dendritic beading, while the activation of existing voltage-gated sodium channels by veratridine mimicked the kainic acid-induced dendritic beading. Finally, the removal of extracellular chloride prevented the kainic acid-induced dendritic beading.Thus, we suggest that the movement of Na(+) and Cl(-), rather than Ca(2+), into cells underlies the focal swellings of interneuron dendrites in hippocampus.

  14. Calcium Uptake via Mitochondrial Uniporter Contributes to Palmitic Acid-induced Apoptosis in Mouse Podocytes.

    PubMed

    Yuan, Zeting; Cao, Aili; Liu, Hua; Guo, Henjiang; Zang, Yingjun; Wang, Yi; Wang, Yunman; Wang, Hao; Yin, Peihao; Peng, Wen

    2017-02-09

    Podocytes are component cells of the glomerular filtration barrier, and their loss by apoptosis is the main cause of proteinuria that leads to diabetic nephropathy (DN). Therefore, insights into podocyte apoptosis mechanism would allow a better understanding of DN pathogenesis and thus help develop adequate therapeutic strategies. Here, we investigated the molecular mechanism of palmitic acid-inhibited cell death in mouse podocytes, and found that palmitic acid increased cell death in a dose- and time-dependent manner. Palmitic acid induces apoptosis in podocytes through up-regulation of cytosolic and mitochondrial Ca(2+) , mitochondrial membrane potential (MMP), cytochrome c release and depletion of endoplasmic reticulum (ER) Ca(2+) , The intracellular calcium chelator, 1,2-bis (2-aminophenoxy) ethane-N,N,N, N'-tetraacetic acid tetrakis acetoxymethyl ester (BAPTA-AM), partially prevented this up-regulation whereas 2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-triphosphate receptor (IP3R) inhibitor; dantrolene, a ryanodine receptor (RyR) inhibitor; and 4,4'-diisothiocyanatostibene-2,2'-disulfonic acid (DIDS), an anion exchange inhibitor, had no effect. Interestingly, ruthenium red and Ru360, both inhibitors of the mitochondrial Ca(2+) uniporter (MCU), blocked palmitic acid-induced mitochondrial Ca(2+) elevation, cytochrome c release from mitochondria to cytosol, and apoptosis. siRNA to MCU markedly reduced curcumin-induced apoptosis. These data indicate that Ca(2+) uptake via mitochondrial uniporter contributes to palmitic acid-induced apoptosis in mouse podocytes. This article is protected by copyright. All rights reserved.

  15. Clavulanic acid induces penile erection and yawning in male rats: comparison with apomorphine.

    PubMed

    Sanna, Fabrizio; Melis, Maria Rosaria; Angioni, Laura; Argiolas, Antonio

    2013-02-01

    The beta-lactamase inhibitor clavulanic acid induced penile erection and yawning in a dose dependent manner when given intraperitoneally (IP, 0.05-5mg/kg), perorally (OS, 0.1-5mg/kg) and intracereboventricularly (ICV, 0.01-5 μg/rat) to male rats. The effect resembles that of the dopamine receptor agonist apomorphine given subcutaneously (SC) (0.02-0.25mg/kg), although the responses of the latter followed a U inverted dose-response curve, disappearing at doses higher than 0.1mg/kg. Clavulanic acid responses were reduced by about 55% by haloperidol, a dopamine D2 receptor antagonist (0.1mg/kg IP), and by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin, an oxytocin receptor antagonist (2 μg/rat ICV), both given 15 min before clavulanic acid. A higher reduction of clavulanic acid responses (more than 80%) was also found with morphine, an opioid receptor agonist (5mg/kg IP), and with mianserin, a serotonin 5HT(2c) receptor antagonist (0.2mg/kg SC). In contrast, no reduction was found with naloxone, an opioid receptor antagonist (1mg/kg IP). The ability of haloperidol, d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin and morphine to reduce clavulanic acid induced penile erection and yawning suggests that clavulanic acid induces these responses, at least in part, by increasing central dopaminergic neurotransmission. Dopamine in turn activates oxytocinergic neurotransmission and centrally released oxytocin induces penile erection and yawning. However, since both penile erection and yawning episodes were reduced not only by the blockade of central dopamine and oxytocin receptors and by the stimulation of opioid receptors, which inhibits oxytocinergic neurotransmission, but also by mianserin, an increase of central serotonin neurotransmission is also likely to participate in these clavulanic acid responses.

  16. Lipopolysaccharide Stimulates Butyric Acid-Induced Apoptosis in Human Peripheral Blood Mononuclear Cells

    PubMed Central

    Kurita-Ochiai, Tomoko; Fukushima, Kazuo; Ochiai, Kuniyasu

    1999-01-01

    We previously reported that butyric acid, an extracellular metabolite from periodontopathic bacteria, induced apoptosis in murine thymocytes, splenic T cells, and human Jurkat T cells. In this study, we examined the ability of butyric acid to induce apoptosis in peripheral blood mononuclear cells (PBMC) and the effect of bacterial lipopolysaccharide (LPS) on this apoptosis. Butyric acid significantly inhibited the anti-CD3 monoclonal antibody- and concanavalin A-induced proliferative responses in a dose-dependent fashion. This inhibition of PBMC growth by butyric acid depended on apoptosis in vitro. It was characterized by internucleosomal DNA digestion and revealed by gel electrophoresis followed by a colorimetric DNA fragmentation assay to occur in a concentration-dependent fashion. Butyric acid-induced PBMC apoptosis was accompanied by caspase-3 protease activity but not by caspase-1 protease activity. LPS potentiated butyric acid-induced PBMC apoptosis in a dose-dependent manner. Flow-cytometric analysis revealed that LPS increased the proportion of sub-G1 cells and the number of late-stage apoptotic cells induced by butyric acid. Annexin V binding experiments with fractionated subpopulations of PBMC in flow cytometory revealed that LPS accelerated the butyric acid-induced CD3+-T-cell apoptosis followed by similar levels of both CD4+- and CD8+-T-cell apoptosis. The addition of LPS to PBMC cultures did not cause DNA fragmentation, suggesting that LPS was unable to induce PBMC apoptosis directly. These data suggest that LPS, in combination with butyric acid, potentiates CD3+ PBMC T-cell apoptosis and plays a role in the apoptotic depletion of CD4+ and CD8+ cells. PMID:9864191

  17. The acid-induced folded state of Sac7d is the native state.

    PubMed Central

    Bedell, J. L.; McCrary, B. S.; Edmondson, S. P.; Shriver, J. W.

    2000-01-01

    Sac7d unfolds at low pH in the absence of salt, with the greatest extent of unfolding obtained at pH 2. We have previously shown that the acid unfolded protein is induced to refold by decreasing the pH to 0 or by addition of salt (McCrary BS, Bedell J. Edmondson SP, Shriver JW, 1998, J Mol Biol 276:203-224). Both near-ultraviolet circular dichroism spectra and ANS fluorescence enhancements indicate that the acid- and salt-induced folded states have a native fold and are not molten globular. 1H,15N heteronuclear single quantum coherence NMR spectra confirm that the native, acid-, and salt-induced folded states are essentially identical. The most significant differences in amide 1H and 15N chemical shifts are attributed to hydrogen bonding to titrating carboxyl side chains and through-bond inductive effects. The 1H NMR chemical shifts of protons affected by ring currents in the hydrophobic core of the acid- and salt-induced folded states are identical to those observed in the native. The radius of gyration of the acid-induced folded state at pH 0 is shown to be identical to that of the native state at pH 7 by small angle X-ray scattering. We conclude that acid-induced collapse of Sac7d does not lead to a molten globule but proceeds directly to the native state. The folding of Sac7d as a function of pH and anion concentration is summarized with a phase diagram that is similar to those observed for other proteins that undergo acid-induced folding except that the A-state is encompassed by the native state. These results demonstrate that formation of a molten globule is not a general property of proteins that are refolded by acid. PMID:11106160

  18. Involvement of bradykinin, cytokines, sympathetic amines and prostaglandins in formalin-induced orofacial nociception in rats

    PubMed Central

    Chichorro, Juliana G; Lorenzetti, Berenice B; Zampronio, Aleksander R

    2004-01-01

    This study characterises some of the mechanisms and mediators involved in the orofacial nociception triggered by injection of formalin into the upper lip of the rat, by assessing the influence of various treatments on behavioural nociceptive responses (duration of facial rubbing) elicited either by a low subthreshold (i.e. non-nociceptive; 0.63%) or a higher concentration of the algogen (2.5%). The kininase II inhibitor captopril (5 mg kg−1, s.c.) and prostaglandin(PG) E2 (100 ng lip−1) potentiated both phases of the response to 0.63% formalin, whereas tumour necrosis factor (TNFα; 5 pg lip−1), interleukin(IL)-1β (0.5 pg lip−1), IL-6 (2 ng lip−1) and IL-8 (200 pg lip−1), or the indirectly acting sympathomimetic drug tyramine (200 μg lip−1), each augmented only the second phase of nociception. Conversely, both phases of nociception induced by 2.5% formalin were inhibited by the bradykinin (BK) B2 receptor antagonist HOE140 (5 μg lip−1) or the selective β1-adrenoceptor antagonist atenolol (100 μg lip−1). However, the BK B1 receptor antagonist des-Arg9-Leu8-BK (1 and 2 μg lip−1), antibody and/or antiserum against each of the cytokines, the adrenergic neurone blocker guanethidine (30 mg kg−1 day−1, s.c., for 3 days) and the cyclooxygenase(COX)-2 inhibitor celecoxib (50 and 200 μg lip−1, s.c.; or 1 and 3 mg kg−1, i.p.) reduced only the second phase of the response. The nonselective COX inhibitor indomethacin and the 5-lipoxygenase activating protein inhibitor MK886 did not change formalin-induced nociception. Our results indicate that BK, TNF-α, IL-1β, IL-6, IL-8, sympathetic amines and PGs (but not leukotrienes) contribute significantly to formalin-induced orofacial nociception in the rat and the response seems to be more susceptible to inhibition by B2 receptor antagonist and selective COX-2 inhibitor than by B1 receptor antagonist or nonselective COX inhibitor. PMID:15006904

  19. 21 CFR 582.1721 - Sodium acetate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Sodium acetate. 582.1721 Section 582.1721 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1721 Sodium acetate. (a) Product. Sodium acetate. (b) Conditions of use. This substance is...

  20. 21 CFR 582.1721 - Sodium acetate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Sodium acetate. 582.1721 Section 582.1721 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1721 Sodium acetate. (a) Product. Sodium acetate. (b) Conditions of use. This substance is...

  1. 21 CFR 582.1721 - Sodium acetate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Sodium acetate. 582.1721 Section 582.1721 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1721 Sodium acetate. (a) Product. Sodium acetate. (b) Conditions of use. This substance is...

  2. 21 CFR 582.1721 - Sodium acetate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Sodium acetate. 582.1721 Section 582.1721 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1721 Sodium acetate. (a) Product. Sodium acetate. (b) Conditions of use. This substance is...

  3. 21 CFR 582.1721 - Sodium acetate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Sodium acetate. 582.1721 Section 582.1721 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1721 Sodium acetate. (a) Product. Sodium acetate. (b) Conditions of use. This substance is...

  4. 21 CFR 582.1005 - Acetic acid.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Acetic acid. 582.1005 Section 582.1005 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1005 Acetic acid. (a) Product. Acetic acid. (b) Conditions of use. This substance is...

  5. 21 CFR 582.1005 - Acetic acid.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Acetic acid. 582.1005 Section 582.1005 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1005 Acetic acid. (a) Product. Acetic acid. (b) Conditions of use. This substance is...

  6. 21 CFR 184.1005 - Acetic acid.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Acetic acid. 184.1005 Section 184.1005 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DIRECT FOOD....1005 Acetic acid. (a) Acetic acid (C2H4O2, CAS Reg. No. 64-19-7) is known as ethanoic acid. It...

  7. 21 CFR 582.1005 - Acetic acid.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Acetic acid. 582.1005 Section 582.1005 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1005 Acetic acid. (a) Product. Acetic acid. (b) Conditions of use. This substance is...

  8. 21 CFR 582.1005 - Acetic acid.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Acetic acid. 582.1005 Section 582.1005 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1005 Acetic acid. (a) Product. Acetic acid. (b) Conditions of use. This substance is...

  9. 21 CFR 582.1005 - Acetic acid.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Acetic acid. 582.1005 Section 582.1005 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS....1005 Acetic acid. (a) Product. Acetic acid. (b) Conditions of use. This substance is...

  10. 21 CFR 522.2476 - Trenbolone acetate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... days. (A) 140 milligrams (mg) trenbolone acetate (one implant consisting of 7 pellets, each pellet containing 20 mg trenbolone acetate) per implant dose. (B) 140 mg trenbolone acetate (one implant consisting... 29 mg tylosin tartrate) per implant dose. (ii) Indications for use. For improved feed...

  11. 21 CFR 522.2476 - Trenbolone acetate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... days. (A) 140 milligrams (mg) trenbolone acetate (one implant consisting of 7 pellets, each pellet containing 20 mg trenbolone acetate) per implant dose. (B) 140 mg trenbolone acetate (one implant consisting... 29 mg tylosin tartrate) per implant dose. (ii) Indications for use. For improved feed...

  12. Photochemistry of 2-nitrobenzylidene acetals.

    PubMed

    Sebej, Peter; Solomek, Tomás; Hroudná, L'ubica; Brancová, Pavla; Klán, Petr

    2009-11-20

    Photolysis of dihydroxy compounds (diols) protected as 2-nitrobenzylidene acetals (ONBA) and subsequent acid- or base-catalyzed hydrolysis of the 2-nitrosobenzoic acid ester intermediates result in an efficient and high-yielding release of the substrates. We investigated the scope and limitations of ONBA photochemistry and expanded upon earlier described two-step procedures to show that the protected diols of many structural varieties can also be liberated in a one-pot procedure. In view of the fact that the acetals of nonsymmetrically substituted diols are converted into one of the corresponding 2-nitrosobenzoic acid ester isomers with moderate to high regioselectivity, the mechanism of their formation was studied using various experimental techniques. The experimental data were found to be in agreement with DFT-based quantum chemical calculations that showed the preferential cleavage occurs on the acetal C-O bond in the vicinity of more electron-withdrawing (or less electron-donating) groups. The study also revealed considerable complexity in the cleavage mechanism and that the structural variations in the substrate can significantly alter the reaction pathway. This deprotection strategy was found to be also applicable for 2-thioethanol when released from the corresponding monothioacetal in the presence of a reducing agent, such as ascorbic acid.

  13. Systemic administration of resveratrol suppress the nociceptive neuronal activity of spinal trigeminal nucleus caudalis in rats.

    PubMed

    Takehana, Shiori; Sekiguchi, Kenta; Inoue, Maki; Kubota, Yoshiko; Ito, Yukihiko; Yui, Kei; Shimazu, Yoshihito; Takeda, Mamoru

    2016-01-01

    Although a modulatory role has been reported for the red wine polyphenol resveratrol on several types of ion channels and excitatory synaptic transmission in the nervous system, the acute effects of resveratrol in vivo, particularly on nociceptive transmission of the trigeminal system, remain to be determined. The aim of the present study was to investigate whether acute intravenous resveratrol administration to rats attenuates the excitability of wide dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo. Extracellular single unit recordings were made from 18 SpVc neurons in response to orofacial mechanical stimulation of pentobarbital-anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was inhibited by resveratrol (0.5-2 mg/kg, i.v.) and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. These inhibitory effects were reversed after approximately 20 min. The relative magnitude of inhibition by resveratrol of SpVc WDR neuronal discharge frequency was significantly greater for noxious than non-noxious stimulation. These results suggest that, in the absence of inflammatory or neuropathic pain, acute intravenous resveratrol administration suppresses trigeminal sensory transmission, including nociception, and so resveratrol may be used as a complementary and alternative medicine therapeutic agent for the treatment of trigeminal nociceptive pain, including hyperalgesia.

  14. Mechanisms of G protein-coupled estrogen receptor-mediated spinal nociception

    PubMed Central

    Deliu, Elena; Brailoiu, G. Cristina; Arterburn, Jeffrey B.; Oprea, Tudor I.; Benamar, Khalid; Dun, Nae J.; Brailoiu, Eugen

    2012-01-01

    Human and animal studies suggest estrogens are involved in the processing of nociceptive sensory information and analgesic responses in the central nervous system. Rapid pro-nociceptive estrogenic effects have been reported, some of which likely involve G protein-coupled estrogen receptor (GPER) activation. Membrane depolarization, increases in cytosolic calcium and reactive oxygen species (ROS) levels are markers of neuronal activation, underlying pain sensitization in the spinal cord. Using behavioral, electrophysiological and fluorescent imaging studies, we evaluated GPER involvement in spinal nociceptive processing. Intrathecal challenging of mice with the GPER agonist G-1 results in pain-related behaviors. GPER antagonism with G15 reduces the G-1 induced response. Electrophysiological recordings from superficial dorsal horn neurons indicate neuronal membrane depolarization upon G-1 application, which is G15 sensitive. In cultured spinal sensory neurons G-1 increases intracellular calcium concentration and induces mitochondrial and cytosolic ROS accumulation. In the presence of G15, G-1 does not elicit the calcium and ROS responses, confirming specific GPER involvement in this process. Following G-1 intracellular microinjections, cytosolic calcium concentration elevates faster and with higher amplitude compared to extracellular exposure, suggesting subcellular GPER functionality. Thus, GPER activation results in spinal nociception, and the downstream mechanisms involve cytosolic calcium increase, ROS accumulation and neuronal membrane depolarization. Perspective Our results suggest that GPER modulates pain processing in spinal sensory neurons via cytosolic calcium increase and ROS accumulation. These findings extend the current knowledge on GPER involvement in physiology and disease, providing the first evidence of its pro-nociceptive effects at central levels and characterizing some of the underlying mechanisms. PMID:22858342

  15. Increased nociceptive sensitivity and nociceptin/orphanin FQ levels in a rat model of PTSD

    PubMed Central

    2012-01-01

    Background Clinical studies indicate that post-traumatic stress disorder (PTSD) frequently shares co-morbidity with chronic pain. Although in animals acute stress-induced antinociception is well documented, the effect of PTSD-like stress on nociceptive sensitivity is unclear. Though a few studies measured nociceptive responses at a single time point, no studies have examined changes in nociceptive sensitivity over time following exposure to PTSD-like stress. Nociceptin/orphanin FQ (N/OFQ), an endogenous ligand for the N/OFQ peptide (NOP) receptor, modulates various biological functions in the central nervous system that are affected by PTSD, including nociceptive sensitivity, stress and anxiety, learning and memory. Results The present study examined thermal and mechanical nociceptive sensitivity in male Sprague Dawley rats between 7 and 28 days after single-prolonged stress (SPS), an established animal model for PTSD. Rat paw withdrawal thresholds (PWT) to von Frey and paw withdrawal latencies (PWL) to radiant heat stimuli, respectively, dramatically decreased as early as 7 days after initiation of SPS and lasted the length of the study, 28 days. In addition, N/OFQ levels increased in cerebrospinal fluid (CSF; on days 9, 14 and 28) and serum (day 28), while levels of circulating corticosterone (CORT) decreased 28 days after initiation of SPS. SPS exposure induced anxiety-like behavior and enhanced inhibition of the hypothalamo-pituitary-adrenal (HPA) axis, as previously reported for this model. Conclusions Our results demonstrate that SPS induces the development of persistent mechanical allodynia and thermal hyperalgesia that is accompanied by increased N/OFQ content in the CSF, and eventually, in serum. These findings suggest a link between N/OFQ and the development of hyperalgesia and allodynia in a rat model of PTSD. PMID:23082795

  16. Roles of isolectin B4-binding afferents in colorectal mechanical nociception

    PubMed Central

    La, Jun-Ho; Feng, Bin; Kaji, Kaori; Schwartz, Erica S.; Gebhart, G. F.

    2015-01-01

    Isolectin B4-binding (IB4+) dorsal root ganglion (DRG) neurons are distinct from peptidergic DRG neurons in their terminal location in the spinal cord and respective contributions to various classes and modalities of nociception. In DRG neurons innervating the mouse colon (c-DRG neurons), the reported proportion of IB4+ population is inconsistent across studies, and little is known regarding their role in colorectal mechano-nociception. To address these issues, in C57BL/6J mice, we quantified IB4-binding (IB4+) after labeling c-DRG neurons with Fast Blue (FB) and examined functional consequences of ablating these neurons by IB4-conjugated saporin (IB4-sap). Sixty one percent of FB-labeled neurons in the L6 DRG were IB4+, and 95% of these IB4+ c-DRG neurons were peptidergic. Intrathecal administration of IB4-sap reduced the proportion of IB4+ c-DRG neurons to 37%, which was due to the loss of c-DRG neurons showing strong to medium IB4+ intensity; c-DRG neurons with weak IB4+ intensity were spared. However, this loss altered neither nociceptive behaviors to colorectal distension nor the relative proportions of stretch-sensitive colorectal afferent classes characterized by single-fiber recordings. These findings demonstrate that more than one half of viscerosensory L6 c-DRG neurons in C57BL/6J mouse are IB4+ and suggest, in contrast to the reported roles of IB4+/non-peptidergic neurons in cutaneous mechano-nociception, c-DRG neurons with strong to medium IB4+ intensity do not play a significant role in colorectal mechano-nociception. PMID:26447707

  17. Central sensitization in thalamic nociceptive neurons induced by mustard oil application to rat molar tooth pulp.

    PubMed

    Zhang, S; Chiang, C Y; Xie, Y F; Park, S J; Lu, Y; Hu, J W; Dostrovsky, J O; Sessle, B J

    2006-10-27

    We have recently demonstrated that application of mustard oil (MO), a small-fiber excitant and inflammatory irritant, to the rat maxillary molar tooth pulp induces central sensitization that is reflected in changes in spontaneous activity, mechanoreceptive field (RF) size, mechanical activation threshold, and responses to graded mechanical stimuli applied to the neuronal RF in trigeminal brainstem subnucleus caudalis and subnucleus oralis. The aim of this study was to test whether central sensitization can be induced in nociceptive neurons of the posterior thalamus by MO application to the pulp. Single unit neuronal activity was recorded in the ventroposterior medial nucleus (VPM) or posterior nuclear group (PO) of the thalamus in anesthetized rats, and nociceptive neurons were classified as wide dynamic range (WDR) or nociceptive-specific (NS). MO application to the pulp was studied in 47 thalamic nociceptive neurons and found to excite over 50% of the 35 VPM neurons tested and to produce significant long-lasting (over 40 min) increases in spontaneous activity, cutaneous pinch RF size and responses to graded mechanical stimuli, and a decrease in threshold in the 29 NS neurons tested; a smaller but statistically significant increase in mean spontaneous firing rate and decrease in activation threshold occurred following MO in the six WDR neurons tested. Vehicle application to the pulp did not produce any significant changes in six VPM NS neurons tested. MO application to the pulp produced pronounced increases in spontaneous activity, pinch RF size, and responses to mechanical stimuli, and a decrease in threshold in three of the six PO neurons. In conclusion, application of the inflammatory irritant MO to the tooth pulp results in central sensitization of thalamic nociceptive neurons and this neuronal hyperexcitability likely contributes to the behavioral consequences of peripheral inflammation manifesting as pain referral, hyperalgesia and allodynia.

  18. Increased nociceptive input rapidly modulates spinal GABAergic transmission through endogenously released glutamate.

    PubMed

    Zhou, Hong-Yi; Zhang, Hong-Mei; Chen, Shao-Rui; Pan, Hui-Lin

    2007-01-01

    Stimulation of nociceptive primary afferents elicits pain by promoting glutamatergic transmission in the spinal cord. Little is known about how increased nociceptive input controls GABAergic tone in the spinal dorsal horn. In this study, we determined how increased nociceptive inflow affects GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of lamina II neurons by using whole cell recordings in rat spinal cord slices. Bath application of capsaicin for 3 min induced a long-lasting inhibition of sIPSCs in 50% of the neurons tested. In the other half of the neurons, capsaicin either increased the frequency of sIPSCs (34.6%) or had no effect on sIPSCs (15.4%). The GABA(A) current elicited by puff application of GABA was not altered by capsaicin. Capsaicin did not inhibit sIPSCs in rats treated with intrathecal pertussis toxin. Also, capsaicin failed to inhibit sIPSCs in the presence of ionotropic glutamate receptor antagonists or in the presence of both LY341495 and CPPG (group II and group III metabotropic glutamate receptor antagonists, respectively). However, when LY341495 or CPPG was used alone, capsaicin still decreased the frequency of sIPSCs in some neurons. Additionally, bradykinin significantly inhibited sIPSCs in a population of lamina II neurons and this inhibitory effect was also abolished by LY341495 and CPPG. Our study provides novel information that stimulation of nociceptive primary afferents rapidly suppresses GABAergic input to many dorsal horn neurons through endogenous glutamate and activation of presynaptic group II and group III metabotropic glutamate receptors. These findings extend our understanding of the microcircuitry of the spinal dorsal horn involved in nociception.

  19. Intracerebroventricular injection of trazodone produces 5-HT receptor subtype mediated anti-nociception at the supraspinal and spinal levels.

    PubMed

    Zhang, Rihui; Nagata, Tomonari; Hayashi, Takayuki; Miyata, Mariko; Kawakami, Yoriko

    2004-10-01

    Serotonin (5-HT) mediated anti-nociceptive effects induced by an anti-depressant, trazodone, are related to 5-HT(1A) receptor activities at the supraspinal level. 5-HT(3) receptor activation via the descending anti-nociceptive pathways may contribute to the trazodone mediated anti-nociception at the spinal level. Intracerebroventricular (i.c.v.) injection of trazodone dose-dependently impaired nociceptive responses in the formalin test in mice. Six and 15 microg of trazodone inhibited the early (P<0.05 or 0.01) and the late phases of the formalin test (P<0.05 or 0.01), while 3 microg had no effect. We examined the effects of a selective 5-HT(1A) receptor antagonist, WAY-100635, a single injection of which induced hyperalgesia (P<0.05), and blocked the anti-nociceptive effects of trazodone (P<0.01) when the two were simultaneously injected i.c.v. Intrathecal (i.t.) injection of a selective 5-HT(3) receptor antagonist, 3-tropanylindole-3-carboxylate hydrochloride, blocked the anti-nociceptive effects of i.c.v. trazodone (P<0.01), while WAY-100635 (i.t.) did not impair trazodone mediated anti-nociception. Trazodone mediated anti-nocicepton is related to serotonergic activity at both the supraspinal and the spinal level.

  20. Role of hepatocyte S6K1 in palmitic acid-induced endoplasmic reticulum stress, lipotoxicity, insulin resistance and in oleic acid-induced protection.

    PubMed

    Pardo, Virginia; González-Rodríguez, Águeda; Muntané, Jordi; Kozma, Sara C; Valverde, Ángela M

    2015-06-01

    The excess of saturated free fatty acids, such as palmitic acid, that induces lipotoxicity in hepatocytes, has been implicated in the development of non-alcoholic fatty liver disease also associated with insulin resistance. By contrast, oleic acid, a monounsaturated fatty acid, attenuates the effects of palmitic acid. We evaluated whether palmitic acid is directly associated with both insulin resistance and lipoapoptosis in mouse and human hepatocytes and the impact of oleic acid in the molecular mechanisms that mediate both processes. In human and mouse hepatocytes palmitic acid at a lipotoxic concentration triggered early activation of endoplasmic reticulum (ER) stress-related kinases, induced the apoptotic transcription factor CHOP, activated caspase 3 and increased the percentage of apoptotic cells. These effects concurred with decreased IR/IRS1/Akt insulin pathway. Oleic acid suppressed the toxic effects of palmitic acid on ER stress activation, lipoapoptosis and insulin resistance. Besides, oleic acid suppressed palmitic acid-induced activation of S6K1. This protection was mimicked by pharmacological or genetic inhibition of S6K1 in hepatocytes. In conclusion, this is the first study highlighting the activation of S6K1 by palmitic acid as a common and novel mechanism by which its inhibition by oleic acid prevents ER stress, lipoapoptosis and insulin resistance in hepatocytes.

  1. Intracisternal injection of palmitoylethanolamide inhibits the peripheral nociceptive evoked responses of dorsal horn wide dynamic range neurons.

    PubMed

    González-Hernández, Abimael; Martínez-Lorenzana, Guadalupe; Rodríguez-Jiménez, Javier; Rojas-Piloni, Gerardo; Condés-Lara, Miguel

    2015-03-01

    Endogenous palmitoylethanolamide (PEA) has a key role in pain modulation. Central or peripheral PEA can reduce nociceptive behavior, but no study has yet reported a descending inhibitory effect on the neuronal nociceptive activity of Aδ- and C-fibers. This study shows that intracisternal PEA inhibits the peripheral nociceptive responses of dorsal horn wide dynamic range cells (i.e., inhibition of Aδ- and C-fibers), an effect blocked by spinal methiothepin. These results suggest that a descending analgesic mechanism mediated by the serotonergic system could be activated by central PEA.

  2. Comparative neuroprotective profile of statins in quinolinic acid induced neurotoxicity in rats.

    PubMed

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2011-01-01

    A possible neuroprotective role has been recently suggested for 3H3MGCoA reductase inhibitors (statins). Here, we sought to determine neuroprotective effect of statins in quinolinic acid induced neurotoxicity in rats. Rats were surgically administered quinolinic acid and treated with Atorvastatin (10, 20 mg/kg), simvastatin (15, 30 mg/kg) and fluvastatin (5, 10 mg/kg) once daily up to 3 weeks. Atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) treatment significantly attenuated the quinolinic acid induced behavioral (locomotor activity, rotarod performance and beam walk test), biochemical (lipid peroxidation, nitrite concentration, SOD and catalase), mitochondrial enzyme complex alterations in rats suggesting their free radical scavenging potential. Additionally, atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) significantly decrease the TNF-α level and striatal lesion volume in quinolinic acid treated animals indicating their anti-inflammatory effects. In comparing the protective effect of different statins, atorvastatin is effective at both the doses while simvastatin and fluvastatins at respective lower doses were not able to produce the protective effect in quinolinic acid treated animals. These modulations can account, at least partly, for the beneficial effect of statins in our rodent model of striatal degeneration. Our findings show that statins could be explored as possible neuroprotective agents for neurodegenerative disorders such as HD.

  3. Salicylic acid induces mitochondrial injury by inhibiting ferrochelatase heme biosynthesis activity.

    PubMed

    Gupta, Vipul; Liu, Shujie; Ando, Hideki; Ishii, Ryohei; Tateno, Shumpei; Kaneko, Yuki; Yugami, Masato; Sakamoto, Satoshi; Yamaguchi, Yuki; Nureki, Osamu; Handa, Hiroshi

    2013-12-01

    Salicylic acid is a classic nonsteroidal anti-inflammatory drug. Although salicylic acid also induces mitochondrial injury, the mechanism of its antimitochondrial activity is not well understood. In this study, by using a one-step affinity purification scheme with salicylic acid-immobilized beads, ferrochelatase (FECH), a homodimeric enzyme involved in heme biosynthesis in mitochondria, was identified as a new molecular target of salicylic acid. Moreover, the cocrystal structure of the FECH-salicylic acid complex was determined. Structural and biochemical studies showed that salicylic acid binds to the dimer interface of FECH in two possible orientations and inhibits its enzymatic activity. Mutational analysis confirmed that Trp301 and Leu311, hydrophobic amino acid residues located at the dimer interface, are directly involved in salicylic acid binding. On a gel filtration column, salicylic acid caused a shift in the elution profile of FECH, indicating that its conformational change is induced by salicylic acid binding. In cultured human cells, salicylic acid treatment or FECH knockdown inhibited heme synthesis, whereas salicylic acid did not exert its inhibitory effect in FECH knockdown cells. Concordantly, salicylic acid treatment or FECH knockdown inhibited heme synthesis in zebrafish embryos. Strikingly, the salicylic acid-induced effect in zebrafish was partially rescued by FECH overexpression. Taken together, these findings illustrate that FECH is responsible for salicylic acid-induced inhibition of heme synthesis, which may contribute to its antimitochondrial and anti-inflammatory function. This study establishes a novel aspect of the complex pharmacological effects of salicylic acid.

  4. Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells.

    PubMed

    Ignacio Barrasa, Juan; Olmo, Nieves; Pérez-Ramos, Pablo; Santiago-Gómez, Angélica; Lecona, Emilio; Turnay, Javier; Antonia Lizarbe, M

    2011-10-01

    The continuous exposure of the colonic epithelium to high concentrations of bile acids may exert cytotoxic effects and has been related to pathogenesis of colon cancer. A better knowledge of the mechanisms by which bile acids induce toxicity is still required and may be useful for the development of new therapeutic strategies. We have studied the effect of deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) treatments in BCS-TC2 human colon adenocarcinoma cells. Both bile acids promote cell death, being this effect higher for CDCA. Apoptosis is detected after 30 min-2 h of treatment, as observed by cell detachment, loss of membrane asymmetry, internucleosomal DNA degradation, appearance of mitochondrial transition permeability (MPT), and caspase and Bax activation. At longer treatment times, apoptosis is followed in vitro by secondary necrosis due to impaired mitochondrial activity and ATP depletion. Bile acid-induced apoptosis is a result of oxidative stress with increased ROS generation mainly by activation of plasma membrane enzymes, such as NAD(P)H oxidases and, to a lower extent, PLA2. These effects lead to a loss of mitochondrial potential and release of pro-apoptotic factors to the cytosol, which is confirmed by activation of caspase-9 and -3, but not caspase-8. This initial apoptotic steps promote cleavage of Bcl-2, allowing Bax activation and formation of additional pores in the mitochondrial membrane that amplify the apoptotic signal.

  5. Polyunsaturated Branched-Chain Fatty Acid Geranylgeranoic Acid Induces Unfolded Protein Response in Human Hepatoma Cells

    PubMed Central

    Iwao, Chieko; Shidoji, Yoshihiro

    2015-01-01

    The acyclic diterpenoid acid geranylgeranoic acid (GGA) has been reported to induce autophagic cell death in several human hepatoma-derived cell lines; however, the molecular mechanism for this remains unknown. In the present study, several diterpenoids were examined for ability to induce XBP1 splicing and/or lipotoxicity for human hepatoma cell lines. Here we show that three groups of diterpenoids emerged: 1) GGA, 2,3-dihydro GGA and 9-cis retinoic acid induce cell death and XBP1 splicing; 2) all-trans retinoic acid induces XBP1 splicing but little cell death; and 3) phytanic acid, phytenic acid and geranylgeraniol induce neither cell death nor XBP1 splicing. GGA-induced ER stress/ unfolded protein response (UPR) and its lipotoxicity were both blocked by co-treatment with oleic acid. The blocking activity of oleic acid for GGA-induced XBP1 splicing was not attenuated by methylation of oleic acid. These findings strongly suggest that GGA at micromolar concentrations induces the so-called lipid-induced ER stress response/UPR, which is oleate-suppressive, and shows its lipotoxicity in human hepatoma cells. PMID:26186544

  6. Nucleic acid-induced antiviral immunity in invertebrates: an evolutionary perspective.

    PubMed

    Wang, Pei-Hui; Weng, Shao-Ping; He, Jian-Guo

    2015-02-01

    Nucleic acids derived from viral pathogens are typical pathogen associated molecular patterns (PAMPs). In mammals, the recognition of viral nucleic acids by pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs) and retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), induces the release of inflammatory cytokines and type I interferons (IFNs) through the activation of nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) 3/7 pathways, triggering the host antiviral state. However, whether nucleic acids can induce similar antiviral immunity in invertebrates remains ambiguous. Several studies have reported that nucleic acid mimics, especially dsRNA mimic poly(I:C), can strongly induce non-specific antiviral immune responses in insects, shrimp, and oyster. This behavior shows multiple similarities to the hallmarks of mammalian IFN responses. In this review, we highlight the current understanding of nucleic acid-induced antiviral immunity in invertebrates. We also discuss the potential recognition and regulatory mechanisms that confer non-specific antiviral immunity on invertebrate hosts.

  7. Ginkgolic acids induce neuronal death and activate protein phosphatase type-2C.

    PubMed

    Ahlemeyer, B; Selke, D; Schaper, C; Klumpp, S; Krieglstein, J

    2001-10-26

    The standardized extract from Ginkgo biloba (EGb 761) is used for the treatment of dementia. Because of allergenic and genotoxic effects, ginkgolic acids are restricted in EGb 761 to 5 ppm. The question arises whether ginkgolic acids also have neurotoxic effects. In the present study, ginkgolic acids caused death of cultured chick embryonic neurons in a concentration-dependent manner, in the presence and in the absence of serum. Ginkgolic acids-induced death showed features of apoptosis as we observed chromatin condensation, shrinkage of the nucleus and reduction of the damage by the protein synthesis inhibitor cycloheximide, demonstrating an active type of cell death. However, DNA fragmentation detected by the terminal-transferase-mediated ddUTP-digoxigenin nick-end labeling (TUNEL) assay and caspase-3 activation, which are also considered as hallmarks of apoptosis, were not seen after treatment with 150 microM ginkgolic acids in serum-free medium, a dose which increased the percentage of neurons with chromatin condensation and shrunken nuclei to 88% compared with 25% in serum-deprived, vehicle-treated controls. This suggests that ginkgolic acid-induced death showed signs of apoptosis as well as of necrosis. Ginkgolic acids specifically increased the activity of protein phosphatase type-2C, whereas other protein phosphatases such as protein phosphatases 1A, 2A and 2B, tyrosine phosphatase, and unspecific acid- and alkaline phosphatases were inhibited or remained unchanged, suggesting protein phosphatase 2C to play a role in the neurotoxic effect mediated by ginkgolic acids.

  8. Anti-nociceptive properties in rodents and the possibility of using polyphenol-rich fractions from sida urens L. (Malvaceae) against of dental caries bacteria

    PubMed Central

    2013-01-01

    Background Sida urens L. (Malvaceae) is in flora of Asian medicinal herbs and used traditionally in West of Burkina Faso for the treatment of infectious diseases and particularly used against, dental caries bacteria, fever, pain and possesses analgesic properties. This study was conducted to reveal the antibacterial effect against dental caries bacteria on the one hand, and evaluate their analgesic capacity in experimental model with Swiss mice and on the other hand, with an aim to provide a scientific basis for the traditional use of this plant for the management of dental caries bacteria. Method The antibacterial assays in this study were performed by using inhibition zone diameters, MIC (Minimum inhibitory concentration) and MBC (Minimal bactericidal concentration) methods. On the whole the dental caries bacteria (Gram-positive and Gram-negative bacterial strains) were used. Negative control was prepared using discs impregnated with 10% DMSO in water and commercially available Gentamicin from Alkom Laboratories LTD was used as positive reference standards for all bacterial strains. In acute toxicity test, mice received doses of extract (acetone/water extract) from Sida urens L. by intraperitoneal route and LD50 was determined in Swiss mice. As for analgesic effects, acetic acid writhing method was used in mice. The acetic acid-induced writhing method was used in mice with aim to study analgesic effects. Results The results showed that the highest antibacterial activities were founded with the polyphenol-rich fractions against all bacterial strains compared to the standard antibiotic. About preliminary study in acute toxicity test, LD50 value obtained was more than 5000 mg/kg b.w. Polyphenol-rich fractions produced significant analgesic effects in acetic acid-induced writhing method and in a dose-dependent inhibition was observed. Conclusion These results validate the ethno-botanical use of Sida urens L. (Malvaceae) and demonstrate the potential of this

  9. Glial activation in the collagenase model of nociception associated with osteoarthritis

    PubMed Central

    Almeida, Lígia; Potes, Catarina S; Ferreira, Ana Rita; Castro-Lopes, José M; Ferreira-Gomes, Joana; Neto, Fani L

    2017-01-01

    Background Experimental osteoarthritis entails neuropathic-like changes in dorsal root ganglia (DRG) neurons. Since glial activation has emerged as a key player in nociception, being reported in numerous models of neuropathic pain, we aimed at evaluating if glial cell activation may also occur in the DRG and spinal cord of rats with osteoarthritis induced by intra-articular injection of collagenase. Methods Osteoarthritis was induced by two injections, separated by three days, of 500 U of type II collagenase into the knee joint of rats. Movement-induced nociception was evaluated by the Knee-Bend and CatWalk tests during the following six weeks. Glial fibrillary acidic protein (GFAP) expression in satellite glial cells of the DRG was assessed by immunofluorescence and Western Blot analysis; the pattern of GFAP and activating transcription factor-3 (ATF-3) expression was also compared through double immunofluorescence analysis. GFAP expression in astrocytes and IBA-1 expression in microglia of the L3–L5 spinal cord segments was assessed by immunohistochemistry and Western Blot analysis. The effect of the intrathecal administration of fluorocitrate, an inhibitor of glial activation, on movement-induced nociception was evaluated six weeks after the first collagenase injection. Results GFAP expression in satellite glial cells of collagenase-injected animals was significantly increased six weeks after osteoarthritis induction. Double immunofluorescence showed GFAP upregulation in satellite glial cells surrounding ATF-3-positive neurons. In the spinal cord of collagenase-injected animals, an ipsilateral upregulation of GFAP and IBA-1 was also observed. The inhibition of glial activation with fluorocitrate decreased movement- and loading-induced nociception. Conclusion Collagenase-induced knee osteoarthritis leads to the development of nociception associated with movement of the affected joint and to the activation of glial cells in both the DRG and the spinal cord

  10. Glial activation in the collagenase model of nociception associated with osteoarthritis.

    PubMed

    Adães, Sara; Almeida, Lígia; Potes, Catarina S; Ferreira, Ana Rita; Castro-Lopes, José M; Ferreira-Gomes, Joana; Neto, Fani L

    2017-01-01

    Background Experimental osteoarthritis entails neuropathic-like changes in dorsal root ganglia (DRG) neurons. Since glial activation has emerged as a key player in nociception, being reported in numerous models of neuropathic pain, we aimed at evaluating if glial cell activation may also occur in the DRG and spinal cord of rats with osteoarthritis induced by intra-articular injection of collagenase. Methods Osteoarthritis was induced by two injections, separated by three days, of 500 U of type II collagenase into the knee joint of rats. Movement-induced nociception was evaluated by the Knee-Bend and CatWalk tests during the following six weeks. Glial fibrillary acidic protein (GFAP) expression in satellite glial cells of the DRG was assessed by immunofluorescence and Western Blot analysis; the pattern of GFAP and activating transcription factor-3 (ATF-3) expression was also compared through double immunofluorescence analysis. GFAP expression in astrocytes and IBA-1 expression in microglia of the L3-L5 spinal cord segments was assessed by immunohistochemistry and Western Blot analysis. The effect of the intrathecal administration of fluorocitrate, an inhibitor of glial activation, on movement-induced nociception was evaluated six weeks after the first collagenase injection. Results GFAP expression in satellite glial cells of collagenase-injected animals was significantly increased six weeks after osteoarthritis induction. Double immunofluorescence showed GFAP upregulation in satellite glial cells surrounding ATF-3-positive neurons. In the spinal cord of collagenase-injected animals, an ipsilateral upregulation of GFAP and IBA-1 was also observed. The inhibition of glial activation with fluorocitrate decreased movement- and loading-induced nociception. Conclusion Collagenase-induced knee osteoarthritis leads to the development of nociception associated with movement of the affected joint and to the activation of glial cells in both the DRG and the spinal cord

  11. A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase

    PubMed Central

    Carey, Lawrence M; Slivicki, Richard A; Leishman, Emma; Cornett, Ben; Mackie, Ken; Bradshaw, Heather

    2016-01-01

    Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic

  12. A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase.

    PubMed

    Carey, Lawrence M; Slivicki, Richard A; Leishman, Emma; Cornett, Ben; Mackie, Ken; Bradshaw, Heather; Hohmann, Andrea G

    2016-01-01

    Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wide range of structurally related, biologically active lipid signaling molecules whose functions remain largely unknown. Some of these endogenous lipids, including anandamide itself, may exert pro-nociceptive effects under certain conditions. In our study, FAAH KO mice exhibited a characteristic analgesic phenotype in the tail flick test and in both formalin and carrageenan models of inflammatory nociception. Nonetheless, intradermal injection of the transient receptor potential channel V1 (TRPV1) agonist capsaicin increased nocifensive behavior as well as mechanical and heat hypersensitivity in FAAH KO relative to wild-type mice. This pro-nociceptive phenotype was accompanied by increases in capsaicin-evoked Fos-like immunoreactive (FLI) cells in spinal dorsal horn regions implicated in nociceptive processing and was attenuated by CB1 (AM251) and TRPV1 (AMG9810) antagonists. When central sensitization was established, FAAH KO mice displayed elevated levels of anandamide, other fatty-acid amides, and endogenous TRPV1 agonists in both paw skin and lumbar spinal cord relative to wild-type mice. Capsaicin decreased spinal cord 2-AG levels and increased arachidonic acid and prostaglandin E2 levels in both spinal cord and paw skin irrespective of genotype. Our studies identify a previously unrecognized pro-nociceptive phenotype in FAAH KO mice that was unmasked by capsaicin challenge. The heightened nociceptive response was mediated by CB1 and TRPV1 receptors and accompanied by enhanced spinal neuronal activation. Moreover, genetic deletion of FAAH has a profound impact on the peripheral and central lipidome. Thus, genetic

  13. Utilization of acetate by Beggiatoa.

    PubMed

    Burton, S D; Morita, R Y; Miller, W

    1966-03-01

    Burton, Sheril D. (Institute of Marine Science, University of Alaska, College), Richard Y. Morita, and Wayne Miller. Utilization of acetate by Beggiatoa. J. Bacteriol. 91:1192-1200. 1966.-A proposed system which would permit acetate incorporation into four-carbon compounds without the presence of key enzymes of the citric acid cycle or glyoxylate cycle is described. In this system, acetyl-coenzyme A (CoA) is condensed with glyoxylate to form malate, which, in turn, is converted to oxaloacetate. Oxaloacetate then reacts with glutamate to produce alpha-ketoglutarate, which is subsequently converted to isocitrate. Cleavage of isocitrate produces glyoxylate and succinate. Thus, the proposed system is similar to the glyoxylate bypass in that malate is produced from glyoxylate and acetyl-CoA, but differs from both the citric acid cycle and the glyoxylate bypass, since citrate and fumarate are not involved. Fumarase, aconitase, catalase, citritase, pyruvate kinase, enolase, phosphoenolpyruvate carboxylase, lactic dehydrogenase, alpha-ketoglutarate dehydrogenase, and condensing enzyme were not detectable in crude extracts of Beggiatoa. Succinate was oxidized by a soluble enzyme not associated with an electron-transport particle. Isocitrate was identified as the sole compound labeled when C(14)O(2) was added to a reduced nicotinamide adenine dinucleotide, CO(2) generating system (crystalline glucose-6-phosphate dehydrogenase and glucose-6-phosphate) in the presence of alpha-ketoglutarate.

  14. Peripheral and central antinociceptive effects of the butanolic fraction of Byrsonima verbascifolia leaves on nociception-induced models in mice.

    PubMed

    Saldanha, A A; Siqueira, J M; Castro, A H F; Matos, N A; Klein, A; Silva, D B; Carollo, C A; Soares, A C

    2017-02-01

    Byrsonima verbascifolia (Malpighiaceae), commonly known as 'murici', is used in folk medicine, for example, in the treatment of inflammation. The anti-inflammatory activity of the butanolic fraction of B. verbascifolia leaves (BvBF) was previously reported by our group, and the present study was designed to evaluate their antinociceptive effects. BvBF (25, 50, and 100 mg/kg) administered intraperitoneally (i.p.) inhibited acetic acid induced abdominal writhing. In the formalin test, BvBF (10, 30 and 100 mg/kg, i.p.) caused a reduction in licking time in both the neurogenic and inflammatory phases. Moreover, we demonstrated that BvBF (30 and 100 mg/kg, i.p.) caused an increase in the latency to response in the hot-plate test. These results demonstrate that BvBF possesses marked peripheral and central antinociceptive activities. Pre-treatment with the non-selective receptor antagonist naloxone (5 mg/kg, i.p.) abolished the antinociceptive effects of BvBF (100 mg/kg, i.p.) in the neurogenic phase of the formalin and hot-plate tests. The anti-inflammatory activity of BvBF (previously reported) as well as the participation of the opioidergic system seems to be responsible, at least in part, for these antinociceptive effects. Finally, BvBF at the doses investigated (25, 50 and 100 mg/Kg) did not cause any toxicity signals, showing that the antinociceptive activity is devoid of sedative and hypomotility effects.

  15. Neuropeptidergic Signaling and Active Feeding State Inhibit Nociception in Caenorhabditis elegans.

    PubMed

    Ezcurra, Marina; Walker, Denise S; Beets, Isabel; Swoboda, Peter; Schafer, William R

    2016-03-16

    Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways.

  16. Is temporal summation of pain and spinal nociception altered during normal aging?

    PubMed

    Marouf, Rafik; Piché, Mathieu; Rainville, Pierre

    2015-10-01

    This study examines the effect of normal aging on temporal summation (TS) of pain and the nociceptive flexion reflex (RIII). Two groups of healthy volunteers, young and elderly, received transcutaneous electrical stimulation applied to the right sural nerve to assess pain and the nociceptive flexion reflex (RIII-reflex). Stimulus intensity was adjusted individually to 120% of RIII-reflex threshold, and shocks were delivered as a single stimulus or as a series of 5 stimuli to assess TS at 5 different frequencies (0.17, 0.33, 0.66, 1, and 2 Hz). This study shows that robust TS of pain and RIII-reflex is observable in individuals aged between 18 and 75 years and indicates that these effects are comparable between young and older individuals. These results contrast with some previous findings and imply that at least some pain regulatory processes, including TS, may not be affected by normal aging, although this may vary depending on the method.

  17. Artificial nociception and motor responses to pain, for humans and robots.

    PubMed

    Bagnato, Carlo; Takagi, Atsushi; Burdet, Etienne

    2015-01-01

    This concept paper describes nociception and the role of pain in humans. Understanding the mechanisms of pain can give insight into the implementation of artificial pain for robots. Identification of noxious contacts could help robots to elicit reactions in order to avoid or minimize damage to the robot and the environment. The information processing of artificial pain can also be used to optimally regulate incoming sensory information and prevent accidents or real pain to the users of robotic systems and prostheses, improving the performance of robots and their interaction with human users. Besides the applications of artificial nociception for robotic manipulation and intelligent prostheses, the development of computational models of pain mechanisms for the discrimination of noxious stimuli from innocuous touch can find crucial clinical applications, addressing the vulnerable non-verbal population who are unable to report pain.

  18. Enzymatic production of glycerol acetate from glycerol.

    PubMed

    Oh, Seokhyeon; Park, Chulhwan

    2015-02-01

    In this study, we report the enzymatic production of glycerol acetate from glycerol and methyl acetate. Lipases are essential for the catalysis of this reaction. To find the optimum conditions for glycerol acetate production, sequential experiments were designed. Type of lipase, lipase concentration, molar ratio of reactants, reaction temperature and solvents were investigated for the optimum conversion of glycerol to glycerol acetate. As the result of lipase screening, Novozym 435 (Immobilized Candida antarctica lipase B) was turned out to be the optimal lipase for the reaction. Under the optimal conditions (2.5 g/L of Novozym 435, 1:40 molar ratio of glycerol to methyl acetate, 40 °C and tert-butanol as the solvent), glycerol acetate production was achieved in 95.00% conversion.

  19. Role of the spinal cord heme oxygenase-carbon monoxide-cGMP pathway in the nociceptive response of rats.

    PubMed

    Nascimento, Carlos G O; Branco, Luiz G S

    2008-02-26

    The aim of the present study was to investigate the role of the spinal cord heme oxygenase (HO)-carbon monoxide (CO)-soluble guanylate cyclase (sGC)-cGMP pathway in nociceptive response of rats to the formalin experimental nociceptive model. Animals were handled and adapted to the experimental environment for a few days before the formalin test was applied. For the formalin test 50 microl of a 1% formalin solution was injected subcutaneously in the dorsal surface of the right hind paw. Following injections, animals were observed for 1 h and flinching behavior was measured as the nociceptive response. Thirty min before the test, rats were pretreated with intrathecal injections with the HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) or heme-lysinate, which is known to induce the HO pathway. Control animals were treated with vehicles. We observed a significant increase in nociceptive response of rats treated with ZnDPBG, and a drastic reduction of flinching nociceptive behavioral response in the heme-lysinate treated animals. Furthermore, the HO pathway seems to act via cGMP, since methylene blue (a sGC inhibitor) prevented the reduction of flinching nociceptive behavioral response caused by heme-lysinate. These findings strongly indicate that the HO pathway plays a spinal antinociceptive role during the formalin test, acting via cGMP.

  20. CA3 Synaptic Silencing Attenuates Kainic Acid-Induced Seizures and Hippocampal Network Oscillations123

    PubMed Central

    Yu, Lily M. Y.; Wintzer, Marie E.

    2016-01-01

    Abstract Epilepsy is a neurological disorder defined by the presence of seizure activity, manifest both behaviorally and as abnormal activity in neuronal networks. An established model to study the disorder in rodents is the systemic injection of kainic acid, an excitatory neurotoxin that at low doses quickly induces behavioral and electrophysiological seizures. Although the CA3 region of the hippocampus has been suggested to be crucial for kainic acid-induced seizure, because of its strong expression of kainate glutamate receptors and its high degree of recurrent connectivity, the precise role of excitatory transmission in CA3 in the generation of seizure and the accompanying increase in neuronal oscillations remains largely untested. Here we use transgenic mice in which CA3 pyramidal cell synaptic transmission can be inducibly silenced in the adult to demonstrate CA3 excitatory output is required for both the generation of epileptiform oscillatory activity and the progression of behavioral seizures. PMID:27022627

  1. Heat shock protein 70-dependent protective effect of polaprezinc on acetylsalicylic acid-induced apoptosis of rat intestinal epithelial cells.

    PubMed

    Qin, Ying; Naito, Yuji; Handa, Osamu; Hayashi, Natsuko; Kuki, Aiko; Mizushima, Katsura; Omatsu, Tatsushi; Tanimura, Yuko; Morita, Mayuko; Adachi, Satoko; Fukui, Akifumi; Hirata, Ikuhiro; Kishimoto, Etsuko; Nishikawa, Taichiro; Uchiyama, Kazuhiko; Ishikawa, Takeshi; Takagi, Tomohisa; Yagi, Nobuaki; Kokura, Satoshi; Yoshikawa, Toshikazu

    2011-11-01

    Protection of the small intestine from mucosal injury induced by nonsteroidal anti-inflammatory drugs including acetylsalicylic acid is a critical issue in the field of gastroenterology. Polaprezinc an anti-ulcer drug, consisting of zinc and L-carnosine, provides gastric mucosal protection against various irritants. In this study, we investigated the protective effect of polaprezinc on acetylsalicylic acid-induced apoptosis of the RIE1 rat intestinal epithelial cell line. Confluent rat intestinal epithelial cells were incubated with 70 µM polaprezinc for 24 h, and then stimulated with or without 15 mM acetylsalicylic acid for a further 15 h. Subsequent cellular viability was quantified by fluorometric assay based on cell lysis and staining. Acetylsalicylic acid-induced cell death was also qualified by fluorescent microscopy of Hoechst33342 and propidium iodide. Heat shock proteins 70 protein expression after adding polaprezinc or acetylsalicylic acid was assessed by western blotting. To investigate the role of Heat shock protein 70, Heat shock protein 70-specific small interfering RNA was applied. Cell viability was quantified by fluorometric assay based on cell lysis and staining and apoptosis was analyzed by fluorescence-activated cell sorting. We found that acetylsalicylic acid significantly induced apoptosis of rat intestinal epithelial cells in a dose- and time-dependent manner. Polaprezinc significantly suppressed acetylsalicylic acid-induced apoptosis of rat intestinal epithelial cells at its late phase. At the same time, polaprezinc increased Heat shock protein 70 expressions of rat intestinal epithelial cells in a time-dependent manner. However, in Heat shock protein 70-silenced rat intestinal epithelial cells, polaprezinc could not suppress acetylsalicylic acid -induced apoptosis at its late phase. We conclude that polaprezinc-increased Heat shock protein 70 expression might be an important mechanism by which polaprezinc suppresses acetylsalicylic

  2. Inhibitory control of nociceptive responses of trigeminal spinal nucleus cells by somatosensory corticofugal projection in rat.

    PubMed

    Malmierca, E; Martin, Y B; Nuñez, A

    2012-09-27

    The caudal division of the trigeminal spinal nucleus (Sp5C) is an important brainstem relay station of orofacial pain transmission. The aim of the present study was to examine the effect of cortical electrical stimulation on nociceptive responses in Sp5C neurons. Extracellular recordings were performed in the Sp5C nucleus by tungsten microelectrodes in urethane-anesthetized Sprague-Dawley rats. Nociceptive stimulation was produced by application of capsaicin cream on the whisker pad or by constriction of the infraorbital nerve. Capsaicin application evoked a long-lasting increase in the spontaneous firing rate from 1.4±0.2 to 3.4±0.6 spikes/s. Non-noxious tactile responses from stimuli delivered to the receptive field (RF) center decreased 5 min. after capsaicin application (from 2.3±0.1 to 1.6±0.1 spikes/stimulus) while responses from the whisker located at the RF periphery increased (from 1.3±0.2 to 2.0±0.1 spikes/stimulus under capsaicin). Electrical train stimulation of the primary (S1) or secondary (S2) somatosensory cortical areas reduced the increase in the firing rate evoked by capsaicin. Also, S1, but not S2, cortical stimulation reduced the increase in non-noxious tactile responses from the RF periphery. Inhibitory cortical effects were mediated by the activation of GABAergic and glycinergic neurons because they were blocked by bicuculline or strychnine. The S1 and S2 cortical stimulation also inhibited Sp5C neurons in animals with constriction of the infraorbital nerve. Consequently, the corticofugal projection from S1 and S2 cortical areas modulates nociceptive responses of Sp5C neurons and may control the transmission of nociceptive sensory stimulus.

  3. Identification of multisegmental nociceptive afferents that modulate locomotor circuits in the neonatal mouse spinal cord.

    PubMed

    Mandadi, Sravan; Hong, Peter; Tran, Michelle A; Bráz, Joao M; Colarusso, Pina; Basbaum, Allan I; Whelan, Patrick J

    2013-08-15

    Compared to proprioceptive afferent collateral projections, less is known about the anatomical, neurochemical, and functional basis of nociceptive collateral projections modulating lumbar central pattern generators (CPG). Quick response times are critical to ensure rapid escape from aversive stimuli. Furthermore, sensitization of nociceptive afferent pathways can contribute to a pathological activation of motor circuits. We investigated the extent and role of collaterals of capsaicin-sensitive nociceptive sacrocaudal afferent (nSCA) nerves that directly ascend several spinal segments in Lissauer's tract and the dorsal column and regulate motor activity. Anterograde tracing demonstrated direct multisegmental projections of the sacral dorsal root 4 (S4) afferent collaterals in Lissauer's tract and in the dorsal column. Subsets of the traced S4 afferent collaterals expressed transient receptor potential vanilloid 1 (TRPV1), which transduces a nociceptive response to capsaicin. Electrophysiological data revealed that S4 dorsal root stimulation could evoke regular rhythmic bursting activity, and our data suggested that capsaicin-sensitive collaterals contribute to CPG activation across multiple segments. Capsaicin's effect on S4-evoked locomotor activity was potent until the lumbar 5 (L5) segments, and diminished in rostral segments. Using calcium imaging we found elevated calcium transients within Lissauer's tract and dorsal column at L5 segments when compared to the calcium transients only within the dorsal column at the lumbar 2 (L2) segments, which were desensitized by capsaicin. We conclude that lumbar locomotor networks in the neonatal mouse spinal cord are targets for modulation by direct multisegmental nSCA, subsets of which express TRPV1 in Lissauer's tract and the dorsal column. J. Comp. Neurol. 521:2870-2887, 2013. © 2013 Wiley Periodicals, Inc.

  4. Nociceptive and Inflammatory Mediator Upregulation in a Mouse Model of Chronic Prostatitis

    PubMed Central

    Schwartz, Erica S.; Xie, Amy; La, Jun-Ho; Gebhart, G.F.

    2015-01-01

    Chronic nonbacterial prostatitis, characterized by genitourinary pain in the pelvic region in the absence of an identifiable cause, is common in adult males. Surprisingly, the sensory innervation of the prostate and mediators that sensitize its innervation have received little attention. We thus characterized a mouse model of chronic prostatitis, focusing on the prostate innervation and how organ inflammation affects gene expression of putative nociceptive markers in prostate afferent somata in dorsal root ganglia (DRG) and mediators in the prostate. Retrograde tracing (fast blue, FB) from the prostate revealed that thoracolumbar (TL) and lumbosacral (LS) DRG are the principal sources of somata of prostate afferents. Nociceptive markers (e.g., TRP, TREK and P2X channels) were upregulated in FB-labeled TL and LS somata for up to four weeks after inflaming the prostate (intra-prostate injection of zymosan). Prostatic inflammation was evident histologically, by monocyte infiltration and a significant increase in mast cell tryptase activity 14, 21 and 28 days after zymosan injection. Interleukin-10 and NGF were also significantly upregulated in the prostate throughout the four weeks of inflammation. Open field pain-related behaviors (e.g., rearing) were unchanged in prostate-inflamed mice, suggesting the absence of ongoing nociception, but withdrawal thresholds to lower abdominal pressure were significantly reduced. The increases in IL-10, mast cell tryptase and NGF in the inflamed prostate were cotemporaneous with reduced thresholds to probing of the abdomen and upregulation of nociceptive markers in DRG somata innervating the prostate. The results provide insight and direction for study of mechanisms underlying pain in chronic prostatitis. PMID:25915147

  5. Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers.

    PubMed

    Nilsson, H J; Schouenborg, J

    1999-03-01

    It is known that stimulation of thin cutaneous nerve fibers can induce long lasting analgesia through both supraspinal and segmental mechanisms, the latter often exhibiting restricted receptive fields. On this basis, we recently developed a new method, termed cutaneous field stimulation (CFS), for localized stimulation of A delta and C fibers in the superficial part of the skin. In the present study, we have evaluated the effects of CFS on non-nociceptive and nociceptive skin senses. We compared the effects of CFS with those of conventional transcutaneous electrical nerve stimulation (TENS), known to preferentially activate coarse myelinated fibers. A battery of sensory tests were made on the right volar forearm of 20 healthy subjects. CFS (16 electrodes, 4 Hz per electrode, 1 ms, up to 0.8 mA) and TENS (100 Hz, 0.2 ms, up to 26 mA) applied either on the right volar forearm (homotopically), or on the lower right leg (heterotopically) were used as conditioning stimulation for 25 min. The tactile threshold was not affected by either homo- or heterotopical CFS or TENS. The mean thresholds for detecting warming or cooling of the skin were increased by 0.4-0.9 degrees C after homo- but not heterotopical CFS and TENS. Regarding nociceptive skin senses, homo- but not heterotopical CFS, markedly reduced CO2-laser evoked A delta- and C fiber mediated heat pain to 75 and 48% of control, respectively, and mechanically evoked pain to 73% of control. Fabric evoked prickle, was not affected by CFS. Neither homo- nor heterotopical TENS induced any marked analgesic effects. It is concluded that different qualities of nociception can be differentially controlled by CFS.

  6. Endogenous inhibition of pain and spinal nociception in women with premenstrual dysphoric disorder

    PubMed Central

    Palit, Shreela; Bartley, Emily J; Kuhn, Bethany L; Kerr, Kara L; DelVentura, Jennifer L; Terry, Ellen L; Rhudy, Jamie L

    2016-01-01

    Purpose Premenstrual dysphoric disorder (PMDD) is characterized by severe affective and physical symptoms, such as increased pain, during the late-luteal phase of the menstrual cycle. The mechanisms underlying hyperalgesia in women with PMDD have yet to be identified, and supraspinal pain modulation has yet to be examined in this population. The present study assessed endogenous pain inhibitory processing by examining conditioned pain modulation (CPM, a painful conditioning stimulus inhibiting pain evoked by a test stimulus at a distal body site) of pain and the nociceptive flexion reflex (NFR, a spinally-mediated withdrawal reflex) during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle. Methods Participants were regularly-cycling women (14 without PMDD; 14 with PMDD). CPM was assessed by delivering electrocutaneous test stimuli to the sural nerve before, during, and after a painful conditioning ischemia task. Participants rated their pain to electrocutaneous stimuli, and NFR magnitudes were measured. A linear mixed model analysis was used to assess the influence of group and menstrual phase on CPM. Results Compared with controls, women with PMDD experienced greater pain during the late-luteal phase and enhanced spinal nociception during the ovulation phase, both of which were independent of CPM. Both groups showed CPM inhibition of pain that did not differ by menstrual phase. Only women with PMDD evidenced CPM inhibition of NFR. Conclusion Endogenous modulation of pain and spinal nociception is not disrupted in women with PMDD. Additionally, greater NFR magnitudes during ovulation in PMDD may be due to tonically-engaged descending mechanisms that facilitate spinal nociception, leading to enhanced pain during the premenstrual phase. PMID:26929663

  7. Substance P spinal signaling induces glial activation and nociceptive sensitization after fracture

    PubMed Central

    Li, Wen-Wu; Guo, Tian-Zhi; Shi, Xiaoyou; Sun, Yuan; Wei, Tzuping; Clark, David J; Kingery, Wade S

    2015-01-01

    Tibia fracture in rodents induces substance P (SP)-dependent keratinocyte activation and inflammatory changes in the hindlimb, similar to those seen in complex regional pain syndrome (CRPS). In animal pain models spinal glial cell activation results in nociceptive sensitization. This study tested the hypothesis that limb fracture triggers afferent C-fiber SP release in the dorsal horn, resulting in chronic glia activation and central sensitization. At 4 weeks after tibia fracture and casting in rats, the cast was removed and hind paw allodynia, unweighting, warmth, and edema were measured, then the antinociceptive effects of microglia (minocycline) or astrocyte (LAA) inhibitors or an SP receptor antagonist (LY303870) were tested. Immunohistochemistry and PCR were used to evaluate microglia and astrocyte activation in the dorsal horn. Similar experiments were performed in intact rats after brief sciatic nerve electric stimulation at C-fiber intensity. Microglia and astrocytes were chronically activated at 4 weeks after fracture and contributed to the maintenance of hind paw allodynia and unweighting. Furthermore, LY303870 treatment initiated at 4 weeks after fracture partially reversed both spinal glial activation and nociceptive sensitization. Similarly, persistent spinal microglial activation and hind paw nociceptive sensitization were observed at 48 hours after sciatic nerve C-fiber stimulation and this effect was inhibited by treatment with minocycline, LAA, or LY303870. These data support the hypothesis that C-fiber afferent SP signaling chronically supports spinal neuroglia activation after limb fracture and that glial activation contributes to the maintenance of central nociceptive sensitization in CRPS. Treatments inhibiting glial activation and spinal inflammation may be therapeutic for CRPS. PMID:26386297

  8. Two histamine H2 receptor antagonists, zolantidine and cimetidine, modulate nociception in cholestatic rats.

    PubMed

    Hasanein, Parisa

    2011-02-01

    Cholestasis is associated with analgesia. The histamine H(2) receptors control pain perception. The involvement of histamine H(2) receptors on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using zolantidine and cimetidine as two H(2) receptor antagonists and dimaprit as a selective H(2) receptor agonist. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct at the midpoint between them. A significant increase in tail-flick latencies was observed in cholestatic rats compared to non-cholestatic rats. Administration of zolantidine (10, 20 and 40 mg/kg) and cimetidine (25, 50 and 100 mg/kg) in the cholestatic group significantly increased tail-flick latencies while dimaprit (10 and 20 mg/kg) injection in the cholestatic group decreased tail-flick latencies compared to the saline treated cholestatic group. Antinociception produced by injection of zolantidine and cimetidine in cholestatic rats was attenuated by co-administration of naloxone. Drug injection in non-cholestatic rats did not alter tail-flick latencies compared to the saline treated rats at any of the doses. At the doses used here, none of the drugs impaired motor coordination as revealed by the rota rod test. These data show that the histamine H(2) receptor system may be involved in the regulation of nociception during cholestasis. According to the hypothesis that increasing the nociception threshold in cholestasis may lead to a decrease in the perception of pruritus, the provision of the drugs that increase the threshold to nociception may be a novel approach to the treatment of cholestatic pruritus.

  9. Transforming growth factor-β in normal nociceptive processing and pathological pain models.

    PubMed

    Lantero, Aquilino; Tramullas, Mónica; Díaz, Alvaro; Hurlé, María A

    2012-02-01

    The transforming growth factor-β (TGF-β) superfamily is a multifunctional, contextually acting family of cytokines that participate in the regulation of development, disease and tissue repair in the nervous system. The TGF-β family is composed of several members, including TGF-βs, bone morphogenetic proteins (BMPs) and activins. In this review, we discuss recent findings that suggest TGF-β function as important pleiotropic modulators of nociceptive processing both physiologically and under pathological painful conditions. The strategy of increasing TGF-β signaling by deleting "BMP and activin membrane-bound inhibitor" (BAMBI), a TGF-β pseudoreceptor, has demonstrated the inhibitory role of TGF-β signaling pathways in normal nociception and in inflammatory and neuropathic pain models. In particular, strong evidence suggests that TGF-β1 is a relevant mediator of nociception and has protective effects against the development of chronic neuropathic pain by inhibiting the neuroimmune responses of neurons and glia and promoting the expression of endogenous opioids within the spinal cord. In the peripheral nervous system, activins and BMPs function as target-derived differentiation factors that determine and maintain the phenotypic identity and circuit assembly of peptidergic nociceptors. In this context, activin is involved in the complex events of neuroinflammation that modulate the expression of pain during wound healing. These findings have provided new insights into the physiopathology of nociception. Moreover, specific members of the TGF-β family and their signaling effectors and modulator molecules may be promising molecular targets for novel therapeutic agents for pain management.

  10. Privileged crosstalk between TRPV1 channels and mitochondrial calcium shuttling machinery controls nociception.

    PubMed

    Nita, Iulia I; Caspi, Yaki; Gudes, Sagi; Fishman, Dimitri; Lev, Shaya; Hersfinkel, Michal; Sekler, Israel; Binshtok, Alexander M

    2016-12-01

    The nociceptive noxious heat-activated receptor - TRPV1, conducts calcium and sodium, thus producing a depolarizing receptor potential, leading to activation of nociceptive neurons. TRPV1-mediated calcium and sodium influx is negatively modulated by calcium, via calcium-dependent desensitization of TRPV1 channels. A mitochondrial Ca(2+) uniporter - MCU, controls mitochondrial Ca(2+) entry while a sodium/calcium transporter - NCLX shapes calcium and sodium transients by mediating sodium entry into and removing calcium from the mitochondria. The functional interplay between TRPV1, MCU and NCLX, in controlling the cytosolic and mitochondrial calcium and sodium transients and subsequently the nociceptive excitability, is poorly understood. Here, we used cytosolic and mitochondrial fluorescent calcium and sodium imaging together with electrophysiological recordings of TRPV1-induced currents in HEK293T cells and nociceptor-like dissociated rat dorsal root ganglion neurons, while modulating NCLX or MCU expression using specific small interfering RNA (siNCLX). We show that the propagation of the TRPV1-induced cytosolic calcium and sodium fluxes into mitochondria is dependent on coordinated activity of NCLX and MCU. Thus, knocking-down of NCLX triggers down regulation of MCU dependent mitochondrial Ca(2+) uptake. This in turn decreases rate and amplitude of TRPV1-mediated cytosolic calcium, which inhibits capsaicin-induced inward current and neuronal firing. TRPV1-mediated currents were fully rescued by intracellular inclusion of the fast calcium chelator BAPTA. Finally, NCLX controls capsaicin-induced cell death, by supporting massive mitochondrial Ca(2+) shuttling. Altogether, our results suggest that NCLX, by regulating cytosolic and mitochondrial ionic transients, modulates calcium-dependent desensitization of TRPV1 channels, thereby, controlling nociceptive signaling.

  11. Differential effects of stress on escape and reflex responses to nociceptive thermal stimuli in the rat.

    PubMed

    King, C D; Devine, D P; Vierck, C J; Rodgers, J; Yezierski, R P

    2003-10-17

    Acute stress has been shown to increase latencies of nociceptive reflexes, and this effect is considered evidence for stress-induced analgesia. However, tests for nociception that rely on motivated operant escape assess cerebral processing of pain and could be modulated independent of reflex responses. We therefore compared the effects of an acute stressor (restraint) on escape responses and lick/guard reflexes to stimulation of the paws by a thermally regulated floor. Testing sessions included a pre-test exposure to 36 degrees C, followed by a test trial in which either escape from 44 or 36 degrees C or reflex responses to 44 degrees C were observed. Behavioral responses to stress were assessed during a three day period, with baseline testing on day 1, post-stress or control testing on day 2, and evaluation of long-term stress effects on day 3. On day 2, half the animals received 15 min of restraint stress, followed by 15-min pre-test and test trials. Licking and guarding responses to thermal stimulation during 44 degrees C test trials were significantly reduced by restraint stress, confirming previously reported stress effects on nociceptive reflexes. In contrast, learned escape responses to the same thermal stimulus were significantly enhanced after stress. The increase in operant sensitivity suggests that acute restraint, a form of psychological stress, produces hyperalgesia for a level of thermal stimulation that preferentially activates C nociceptors. These results are discussed in relation to studies involving physical or psychological forms of stress, different nociceptive stimuli, and assessment strategies used to evaluate thermal pain sensitivity.

  12. 21 CFR 184.1005 - Acetic acid.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Acetic acid. 184.1005 Section 184.1005 Food and... Substances Affirmed as GRAS § 184.1005 Acetic acid. (a) Acetic acid (C2H4O2, CAS Reg. No. 64-19-7) is known as ethanoic acid. It occurs naturally in plant and animal tissues. It is produced by fermentation...

  13. 21 CFR 184.1005 - Acetic acid.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Acetic acid. 184.1005 Section 184.1005 Food and... Substances Affirmed as GRAS § 184.1005 Acetic acid. (a) Acetic acid (C2H4O2, CAS Reg. No. 64-19-7) is known as ethanoic acid. It occurs naturally in plant and animal tissues. It is produced by fermentation...

  14. 21 CFR 184.1005 - Acetic acid.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Acetic acid. 184.1005 Section 184.1005 Food and... Substances Affirmed as GRAS § 184.1005 Acetic acid. (a) Acetic acid (C2H4O2, CAS Reg. No. 64-19-7) is known as ethanoic acid. It occurs naturally in plant and animal tissues. It is produced by fermentation...

  15. 21 CFR 184.1005 - Acetic acid.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Acetic acid. 184.1005 Section 184.1005 Food and... Substances Affirmed as GRAS § 184.1005 Acetic acid. (a) Acetic acid (C2H4O2, CAS Reg. No. 64-19-7) is known as ethanoic acid. It occurs naturally in plant and animal tissues. It is produced by fermentation...

  16. Neuroprotective effects of butterbur and rough aster against kainic Acid-induced oxidative stress in mice.

    PubMed

    Oh, Sang Hee; Sok, Dai-Eun; Kim, Mee Ree

    2005-01-01

    The separate and combined neuroprotective effects of rough aster (Aster scaber) and butterbur (Petasite japonicus) extracts against oxidative damage in the brain of mice challenged with kainic acid were examined by comparing behavioral changes and biochemical parameters of oxidative stress. Rough aster butanol extract (400 mg/kg) and/or butterbur butanol extract (150 or 400 mg/kg) were administered to male ICR mice, 6-8 weeks old, through a gavage for 4 days consecutively, and on day 4, kainic acid (50 mg/kg) was administered intraperitoneally. Compared with the vehicle-treated control, no significant changes in body and brain weight were observed in mice administered rough aster or butterbur butanol extract. Administration of kainic acid only, causing a lethality of approximately 54%, resulted in a significant decrease of total glutathione level and increase of thiobarbituric acid-reactive substances (TBARS) value in brain tissue. The administration of butterbur or rough aster extract (400 mg/kg) decreased the lethality (50%) of kainic acid to 25%, alleviated the behavioral signs of neurotoxicity, restored the cytosolic glutathione level of brain homogenate to approximately 80% (P < .05), and reduced kainic acid-induced increases in TBARS values. In contrast to no significant neuroprotection by butterbur extract at a low dose (150 mg/kg), the combination of rough aster extract and butterbur extract reduced the lethality to 12.5%. Moreover, the combination delayed the onset time of behavioral signs by twofold, and significantly preserved the level of cytosolic glutathione peroxidase and glutathione reductase activities. However, the other biochemical parameters were not altered significantly by the combination. Thus, the combination of two vegetable extracts significantly increased the neuroprotective action against kainic acid-induced neurotoxicity. Based on these findings, the combination of butterbur extract and rough aster extract contains a functional agent or

  17. The Ayurvedic drug, Ksheerabala, ameliorates quinolinic acid-induced oxidative stress in rat brain.

    PubMed

    Swathy, S S; Indira, M

    2010-01-01

    One of the mechanisms of neurotoxicity is the induction of oxidative stress. There is hardly any cure for neurotoxicity in modern medicine, whereas many drugs in Ayurveda possess neuroprotective effects; however, there is no scientific validation for these drugs. Ksheerabala is an ayurvedic drug which is used to treat central nervous system disorders, arthritis, and insomnia. The aim of our study was to evaluate the effect of Ksheerabala on quinolinic acid-induced toxicity in rat brain. The optimal dose of Ksheerabala was found from a dose escalation study, wherein it was found that Ksheerabala showed maximum protection against quinolinic acid-induced neurotoxicity at a dose of 15 microL/100 g body weight/day, which was selected for further experiments. Four groups of female albino rats were maintained for 21 days as follows: 1. Control group, 2. Quinolinic acid (55 microg/100 g body weight), 3. Ksheerabala (15 microL/100 g body weight), 4. Ksheerabala (15 microL/100 g body weight) + Quinolinic acid (55 microg/100 g body weight). At the end of the experimental period, levels of lipid peroxidation products, protein carbonyls, and activities of scavenging enzymes were analyzed. The results revealed that quinolinic acid intake caused enhanced lipid and protein peroxidation as evidenced by increased levels of peroxidation products such as malondialdehyde, hydroperoxide, conjugated dienes, and protein carbonyls. On the other hand, the activities of scavenging enzymes such as catalase, superoxide dismutase (SOD), glutathione peroxidase, and glutathione reductase as well as the concentration of glutathione were reduced. On coadminstration of Ksheerabala along with quinolinic acid, the levels of all the biochemical parameters were restored to near-normal levels, indicating the protective effect of the drug. These results were reinforced by histopathological studies.

  18. Proteomic investigation into betulinic acid-induced apoptosis of human cervical cancer HeLa cells.

    PubMed

    Xu, Tao; Pang, Qiuying; Zhou, Dong; Zhang, Aiqin; Luo, Shaman; Wang, Yang; Yan, Xiufeng

    2014-01-01

    Betulinic acid is a pentacyclic triterpenoid that exhibits anticancer functions in human cancer cells. This study provides evidence that betulinic acid is highly effective against the human cervical cancer cell line HeLa by inducing dose- and time-dependent apoptosis. The apoptotic process was further investigated using a proteomics approach to reveal protein expression changes in HeLa cells following betulinic acid treatment. Proteomic analysis revealed that there were six up- and thirty down-regulated proteins in betulinic acid-induced HeLa cells, and these proteins were then subjected to functional pathway analysis using multiple analysis software. UDP-glucose 6-dehydrogenase, 6-phosphogluconate dehydrogenase decarboxylating, chain A Horf6-a novel human peroxidase enzyme that involved in redox process, was found to be down-regulated during the apoptosis process of the oxidative stress response pathway. Consistent with our results at the protein level, an increase in intracellular reactive oxygen species was observed in betulinic acid-treated cells. The proteins glucose-regulated protein and cargo-selection protein TIP47, which are involved in the endoplasmic reticulum pathway, were up-regulated by betulinic acid treatment. Meanwhile, 14-3-3 family proteins, including 14-3-3β and 14-3-3ε, were down-regulated in response to betulinic acid treatment, which is consistent with the decrease in expression of the target genes 14-3-3β and 14-3-3ε. Furthermore, it was found that the antiapoptotic bcl-2 gene was down-regulated while the proapoptotic bax gene was up-regulated after betulinic acid treatment in HeLa cells. These results suggest that betulinic acid induces apoptosis of HeLa cells by triggering both the endoplasmic reticulum pathway and the ROS-mediated mitochondrial pathway.

  19. Activation of TRESK channels by the inflammatory mediator lysophosphatidic acid balances nociceptive signalling

    PubMed Central

    Kollert, Sina; Dombert, Benjamin; Döring, Frank; Wischmeyer, Erhard

    2015-01-01

    In dorsal root ganglia (DRG) neurons TRESK channels constitute a major current component of the standing outward current IKSO. A prominent physiological role of TRESK has been attributed to pain sensation. During inflammation mediators of pain e.g. lysophosphatidic acid (LPA) are released and modulate nociception. We demonstrate co-expression of TRESK and LPA receptors in DRG neurons. Heterologous expression of TRESK and LPA receptors in Xenopus oocytes revealed augmentation of basal K+ currents upon LPA application. In DRG neurons nociception can result from TRPV1 activation by capsaicin or LPA. Upon co-expression in Xenopus oocytes LPA simultaneously increased both depolarising TRPV1 and hyperpolarising TRESK currents. Patch-clamp recordings in cultured DRG neurons from TRESK[wt] mice displayed increased IKSO after application of LPA whereas under these conditions IKSO in neurons from TRESK[ko] mice remained unaltered. Under current-clamp conditions LPA application differentially modulated excitability in these genotypes upon depolarising pulses. Spike frequency was attenuated in TRESK[wt] neurons and, in contrast, augmented in TRESK[ko] neurons. Accordingly, excitation of nociceptive neurons by LPA is balanced by co-activation of TRESK channels. Hence excitation of sensory neurons is strongly controlled by the activity of TRESK channels, which therefore are good candidates for the treatment of pain disorders. PMID:26224542

  20. Validation of a Modified Algometer to Measure Mechanical Nociceptive Thresholds in Awake Dogs

    PubMed Central

    Chen, Hui Cheng; Goh, Yong Meng; Abubakar, Adamu Abdul; Fakurazi, Sharida

    2015-01-01

    This study was conducted to validate the use of a modified algometer device to measure mechanical nociceptive thresholds in six dogs. Dogs were administered morphine intravenously (IV) at 1 mg/kg or saline at equivolume in a crossover design with one-week washout period. Mechanical nociceptive thresholds were determined before, after the administration of treatments at 5 minutes, and hourly for 8 hours. Thresholds were recorded at the carpal pad, metacarpal foot pad, tibia, femur, and abdomen. Heart rates, body temperature, and respiration were recorded at similar time points. Thresholds increased significantly (P < 0.05) from baseline values for up to 3 hours at tibia and abdomen, 4 hours at metacarpal pad, and 5 hours at the carpal pad and femur. Hypothermia, bradycardia, and change in respiration were observed in all dogs after morphine injection. Saline did not alter any threshold levels during the eight-hour study period, indicating no evidence of tolerance, learned avoidance, or local hyperaesthesia. The device and methods of testing were well tolerated by all the dogs. Results suggest that the modified algometer and method of application are useful to measure nociceptive mechanical thresholds in awake dogs. PMID:26075236

  1. Analysis of nociception, sex and peripheral nerve innervation in the TMEV animal model of multiple sclerosis

    PubMed Central

    Lynch, Jessica L.; Gallus, Nathan J.; Ericson, Marna E.; Beitz, Alvin J.

    2009-01-01

    Although pain was previously not considered an important element of multiple sclerosis (MS), recent evidence indicates that over 50% of MS patients suffer from chronic pain. In the present study, we utilized the Theiler’s murine encephalomyelitis virus (TMEV) model of MS to examine whether changes in nociception occur during disease progression and to investigate whether sex influences the development of nociception or disease-associated neurological symptoms. Using the rotarod assay, TMEV infected male mice displayed increased neurological deficits when compared to TMEV infected female mice, which mimics what is observed in human MS. While both male and female TMEV infected mice exhibited thermal hyperalgesia and mechanical allodynia, female mice developed mechanical allodynia at a faster rate and displayed significantly more mechanical allodynia than male mice. Since neuropathic symptoms have been described in MS patients, we quantified sensory nerve fibers in the epidermis of TMEV-infected and non-infected mice to determine if there were alterations in epidermal nerve density. There was a significantly higher density of PGP9.5 and CGRP immunoreactive axons in the epidermis of TMEV-infected mice versus controls. Collectively these results indicate that the TMEV model is well suited to study the mechanisms of MS-induced nociception and suggest that alterations in peripheral nerve innervation may contribute to MS pain. PMID:17766043

  2. Prenatal and perinatal factors influencing nociception, addiction and behavior during ontogenetic development.

    PubMed

    Rokyta, R; Yamamotová, A; Slamberová, R; Franek, M; Vaculín, S; Hrubá, L; Schutová, B; Pometlová, M

    2008-01-01

    This review, which summarizes our findings concerning the long-term effects of pre-, peri- and postnatal factors affecting development, nociception and sensorimotor functions, focuses on three areas: 1) perinatal factors influencing nociception in adult rats were examined in rats with hippocampal lesions, after the administration of stress influencing and psychostimulant drugs (dexamethasone, indomethacine and methamphetamine); 2) the effect of pre- and early postnatal methamphetamine administration was shown to impair the development of sensorimotor functions tested in rat pups throughout the preweaning period; 3) the effect of extensive dorsal rhizotomy of the brachial plexus during the early postnatal period was studied with respect to neuropathic pain development and sensorimotor functions. The present study indicates that prenatal or neonatal stress, as well as various drugs, may disturb the development of the nociceptive system and cause long-term behavioral changes persisting to adulthood and that some types of neuropathic pain cannot be induced during the first two postnatal weeks at all. A mature nervous system is required for the development of the described pathological behaviors.

  3. Visceral Nociceptive Afferent Facilitates Reaction of Subnucleus Reticularis Dorsalis to Acupoint Stimulation in Rats

    PubMed Central

    Li, Liang; Yu, Lingling; Rong, Peijing; Ben, Hui; Li, Xia; Zhu, Bing; Chen, Rixin

    2013-01-01

    Objective. To explore the area and sensitization variance of acupoint when internal organs are under pathological condition. To observe quantity-effect variance of subnucleus reticularis dorsalis (SRD) to electroacupuncture under both physiological and pathological conditions. To explain medulla oblongata mechanism of acupoint sensitization. Method. Mustard oil was imported into colon and rectum of 20 male SD rats in order to observe its influence on acupoint sensitization. SRD neuron activity was recorded. Visceral nociceptive stimulus was generated by colorectal distension (CRD). Quantity-effect variance of neuron activity to electroacupuncture to “Zusanli-Shangjuxu” area both before and after CRD was observed. Paired t-test is used for cross-group comparison; P < 0.05 is deemed as of statistical differences. Result. Visceral inflammation could facilitate SRD neuron activity to acupoint stimulation. Visceral nociceptive afference could enhance neuron activity to acupoint acupuncture. Wide dynamic range (WDR) neuron activity caused by electroacupuncture increased when visceral nociception increased. Conclusion. The size and function of the acupoints comply with the functionality of the internal organs. The sensitive degree of acupoints changed according to malfunction of internal organs. PMID:23762171

  4. Do sex hormones influence emotional modulation of pain and nociception in healthy women?

    PubMed

    Rhudy, Jamie L; Bartley, Emily J; Palit, Shreela; Kerr, Kara L; Kuhn, Bethany L; Martin, Satin L; Delventura, Jennifer L; Terry, Ellen L

    2013-12-01

    Sex hormones may contribute to inter- and intra-individual differences in pain by influencing emotional modulation of pain and nociception. To study this, a well-validated picture-viewing paradigm was used to assess emotional modulation of pain and the nociceptive flexion reflex (NFR; physiologic measure of nociception) during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle in healthy normally cycling women (n=40). Salivary estradiol, progesterone, and testosterone were assessed at each testing session. Emotional modulation of pain/NFR did not differ across menstrual phases, but low estradiol was associated with weaker emotional modulation of NFR (during all phases) and emotional modulation of pain (ovulatory and late-luteal phases). Given evidence that a failure to emotionally modulate pain might be a risk factor for chronic pain, low estradiol may promote chronic pain via this mechanism. However, future research is needed to extend these findings to women with disturbances of pain, emotion, and/or sex hormones.

  5. Emotional modulation of pain and spinal nociception in persons with major depressive disorder (MDD).

    PubMed

    Terry, Ellen L; DelVentura, Jennifer L; Bartley, Emily J; Vincent, Ashley L; Rhudy, Jamie L

    2013-12-01

    Major depressive disorder (MDD) is associated with risk for chronic pain, but the mechanisms contributing to the MDD and pain relationship are unclear. To examine whether disrupted emotional modulation of pain might contribute, this study assessed emotional processing and emotional modulation of pain in healthy controls and unmedicated persons with MDD (14 MDD, 14 controls). Emotionally charged pictures (erotica, neutral, mutilation) were presented in 4 blocks. Two blocks assessed physiological-emotional reactions (pleasure/arousal ratings, corrugator electromyography (EMG), startle modulation, skin conductance) in the absence of pain and 2 blocks assessed emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations. Results indicated pictures generally evoked the intended emotional responses; erotic pictures elicited pleasure, subjective arousal, and smaller startle magnitudes, whereas mutilation pictures elicited displeasure, corrugator EMG activation, and subjective/physiological arousal. However, emotional processing was partially disrupted in MDD, as evidenced by a blunted pleasure response to erotica and a failure to modulate startle according to a valence linear trend. Furthermore, emotional modulation of pain was observed in controls but not MDD, even though there were no group differences in NFR threshold or emotional modulation of NFR. Together, these results suggest supraspinal processes associated with emotion processing and emotional modulation of pain may be disrupted in MDD, but brain to spinal cord processes that modulate spinal nociception are intact. Thus, emotional modulation of pain deficits may be a phenotypic marker for future pain risk in MDD.

  6. Spinal vasopressin alleviates formalin-induced nociception by enhancing GABAA receptor function in mice.

    PubMed

    Peng, Fang; Qu, Zu-Wei; Qiu, Chun-Yu; Liao, Min; Hu, Wang-Ping

    2015-04-23

    Arginine vasopressin (AVP) plays a regulatory role in nociception. Intrathecal administration of AVP displays an antinociceptive effect. However, little is understood about the mechanism underlying spinal AVP analgesia. Here, we have found that spinal AVP dose dependently reduced the second, but not first, phase of formalin-induced spontaneous nociception in mice. The AVP analgesia was completely blocked by intrathecal injected SR 49059, a vasopressin-1A (V1A) receptor antagonist. However, spinal AVP failed to exert its antinociceptive effect on the second phase formalin-induced spontaneous nociception in V1A receptor knock-out (V1A-/-) mice. The AVP analgesia was also reversed by bicuculline, a GABAA receptor antagonist. Moreover, AVP potentiated GABA-activated currents in dorsal root ganglion neurons from wild-type littermates, but not from V1A-/- mice. Our results may reveal a novel spinal mechanism of AVP analgesia by enhancing the GABAA receptor function in the spinal cord through V1A receptors.

  7. Examining emotional modulation of pain and spinal nociception in Native Americans: a preliminary investigation.

    PubMed

    Palit, Shreela; Kerr, Kara L; Kuhn, Bethany L; DelVentura, Jennifer L; Terry, Ellen L; Bartley, Emily J; Shadlow, Joanna O; Rhudy, Jamie L

    2013-11-01

    Pain problems are more prevalent in Native Americans than in any other group in the U.S., and this might result from group differences in pain modulation. This study was designed to examine emotional modulation of pain and spinal nociception in healthy, pain-free Native Americans (n = 21) relative to non-Hispanic Whites (n = 20). To assess emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception), participants underwent a well-validated emotional picture-viewing paradigm during which suprathreshold pain stimuli were delivered to the ankle. Compared to Whites, Native Americans reported less pleasure to erotic pictures and failed to show corrugator reactivity to mutilation pictures. Unlike Whites, Native Americans only evidenced pain inhibition in response to erotica, but no pain facilitation (disinhibition) to mutilation pictures. Emotional modulation of NFR was similar in both groups. These preliminary findings suggest that Native Americans failed to disinhibit pain, perhaps due to over-activation of pain inhibitory mechanisms. Chronic over-activation of this system could ultimately exhaust it, thus putting Native Americans at future risk for chronic pain.

  8. Cognitive aspects of nociception and pain: bridging neurophysiology with cognitive psychology.

    PubMed

    Legrain, V; Mancini, F; Sambo, C F; Torta, D M; Ronga, I; Valentini, E

    2012-10-01

    The event-related brain potentials (ERPs) elicited by nociceptive stimuli are largely influenced by vigilance, emotion, alertness, and attention. Studies that specifically investigated the effects of cognition on nociceptive ERPs support the idea that most of these ERP components can be regarded as the neurophysiological indexes of the processes underlying detection and orientation of attention toward the eliciting stimulus. Such detection is determined both by the salience of the stimulus that makes it pop out from the environmental context (bottom-up capture of attention) and by its relevance according to the subject's goals and motivation (top-down attentional control). The fact that nociceptive ERPs are largely influenced by information from other sensory modalities such as vision and proprioception, as well as from motor preparation, suggests that these ERPs reflect a cortical system involved in the detection of potentially meaningful stimuli for the body, with the purpose to respond adequately to potential threats. In such a theoretical framework, pain is seen as an epiphenomenon of warning processes, encoded in multimodal and multiframe representations of the body, well suited to guide defensive actions. The findings here reviewed highlight that the ERPs elicited by selective activation of nociceptors may reflect an attentional gain apt to bridge a coherent perception of salient sensory events with action selection processes.

  9. Serotonin enhances urinary bladder nociceptive processing via a 5-HT3 receptor mechanism.

    PubMed

    Hall, Jason D; DeWitte, Cary; Ness, Timothy J; Robbins, Meredith T

    2015-09-14

    Serotonin from the descending pain modulatory pathway is critical to nociceptive processing. Its effects on pain modulation may either be inhibitory or facilitatory, depending on the type of pain and which receptors are involved. Little is known about the role of serotonergic systems in bladder nociceptive processing. These studies examined the effect of systemic administration of the serotonin precursor, 5-hydroxytryptophan (5-HTP), on normal bladder and somatic sensation in rats. ELISA was used to quantify peripheral and central changes in serotonin and its major metabolite following 5-HTP administration, and the potential role of the 5-HT3 receptor on changes in bladder sensation elicited by 5-HTP was investigated. 5-HTP produced bladder hypersensitivity and somatic analgesia. The pro-nociceptive effect of 5-HTP was attenuated by intrathecal, but not systemic, ondansetron. Peripheral increases in serotonin, its metabolism and rate of turnover were detectable within 30min of 5-HTP administration. Significant enhancement of serotonin metabolism was observed centrally. These findings suggest that 5-HTP increases serotonin, which may then affect descending facilitatory systems to produce bladder hypersensitivity via activation of spinal 5-HT3 receptors.

  10. Encoding of mechanical nociception differs in the adult and infant brain

    PubMed Central

    Fabrizi, Lorenzo; Verriotis, Madeleine; Williams, Gemma; Lee, Amy; Meek, Judith; Olhede, Sofia; Fitzgerald, Maria

    2016-01-01

    Newborn human infants display robust pain behaviour and specific cortical activity following noxious skin stimulation, but it is not known whether brain processing of nociceptive information differs in infants and adults. Imaging studies have emphasised the overlap between infant and adult brain connectome architecture, but electrophysiological analysis of infant brain nociceptive networks can provide further understanding of the functional postnatal development of pain perception. Here we hypothesise that the human infant brain encodes noxious information with different neuronal patterns compared to adults. To test this we compared EEG responses to the same time-locked noxious skin lance in infants aged 0–19 days (n = 18, clinically required) and adults aged 23–48 years (n = 21). Time-frequency analysis revealed that while some features of adult nociceptive network activity are present in infants at longer latencies, including beta-gamma oscillations, infants display a distinct, long latency, noxious evoked 18-fold energy increase in the fast delta band (2–4 Hz) that is absent in adults. The differences in activity between infants and adults have a widespread topographic distribution across the brain. These data support our hypothesis and indicate important postnatal changes in the encoding of mechanical pain in the human brain. PMID:27345331

  11. Dependence of Nociceptive Detection Thresholds on Physiological Parameters and Capsaicin-Induced Neuroplasticity: A Computational Study

    PubMed Central

    Yang, Huan; Meijer, Hil G. E.; Doll, Robert J.; Buitenweg, Jan R.; van Gils, Stephan A.

    2016-01-01

    Physiological properties of peripheral and central nociceptive subsystems can be altered over time due to medical interventions. The effective change for the whole nociceptive system can be reflected in changes of psychophysical characteristics, e.g., detection thresholds. However, it is challenging to separate contributions of distinct altered mechanisms with measurements of thresholds only. Here, we aim to understand how these alterations affect Aδ-fiber-mediated nociceptive detection of electrocutaneous stimuli. First, with a neurophysiology-based model, we study the effects of single-model parameters on detection thresholds. Second, we derive an expression of model parameters determining the functional relationship between detection thresholds and the interpulse interval for double-pulse stimuli. Third, in a case study with topical capsaicin treatment, we translate neuroplasticity into plausible changes of model parameters. Model simulations qualitatively agree with changes in experimental detection thresholds. The simulations with individual forms of neuroplasticity confirm that nerve degeneration is the dominant mechanism for capsaicin-induced increases in detection thresholds. In addition, our study suggests that capsaicin-induced central plasticity may last at least 1 month. PMID:27252644

  12. New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input

    PubMed Central

    Henssen, Dylan J. H. A.; Kurt, Erkan; Kozicz, Tamas; van Dongen, Robert; Bartels, Ronald H. M. A.; van Cappellen van Walsum, Anne-Marie

    2016-01-01

    Orofacial pain in patients relies on the anatomical pathways that conduct nociceptive information, originating from the periphery towards the trigeminal sensory nucleus complex (TSNC) and finally, to the thalami and the somatosensorical cortical regions. The anatomy and function of the so-called trigeminothalamic tracts have been investigated before. In these animal-based studies from the previous century, the intracerebral pathways were mapped using different retro- and anterograde tracing methods. We review the literature on the trigeminothalamic tracts focusing on these animal tracer studies. Subsequently, we related the observations of these studies to clinical findings using fMRI trials. The intracerebral trigeminal pathways can be subdivided into three pathways: a ventral (contralateral) and dorsal (mainly ipsilateral) trigeminothalamic tract and the intranuclear pathway. Based on the reviewed evidence we hypothesize the co-existence of an ipsilateral nociceptive conduction tract to the cerebral cortex and we translate evidence from animal-based research to the human anatomy. Our hypothesis differs from the classical idea that orofacial pain arises only from nociceptive information via the contralateral, ventral trigeminothalamic pathway. Better understanding of the histology, anatomy and connectivity of the trigeminal fibers could contribute to the discovery of a more effective pain treatment in patients suffering from various orofacial pain syndromes. PMID:27242449

  13. Memantine elicits spinal blockades of motor function, proprioception, and nociception in rats.

    PubMed

    Chen, Yu-Wen; Chiu, Chong-Chi; Liu, Kuo-Sheng; Hung, Ching-Hsia; Wang, Jhi-Joung

    2015-12-01

    Although memantine blocks sodium currents and produces local skin anesthesia, spinal anesthesia with memantine is unknown. The purpose of the study was to evaluate the local anesthetic effect of memantine in spinal anesthesia and its comparison with a widely used local anesthetic lidocaine. After intrathecally injecting the rats with five doses of each drug, the dose-response curves of memantine and lidocaine were constructed. The potencies of the drugs and durations of spinal anesthetic effects on motor function, proprioception, and nociception were compared with those of lidocaine. We showed that memantine produced dose-dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED50 ) basis, the rank of potency was lidocaine greater than memantine (P < 0.05 for the differences). At the equipotent doses (ED25 , ED50 , ED75 ), the block duration produced by memantine was longer than that produced by lidocaine (P < 0.05 for the differences). Memantine, but not lidocaine, displayed more sensory/nociceptive block than motor block. The preclinical data demonstrated that memantine is less potent than lidocaine, whereas memantine produces longer duration of spinal anesthesia than lidocaine. Memantine shows a more sensory-selective action over motor blockade.

  14. Modulation of the human nociceptive flexion reflex by pleasant and unpleasant odors.

    PubMed

    Bartolo, Michelangelo; Serrao, Mariano; Gamgebeli, Zurab; Alpaidze, Marina; Perrotta, Armando; Padua, Luca; Pierelli, Francesco; Nappi, Giuseppe; Sandrini, Giorgio

    2013-10-01

    The nociceptive withdrawal reflex (NWR), a defensive response that allows withdrawal from a noxious stimulus, is a reliable index of spinal nociception in humans. It has been shown that various kinds of stimuli (emotional, visual, auditory) can modulate the transmission and perception of pain. The aim of the present study was to evaluate, by means of the NWR, the modulatory effect on the spinal circuitry of olfactory stimuli with different emotional valence. The magnitude of the NWR elicited by electrical stimulation of the sural nerve was measured while 18 subjects (9 women, 9 men) smelled pleasant, unpleasant, or neutral odors. The NWR was conditioned by odor probe with interstimulus intervals (ISIs) of 500 ms and 1,500 ms. The magnitude of NWR was significantly greater after the unpleasant odor probe (P <.001) and reduced following the pleasant odor probe (P<.001) at both ISIs. A significant effect of olfactory stimuli on subjective pain ratings were found at both ISIs for pleasant vs unpleasant odors (P<.000), and for both pleasant and unpleasant odors vs neutral and basal conditions (P<.000). No statistical differences in subjective pain ratings at different ISIs were found. Consistent with the notion that NWR magnitude and pain perception can be modulated by stimuli with different emotional valence, these results show that olfactory stimuli, too, can modulate spinal nociception in humans.

  15. 21 CFR 184.1721 - Sodium acetate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Sodium acetate. 184.1721 Section 184.1721 Food and... Substances Affirmed as GRAS § 184.1721 Sodium acetate. (a) Sodium acetate (C2H3O2Na, CAS Reg. No. 127-09-3 or C2H3O2Na·3H2O, CAS Reg. No. 6131-90-4) is the sodium salt of acetic acid and occurs naturally in plant...

  16. 21 CFR 184.1721 - Sodium acetate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Sodium acetate. 184.1721 Section 184.1721 Food and... Substances Affirmed as GRAS § 184.1721 Sodium acetate. (a) Sodium acetate (C2H3O2Na, CAS Reg. No. 127-09-3 or C2H3O2Na·3H2O, CAS Reg. No. 6131-90-4) is the sodium salt of acetic acid and occurs naturally in plant...

  17. 21 CFR 184.1721 - Sodium acetate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Sodium acetate. 184.1721 Section 184.1721 Food and... Substances Affirmed as GRAS § 184.1721 Sodium acetate. (a) Sodium acetate (C2H3O2Na, CAS Reg. No. 127-09-3 or C2H3O2Na·3H2O, CAS Reg. No. 6131-90-4) is the sodium salt of acetic acid and occurs naturally in plant...

  18. 21 CFR 184.1721 - Sodium acetate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Sodium acetate. 184.1721 Section 184.1721 Food and... Substances Affirmed as GRAS § 184.1721 Sodium acetate. (a) Sodium acetate (C2H3O2Na, CAS Reg. No. 127-09-3 or C2H3O2Na·3H2O, CAS Reg. No. 6131-90-4) is the sodium salt of acetic acid and occurs naturally in plant...

  19. Extractive fermentation of acetic acid

    SciTech Connect

    Busche, R.M.

    1991-12-31

    In this technoeconomic evaluation of the manufacture of acetic acid by fermentation, the use of the bacterium: Acetobacter suboxydans from the old vinegar process was compared with expected performance of the newer Clostridium thermoaceticum bacterium. Both systems were projected to operate as immobilized cells in a continuous, fluidized bed bioreactor, using solvent extraction to recover the product. Acetobacter metabolizes ethanol aerobically to produce acid at 100 g/L in a low pH medium. This ensures that the product is in the form of a concentrated extractable free acid, rather than as an unextractable salt. Unfortunately, yields from glucose by way of the ethanol fermentation are poor, but near the biological limits of the organisms involved. Conversely, C. thermoaceticum is a thermophilic anaerobe that operates at high fermentation rates on glucose at neutral pH to produce acetate salts directly in substantially quantitative yields. However, it is severely inhibited by product, which restricts concentration to a dilute 20 g/L. An improved Acetobacter system operating with recycled cells at 50 g/L appears capable of producing acid at $0.38/lb, as compared with a $0.29/lb price for synthetic acid. However, this system has only a limited margin for process improvement. The present Clostridium system cannot compete, since the required selling price would be $0.42/lb. However, if the organism could be adapted to tolerate higher product concentrations at acid pH, selling price could be reduced to $0.22/lb, or about 80% of the price of synthetic acid.

  20. Manufacturing Ethyl Acetate From Fermentation Ethanol

    NASA Technical Reports Server (NTRS)

    Rohatgi, Naresh K.; Ingham, John D.

    1991-01-01

    Conceptual process uses dilute product of fermentation instead of concentrated ethanol. Low-concentration ethanol, extracted by vacuum from fermentation tank, and acetic acid constitutes feedstock for catalytic reaction. Product of reaction goes through steps that increases ethyl acetate content to 93 percent by weight. To conserve energy, heat exchangers recycle waste heat to preheat process streams at various points.

  1. Electron transfer induced fragmentation of acetic acid

    NASA Astrophysics Data System (ADS)

    Ferreira da Silva, F.; Meneses, G.; Almeida, D.; Limão-Vieira, P.

    2014-04-01

    We present negative ion formation driven by electron transfer in atom (K) molecule (acetic acid) collisions. Acetic acid has been found in the interstellar medium, is also considered a biological related compound and as such studying low energy electron interactions will bring new insights as far as induced chemistry is concerned.

  2. CELLULOSE NITRATE-ACETATE MIXED ESTERS

    DTIC Science & Technology

    cellulose acetate . The degree of polymerization of the products, as estimated from viscosity data, shows the occurrence of chain degradation for both...mixed esters showed tensile strength at least comparable to that of films of cellulose nitrate or cellulose acetate . The impact sensitivity of the

  3. DIBROMOACETIC ACID-INDUCED ELEVATIONS OF ESTRADIOL IN THE CYCLING AND OVARIECTOMOZED/ESTRADIOL-IMPLANTED FEMALE RAT

    EPA Science Inventory

    Goldman, JM and Murr, AS. Dibromoacetic Acid-induced Elevations of Estradiol in Both Cycling and Ovariectomized / Estradiol-implanted Female Rats

    ABSTRACT
    Haloacetic acids are one of the principal classes of disinfection by-products generated by the chlorination of mun...

  4. DIBROMOACETIC ACID-INDUCED ELEVATIONS IN CIRCULATING ESTRADIOL: EFFECTS IN BOTH CYCLING AND OVARIECTOMIZED/STEROID-PRIMED FEMALE RATS

    EPA Science Inventory

    RTD-03-031
    Goldman, JM and Murr, AS. Dibromoacetic Acid-induced Elevations in Circulating Estradiol: Effects in Both Cycling and Ovariectomized/Steroid-primed Female Rats. Reproductive Toxicology (in press).

    Abstract

    Oral exposures to high concentrations of th...

  5. Mechanisms involved in abdominal nociception induced by either TRPV1 or TRPA1 stimulation of rat peritoneum.

    PubMed

    Trevisan, Gabriela; Rossato, Mateus F; Hoffmeister, Carin; Oliveira, Sara M; Silva, Cássia R; Matheus, Filipe C; Mello, Gláucia C; Antunes, Edson; Prediger, Rui D S; Ferreira, Juliano

    2013-08-15

    Abdominal pain is a frequent symptom of peritoneal cavity irritation, but little is known about the role of the receptors for irritant substances, transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1), in this painful condition. Thus, we investigated the abdominal nociception caused by peritoneal stimulation with TRPV1 (capsaicin) and TRPA1 (allyl isothiocyanate, AITC) agonists and their mechanisms in rats. The intraperitoneal (i.p.) injection of either capsaicin or AITC (0.03-10 mg/kg) induced short-term (up to 20 min) and dose-dependent abdominal nociception, and also produced c-fos expression in spinal afferents of the dorsal horn. TRPV1 antagonism prevented (94 ± 4% inhibition) nociception induced by capsaicin but not by AITC. In contrast, the TRPA1 antagonism almost abolished AITC-induced nociception (95 ± 2% inhibition) without altering the capsaicin response. Moreover, nociception induced by either capsaicin or AITC was reduced by the desensitisation of TRPV1-positive sensory fibres with resiniferatoxin (73 ± 18 and 76 ± 15% inhibitions, respectively) and by the NK1 receptor antagonist aprepitant (56 ± 5 and 53 ± 8% inhibitions, respectively). Likewise, the i.p. injections of capsaicin or AITC increased the content of substance P in the peritoneal fluid. Nevertheless, neither the mast cell membrane stabiliser cromoglycate, nor the H1 antagonist promethazine, nor depletion of peritoneal macrophages affected abdominal nociception induced either by capsaicin or AITC. Accordingly, neither capsaicin nor AITC increased the histamine content in the peritoneal fluid or provoked peritoneal mast cell degranulation in vitro. Collectively, our findings suggest that TRPV1 and TRPA1 stimulation in the peritoneum produces abdominal nociception that is mediated by sensory fibres activation.

  6. Depomedroxyprogesterone acetate for hot flashes.

    PubMed

    Barton, Debra; Loprinzi, Charles; Quella, Susan; Sloan, Jeff; Pruthi, Sandya; Novotny, Paul

    2002-12-01

    To evaluate the efficacy of a long-acting preparation of medroxyprogesterone acetate for hot flash management, 3 men receiving androgen ablation therapy for prostate cancer and 15 women with a history of breast cancer were treated as part of clinical practice with three biweekly intramuscular injections of 500 mg depomedroxyprogesterone. A review of hot flash diaries and patient charts were completed to evaluate the effectiveness and tolerability of these injections for managing hot flashes. Treatment was associated with an approximate 90% decrease in hot flashes (95% CI 82-97%). Daily hot flash frequency decreased from a mean of 10.9 on the first day of treatment (95% CI 8.0-13.8 hot flashes per day) to a mean of 1.1 hot flashes 6 weeks later (95% CI 0.5-1.8 hot flashes) and to a mean of 0.7 hot flashes 12 weeks following therapy initiation (95% CI 0.1-1.2). Improvement in the hot flashes remained for months after discontinuing the injections in many patients. Reported side effects were minimal. This experience suggests that treatment with depomedroxyprogesterone may be an effective and well-tolerated option for the treatment of hot flashes.

  7. Vesicles protect activated acetic acid.

    PubMed

    Todd, Zoe R; House, Christopher H

    2014-10-01

    Abstract Methyl thioacetate, or activated acetic acid, has been proposed to be central to the origin of life and an important energy currency molecule in early cellular evolution. We have investigated the hydrolysis of methyl thioacetate under various conditions. Its uncatalyzed rate of hydrolysis is about 3 orders of magnitude faster (K=0.00663 s(-1); 100°C, pH 7.5, concentration=0.33 mM) than published rates for its catalyzed production, making it unlikely to accumulate under prebiotic conditions. However, our experiments showed that methyl thioacetate was protected from hydrolysis when inside its own hydrophobic droplets. Further, we found that methyl thioacetate protection from hydrolysis was also possible in droplets of hexane and in the membranes of nonanoic acid vesicles. Thus, the hydrophobic regions of prebiotic vesicles and early cell membranes could have offered a refuge for this energetic molecule, increasing its lifetime in close proximity to the reactions for which it would be needed. This model of early energy storage evokes an additional critical function for the earliest cell membranes.

  8. Predominant contribution of syntrophic acetate oxidation to thermophilic methane formation at high acetate concentrations.

    PubMed

    Hao, Li-Ping; Lü, Fan; He, Pin-Jing; Li, Lei; Shao, Li-Ming

    2011-01-15

    To quantify the contribution of syntrophic acetate oxidation to thermophilic anaerobic methanogenesis under the stressed condition induced by acidification, the methanogenic conversion process of 100 mmol/L acetate was monitored simultaneously by using isotopic tracing and selective inhibition techniques, supplemented with the analysis of unculturable microorganisms. Both quantitative methods demonstrated that, in the presence of aceticlastic and hydrogenotrophic methanogens, a large percentage of methane (up to 89%) was initially derived from CO(2) reduction, indicating the predominant contribution of the syntrophic acetate oxidation pathway to acetate degradation at high acid concentrations. A temporal decrease of the fraction of hydrogenotrophic methanogenesis from more than 60% to less than 40% reflected the gradual prevalence of the aceticlastic methanogenesis pathway along with the reduction of acetate. This apparent discrimination of acetate methanization pathways highlighted the importance of the syntrophic acetate-oxidizing bacteria to initialize methanogenesis from high organic loadings.

  9. Estradiol-induced antinociceptive responses on formalin-induced nociception are independent of COX and HPA activation.

    PubMed

    Hunter, Deirtra A; Barr, Gordon A; Amador, Nicole; Shivers, Kai-Yvonne; Kemen, Lynne; Kreiter, Christopher M; Jenab, Shirzad; Inturrisi, Charles E; Quinones-Jenab, Vanya

    2011-07-01

    Estrogen modulates pain perception but how it does so is not fully understood. The aim of this study was to determine if estradiol reduces nociceptive responses in part via hypothalamic-pituitary-adrenal (HPA) axis regulation of cyclooxygenase (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection nonsteroidal antiinflammatory drugs (NSAIDs) on formalin-induced nociceptive responding (flinching) in ovariectomized (OVX) rats. The drugs were ibuprofen (COX-1 and COX-2 inhibitor), SC560 (COX-1 inhibitor), or NS398 (COX-2 inhibitor). In a second study, estradiol's effects on formalin-induced nociception were tested in adrenalectomized (ADX), OVX, and ADX+OVX rats. Serum levels of prostaglandins (PG) PGE(2) and corticosterone were measured. Estradiol significantly decreased nociceptive responses in OVX rats with effects during both the first and the second phase of the formalin test. The nonsteroidal antiinflammatory drugs (NSAIDs) did not alter nociception at the doses used here. Adrenalectomy neither altered flinching responses in female rats nor reversed estradiol-induced antinociceptive responses. Estradiol alone had no effect on corticosterone (CORT) or prostaglandin levels after the formalin test, dissociating the effects of estradiol on behavior and these serum markers. Ibuprofen and NS398 significantly reduced PGE2 levels. CORT was not decreased by OVX surgery or by estradiol below that of ADX. Only IBU significantly increased corticosterone levels. Taken together, our results suggest that estradiol-induced antinociception in female rats is independent of COX activity and HPA axis activation.

  10. GABAergic neurons of the medial septum play a nodal role in facilitation of nociception-induced affect

    PubMed Central

    Ang, Seok Ting; Lee, Andy Thiam Huat; Foo, Fang Chee; Ng, Lynn; Low, Chian-Ming; Khanna, Sanjay

    2015-01-01

    The present study explored the functional details of the influence of medial septal region (MSDB) on spectrum of nociceptive behaviours by manipulating intraseptal GABAergic mechanisms. Results showed that formalin-induced acute nociception was not affected by intraseptal microinjection of bicuculline, a GABAA receptor antagonist, or on selective lesion of septal GABAergic neurons. Indeed, the acute nociceptive responses were dissociated from the regulation of sensorimotor behaviour and generation of theta-rhythm by the GABAergic mechanisms in MSDB. The GABAergic lesion attenuated formalin-induced unconditioned cellular response in the anterior cingulate cortex (ACC) and blocked formalin-induced conditioned place avoidance (F-CPA), and as well as the contextual fear induced on conditioning with brief footshock. The effects of lesion on nociceptive-conditioned cellular responses were, however, variable. Interestingly, the lesion attenuated the conditioned representation of experimental context in dorsal hippocampus field CA1 in the F-CPA task. Collectively, the preceding suggests that the MSDB is a nodal centre wherein the GABAergic neurons mediate nociceptive affect-motivation by regulating cellular mechanisms in ACC that confer an aversive value to the noxious stimulus. Further, in conjunction with a modulatory influence on hippocampal contextual processing, MSDB may integrate affect with context as part of associative learning in the F-CPA task. PMID:26487082

  11. GABAergic neurons of the medial septum play a nodal role in facilitation of nociception-induced affect.

    PubMed

    Ang, Seok Ting; Lee, Andy Thiam Huat; Foo, Fang Chee; Ng, Lynn; Low, Chian-Ming; Khanna, Sanjay

    2015-10-21

    The present study explored the functional details of the influence of medial septal region (MSDB) on spectrum of nociceptive behaviours by manipulating intraseptal GABAergic mechanisms. Results showed that formalin-induced acute nociception was not affected by intraseptal microinjection of bicuculline, a GABAA receptor antagonist, or on selective lesion of septal GABAergic neurons. Indeed, the acute nociceptive responses were dissociated from the regulation of sensorimotor behaviour and generation of theta-rhythm by the GABAergic mechanisms in MSDB. The GABAergic lesion attenuated formalin-induced unconditioned cellular response in the anterior cingulate cortex (ACC) and blocked formalin-induced conditioned place avoidance (F-CPA), and as well as the contextual fear induced on conditioning with brief footshock. The effects of lesion on nociceptive-conditioned cellular responses were, however, variable. Interestingly, the lesion attenuated the conditioned representation of experimental context in dorsal hippocampus field CA1 in the F-CPA task. Collectively, the preceding suggests that the MSDB is a nodal centre wherein the GABAergic neurons mediate nociceptive affect-motivation by regulating cellular mechanisms in ACC that confer an aversive value to the noxious stimulus. Further, in conjunction with a modulatory influence on hippocampal contextual processing, MSDB may integrate affect with context as part of associative learning in the F-CPA task.

  12. Transcriptional analysis of the acid-inducible asr gene in enterobacteria.

    PubMed

    Seputiene, Vaida; Suziedelis, Kestutis; Normark, Staffan; Melefors, Ojar; Suziedeliene, Edita

    2004-09-01

    We show here that transcription of the asr gene in Escherichia coli, Salmonella enterica serovar Typhimurium, Klebsiella pneumoniae and Enterobacter cloacae is strongly dependent on the acidification level of the growth medium, with maximal induction at pH 4.0-4.5 as determined by Northern hybridization analysis. Previous gene array analyses have also shown that asr is the most acid-induced gene in the E. coli genome. Sequence alignment of the asr promoters from different enterobacterial species identified a highly conserved region located at position -70 to -30 relative to the asr transcriptional start site. By deletion of various segments of this region in the E. coli asr promoter it was shown that sequences upstream from the -40 position were important for induction. Transcription from the E. coli asr promoter was demonstrated to be growth-phase-dependent and to require the alternative sigma factor RpoS (sigma(S)) in stationary phase. Transcription of the asr gene was also found to be subject to negative control by the nucleoid protein H-NS.

  13. CCN1 is critical for acid-induced esophageal epithelial cell transformation.

    PubMed

    Modak, Cristina; Mouazzen, Wasim; Narvaez, Reinier; Reavis, Kevin M; Chai, Jianyuan

    2010-02-19

    CCN1 is a matricellular protein involved in both wound healing and cancer cell invasion. Increased CCN1 expression has been associated with the development of Barrett's esophagus and the increased risk of progression to esophageal adenocarcinoma. In both cases, acid reflux is a major contributor. Low pH has been shown to induce CCN1 gene expression in esophageal epithelial cells. Here we demonstrated that both CCN1 and low pH could cause esophageal epithelial cell transformation, including loss of E-cadherin, disruption of cell-cell junctions, and expression of mesenchymal markers. Furthermore, knockdown of CCN1 through RNA interference sufficiently attenuated acid-driven cell phenotypic changes, while over-expression of CCN1 exacerbated these effects, indicating a critical role of CCN1 in acid-induced esophageal epithelial cell transformation. Given the pivotal role of low pH in gastro-esophageal reflux disease and its progression towards esophageal adenocarcinoma, our study identified CCN1 as a key molecule mediating this process.

  14. Acid-induced gelation behavior of casein/whey protein solutions assessed by oscillatory rheology.

    PubMed

    Sadeghi, Mahboubeh; Madadlou, Ashkan; Khosrowshahi, Asghar; Mohammadifar, Mohammadamin

    2014-09-01

    Gelation process of acid-induced casein gels was studied using response surface method (RSM). Ratio of casein to whey proteins, incubation and heating temperatures were independent variables. Final storage modulus (G') measured 200 min after the addition of glucono-δ-lactone and the gelation time i.e. the time at which G' of gels became greater than 1 Pa were the parameters studied. Incubation temperature strongly affected both parameters. The higher the incubation temperature, the lower was the G' and the shorter the gelation time. Increased heating temperature however, increased the G' but again shortened the gelation time. Increase in G' was attributed to the formation of disulphide cross-linkages between denatured whey proteins and casein chains; whilst the latter was legitimized by considering the higher isoelectric pH of whey proteins. Maximum response (G' = 268.93 Pa) was obtained at 2.7 % w/w, 25 °C and 90 °C for casein content, incubation and heating temperatures, respectively.

  15. Folic acid induces salicylic acid-dependent immunity in Arabidopsis and enhances susceptibility to Alternaria brassicicola.

    PubMed

    Wittek, Finni; Kanawati, Basem; Wenig, Marion; Hoffmann, Thomas; Franz-Oberdorf, Katrin; Schwab, Wilfried; Schmitt-Kopplin, Philippe; Vlot, A Corina

    2015-08-01

    Folates are essential for one-carbon transfer reactions in all organisms and contribute, for example, to de novo DNA synthesis. Here, we detected the folate precursors 7,8-dihydropteroate (DHP) and 4-amino-4-deoxychorismate (ADC) in extracts from Arabidopsis thaliana plants by Fourier transform ion cyclotron resonance-mass spectrometry. The accumulation of DHP, but not ADC, was induced after infection of plants with Pseudomonas syringae delivering the effector protein AvrRpm1. Application of folic acid or the DHP precursor 7,8-dihydroneopterin (DHN) enhanced resistance in Arabidopsis to P. syringae and elevated the transcript accumulation of the salicylic acid (SA) marker gene pathogenesis-related1 in both the treated and systemic untreated leaves. DHN- and folic acid-induced systemic resistance was dependent on SA biosynthesis and signalling. Similar to SA, folic acid application locally enhanced Arabidopsis susceptibility to the necrotrophic fungus Alternaria brassicicola. Together, the data associate the folic acid pathway with innate immunity in Arabidopsis, simultaneously activating local and systemic SA-dependent resistance to P. syringae and suppressing local resistance to A. brassicicola.

  16. Acupuncture suppresses kainic acid-induced neuronal death and inflammatory events in mouse hippocampus.

    PubMed

    Kim, Seung-Tae; Doo, Ah-Reum; Kim, Seung-Nam; Kim, Song-Yi; Kim, Yoon Young; Kim, Jang-Hyun; Lee, Hyejung; Yin, Chang Shik; Park, Hi-Joon

    2012-09-01

    The administration of kainic acid (KA) causes seizures and produces neurodegeneration in hippocampal CA3 pyramidal cells. The present study investigated a possible role of acupuncture in reducing hippocampal cell death and inflammatory events, using a mouse model of kainic acid-induced epilepsy. Male C57BL/6 mice received acupuncture treatments at acupoint HT8 or in the tail area bilaterally once a day for 2 days and again immediately after an intraperitoneal injection of KA (30 mg/kg). HT8 is located on the palmar surface of the forelimbs, between the fourth and fifth metacarpal bones. Twenty-four hours after the KA injection, neuronal cell survival, the activations of microglia and astrocytes, and mRNA expression of two proinflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were measured in the hippocampus. Acupuncture stimulation at HT8, but not in the tail area, significantly reduced the KA-induced seizure, neuron death, microglial and astrocyte activations, and IL-1β mRNA expression in the hippocampus. The acupuncture stimulation also decreased the mRNA expression of TNF-α, but it was not significant. These results indicate that acupuncture at HT8 can inhibit hippocampal cell death and suppress KA-induced inflammatory events, suggesting a possible role for acupuncture in the treatment of epilepsy.

  17. Ethanol promotes saturated fatty acid-induced hepatoxicity through endoplasmic reticulum (ER) stress response.

    PubMed

    Yi, Hong-Wei; Ma, Yu-Xiang; Wang, Xiao-Ning; Wang, Cui-Fen; Lu, Jian; Cao, Wei; Wu, Xu-Dong

    2015-04-01

    Serum palmitic acid (PA), a type of saturated fatty acid, causes lipid accumulation and induces toxicity in hepatocytes. Ethanol (EtOH) is metabolized by the liver and induces hepatic injury and inflammation. Herein, we analyzed the effects of EtOH on PA-induced lipotoxicity in the liver. Our results indicated that EtOH aggravated PA-induced apoptosis and lipid accumulation in primary rat hepatocytes in dose-dependent manner. EtOH intensified PA-caused endoplasmic reticulum (ER) stress response in vitro and in vivo, and the expressions of CHOP, ATF4, and XBP-1 in nucleus were significantly increased. EtOH also increased PA-caused cleaved caspase-3 in cytoplasm. In wild type and CHOP(-/-) mice treated with EtOH and high fat diet (HFD), EtOH worsened the HFD-induced liver injury and dyslipidemia, while CHOP knockout blocked toxic effects of EtOH and PA. Our study suggested that targeting UPR-signaling pathways is a promising, novel approach to reducing EtOH and saturated fatty acid-induced metabolic complications.

  18. The saturated fatty acid, palmitic acid, induces anxiety-like behavior in mice

    PubMed Central

    Moon, Morgan L.; Joesting, Jennifer J.; Lawson, Marcus A.; Chiu, Gabriel S.; Blevins, Neil A.; Kwakwa, Kristin A.; Freund, Gregory G.

    2014-01-01

    Objectives Excess fat in the diet can impact neuropsychiatric functions by negatively affecting cognition, mood and anxiety. We sought to show that the free fatty acid (FFA), palmitic acid, can cause adverse biobehaviors in mice that lasts beyond an acute elevation in plasma FFAs. Methods Mice were administered palmitic acid or vehicle as a single intraperitoneal (IP) injection. Biobehaviors were profiled 2 and 24 hrs after palmitic acid treatment. Quantification of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their major metabolites was performed in cortex, hippocampus and amygdala. FFA concentration was determined in plasma. Relative fold change in mRNA expression of unfolded protein response (UPR)-associated genes was determined in brain regions. Results In a dose-dependent fashion, palmitic acid rapidly reduced mouse locomotor activity by a mechanism that did not rely on TLR4, MyD88, IL-1, IL-6 or TNFα but was dependent on fatty acid chain length. Twenty-four hrs after palmitic acid administration mice exhibited anxiety-like behavior without impairment in locomotion, food intake, depressive-like behavior or spatial memory. Additionally, the serotonin metabolite 5-HIAA was increased by 33% in the amygdala 24 hrs after palmitic acid treatment. Conclusions Palmitic acid induces anxiety-like behavior in mice while increasing amygdala-based serotonin metabolism. These effects occur at a time point when plasma FFA levels are no longer elevated. PMID:25016520

  19. Palmitoleic acid induces the cardiac mitochondrial membrane permeability transition despite the presence of L-carnitine.

    PubMed

    Oyanagi, Eri; Uchida, Masataka; Miyakawa, Takeshi; Miyachi, Motohiko; Yamaguchi, Hidetaka; Nagami, Kuniatsu; Utsumi, Kozo; Yano, Hiromi

    Although palmitoleic acid (C16:1) is associated with arrhythmias, and increases in an age-dependent matter, the effects of L-carnitine, which is essential for the transport of long-chain fatty acids into the mitochondria, are unclear. It has been postulated that L-carnitine may attenuate palmitate (C16:0)-induced mitochondrial dysfunction and the apoptosis of cardiomyocytes. The aim of this study was to elucidate the activity of L-carnitine in the prevention of the palmitoleic acid-induced mitochondrial membrane permeability transition and cytochrome c release using isolated cardiac mitochondria from rats. Palmitoleoyl-CoA-induced mitochondrial respiration was not accelerated by L-carnitine treatment, and this respiration was slightly inhibited by oligomycin, which is an inhibitor of ATP synthase. Despite pretreatment with L-carnitine, the mitochondrial membrane potential decreased and mitochondrial swelling was induced by palmitoleoyl-CoA. In the presence of a combination of L-carnitine and tiron, a free radical scavenger, there was attenuated mitochondrial swelling and cytochrome c release following palmitoleoyl-CoA treatment. We concluded that palmitoleic acid, but not palmitate, induces the cardiac mitochondrial membrane permeability transition despite the presence of L-carnitine.

  20. Bile acid induced colonic irritation stimulates intracolonic nitric oxide release in humans.

    PubMed Central

    Casellas, F; Mourelle, M; Papo, M; Guarner, F; Antolin, M; Armengol, J R; Malagelada, J R

    1996-01-01

    AIM--To measure the intracolonic release of nitric oxide end products (nitrates plus nitrites) and eicosanoids in response to intraluminal irritation with deoxycholic acid (DCA). PATIENTS--Seven patients with irritable bowel syndrome. METHODS--The left colon was perfused with a solution with or without 3 mM deoxycholic acid. Aspirates were assayed for eicosanoids by specific radioimmuno-assay, and for nitrates plus nitrites by the Griess reaction. To confirm that stimulated colonic mucosa can produce nitric oxide (NO), ancillary studies were performed in vitro using samples of normal mucosa obtained from five surgically resected colons. Samples were incubated for 30 minutes in Kreb's solution, 3 mM DCA or DCA with 1 mM L-nitro-arginine-methyl-ester (L-NAME) to inhibit the NO synthase. Finally, NO synthase activity was measured in five samples of human colonic mucosa. RESULTS--Intracolonic release of nitrates plus nitrites was basally undetectable in six of seven patients. Bile acid considerably increased the release of prostaglandin E2 and nitrates plus nitrites (p < 0.01). By contrast, no increase in thromboxane and leukotriene was seen. In vitro mucosal incubation with DCA increased the production of NO synthase products, which was blocked by L-NAME. Activity of Ca+2 independent NO synthase was detectable in four of five samples of human colonic mucosa. CONCLUSION--The human colonic mucosa responds to bile acid induced irritation by a surge in NO generation via NO synthase. PMID:8707118

  1. Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity.

    PubMed

    Masuda, Masashi; Miyazaki-Anzai, Shinobu; Keenan, Audrey L; Okamura, Kayo; Kendrick, Jessica; Chonchol, Michel; Offermanns, Stefan; Ntambi, James M; Kuro-O, Makoto; Miyazaki, Makoto

    2015-10-26

    Recent evidence indicates that saturated fatty acid-induced (SFA-induced) lipotoxicity contributes to the pathogenesis of cardiovascular and metabolic diseases; however, the molecular mechanisms that underlie SFA-induced lipotoxicity remain unclear. Here, we have shown that repression of stearoyl-CoA desaturase (SCD) enzymes, which regulate the intracellular balance of SFAs and unsaturated FAs, and the subsequent accumulation of SFAs in vascular smooth muscle cells (VSMCs), are characteristic events in the development of vascular calcification. We evaluated whether SMC-specific inhibition of SCD and the resulting SFA accumulation plays a causative role in the pathogenesis of vascular calcification and generated mice with SMC-specific deletion of both Scd1 and Scd2. Mice lacking both SCD1 and SCD2 in SMCs displayed severe vascular calcification with increased ER stress. Moreover, we employed shRNA library screening and radiolabeling approaches, as well as in vitro and in vivo lipidomic analysis, and determined that fully saturated phosphatidic acids such as 1,2-distearoyl-PA (18:0/18:0-PA) mediate SFA-induced lipotoxicity and vascular calcification. Together, these results identify a key lipogenic pathway in SMCs that mediates vascular calcification.

  2. Effect of galactose on acid induced molten globule state of Soybean Agglutinin: Biophysical approach

    NASA Astrophysics Data System (ADS)

    Alam, Parvez; Naseem, Farha; Abdelhameed, Ali Saber; Khan, Rizwan Hasan

    2015-11-01

    In the present study the formation of molten globule-like unfolding intermediate Soybean Agglutinin (SBA) in acidic pH range has been established with the help of acrylamide quenching, intrinsic fluorescence, ANS fluorescence measurement, far UV CD and dynamic light scattering measurement. A marked increase in ANS fluorescence was observed at pH 2.2. Ksv of acrylamide quenching was found to be higher at pH 2.2 than that of native SBA at pH 7. Far UV CD spectra of pH induced state suggest that SBA shows significant retention of secondary structure closure to native. Hydrodynamic radius of SBA at pH 2.2 was found be more as compared to native state and also in other pH induced states. Further we checked the effect of galactose on the molten globule state of SBA. This study suggests that SBA exist as molten globule at pH 2.2 and this study will help in acid induced molten globule state of other proteins.

  3. Pulmonary vasoconstriction in oleic acid induced lung injury. A morphometric study.

    PubMed Central

    Grotjohan, H. P.; van der Heijde, R. M.; Wagenvoort, C. A.; Wagenvoort, N.; Versprille, A.

    1993-01-01

    Distribution and severity of active vasoconstriction of muscular pulmonary arteries were morphometrically assessed in anaesthetized, paralysed and mechanically ventilated pigs with respiratory distress, induced by oleic acid. Vasoconstriction was deduced from the medial thickness which was measured and expressed as a percentage of external diameter. Six pigs received oleic acid (0.12 +/- 0.07 ml/kg), dissolved 1:1 in 96% alcohol, in multiple injections of 0.1 ml. Six pigs were used as controls. After the oleic acid injections a stable hypoxaemia (PaO2 = 57 +/- 8 mmHg, at an inspiratory oxygen fraction of 0.6) and pulmonary hypertension (mean Ppa = 36 +/- 2 mmHg) were obtained for several hours. Electron microscopy revealed swelling of endothelial cells with signs of degeneration. Medial thickness was far greater in the oleic acid group than in the control group; overall mean values were 8.1 +/- 3.2 and 3.8 +/- 1.7% respectively (P < 0.001). Arteries with prominent vasoconstriction were lying in clusters. This pattern was the same in dependent and non-dependent regions. We concluded that in oleic acid induced respiratory distress active vasoconstriction of muscular pulmonary arteries is an important factor in the development of pulmonary hypertension. Besides vasoconstriction, endothelial swelling and intravascular clotting may contribute to the development of pulmonary hypertension. Images Figure 1 Figure 2 Figure 3 PMID:8398807

  4. Tanshinone IIA Protects Against Folic Acid-Induced Acute Kidney Injury.

    PubMed

    Jiang, Chunming; Zhu, Wei; Shao, Qiuyuan; Yan, Xiang; Jin, Bo; Zhang, Miao; Xu, Biao

    2016-01-01

    Tanshinone IIA is a diterpene extracted from Salvia miltiorrhiza, a popular and safe herb medicine that has been widely used in China and other Asian countries. Previous studies have demonstrated the pleiotropic effects of Tanshinone IIA on many disease treatments via its antitoxicity, anti-inflammation, anti-oxidative stress, as well as antifibrosis activities. However, its effect on acute kidney injury (AKI) has not been fully investigated. Here, we show for the first time that systemic administration of Tanshinone IIA can lead to improved kidney function in folic acid-induced kidney injury mice. In the acute phase of AKI, Tanshinone IIA attenuated renal tubular epithelial injury, as determined by histologic changes and the detection of Neutrophil gelatinase-associated lipocalin (NGAL) in the kidney and urine. Additionally, Tanshinone IIA treatment resulted in elevated proliferating cell nuclear antigen (PCNA) expression and decreased inflammatory cells infiltration as well as chemokine expression, suggesting that Tanshinone IIA promoted renal repair following AKI and inhibited local inflammatory response in the injured kidney. This led to decreased long-term fibrosis in the injured kidney, characterized by less accumulation of fibronectin and collagen I in tubulointerstitium. Taken together, these results suggest that Tanshinone IIA may represent a potential approach for AKI treatment.

  5. Targeting oxidative stress attenuates malonic acid induced Huntington like behavioral and mitochondrial alterations in rats.

    PubMed

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2010-05-25

    Objective of the present study was to explore the possible role of oxidative stress in the malonic acid induced behavioral, biochemical and mitochondrial alterations in rats. In the present study, unilateral single injections of malonic acid at different doses (1.5, 3 and 6 micromol) were made into the ipsilateral striatum in rats. Behavioral parameters were accessed on 1st, 7th and 14th day post malonic acid administration. Oxidative stress parameters and mitochondrial enzyme functions were assessed on day 14 after behavioral observations. Ipsilateral striatal malonic acid (3 and 6 micromol) administration significantly reduced body weight, locomotor activity, motor coordination and caused oxidative damage (lipid peroxidation, nitrite, superoxide dismutase, catalase and glutathione) in the striatum as compared to sham treated animal. Mitochondrial enzyme complexes and MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolinium bromide) activity were significantly inhibited by malonic acid. Vitamin E treatment (50 and 100 mg/kg, p.o.) significantly reversed the various behavioral, biochemical and mitochondrial alterations in malonic acid treated animals. Our findings show that targeting oxidative stress by vitamin E in malonic acid model, results in amelioration of behavioral and mitochondrial alterations are linked to inhibition of oxidative damage. Based upon these finding present study hypothesize that protection exerted by vitamin E on behavioral, mitochondrial markers indicates the possible preservation of the functional status of the striatal neurons by targeting the deleterious actions of oxidative stress.

  6. Tiagabine treatment in kainic acid induced cerebellar lesion of dystonia rat model

    PubMed Central

    Wang, Tsui-chin; Ngampramuan, Sukonthar; Kotchabhakdi, Naiphinich

    2016-01-01

    Dystonia is a neurological disorder characterized by excessive involuntary muscle contractions that lead to twisting movements. The exaggerated movements have been studied and have implicated basal ganglia as the point of origin. In more recent studies, the cerebellum has also been identified as the possible target of dystonia, in the search for alternative treatments. Tiagabine is a selective GABA transporter inhibitor, which blocks the reuptake and recycling of GABA. The study of GABAergic drugs as an alternative treatment for cerebellar induced dystonia has not been reported. In our study, tiagabine was i.p. injected into kainic acid induced, cerebellar dystonic adult rats, and the effects were compared with non-tiagabine injected and sham-operated groups. Beam walking apparatus, telemetric electromyography (EMG) recording, and histological verification were performed to confirm dystonic symptoms in the rats on post-surgery treatment. Involuntary dystonic spasm was observed with repetitive rigidity, and twisting movements in the rats were also confirmed by a high score on the dystonic scoring and a high amplitude on the EMG data. The rats with tiagabine treatment were scored based on motor amelioration assessed via beam walking. The result of this study suggests and confirms that low dose of kainic acid microinjection is sufficient to induce dystonia from the cerebellar vermis. In addition, from the results of the EMG recording and the behavioral assessment through beam walking, tiagabine is demonstrated as being effective in reducing dystonic spasm and may be a possible alternative therapeutic drug in the treatment of dystonia. PMID:28337103

  7. [Activation and regulation of nociceptive transient receptor potential (TRP) channels, TRPV1 and TRPA1].

    PubMed

    Tominaga, Makoto

    2010-03-01

    TRP channels are well recognized for their contributions to sensory transduction, responding to a wide variety of stimuli including temperature, nociceptive stimuli, touch, osmolarity and pheromones. In particular, the involvement of TRP channels in nociception has been extensively studied following the cloning of the capsaicin receptor, TRPV1. Painful diabetic peripheral neuropathy is described as a superficial burning pain, and it is one of the most commonly encountered neuropathic pain syndromes in clinical practice. We found that hypoxic and high glucose conditions commonly observed in diabetes potentiate TRPV1 activity without affecting TRPV1 expression both in native rat sensory neurons and HEK293 cells expressing rat TRPV1. The potentiation seems to be caused by phosphorylation of the serine residues of TRPV1 by PKC. These data indicate that PKC-dependent potentiation of TRPV1 activities under hypoxia and hyperglycemia might be involved in early diabetic neuropathy. Mechanisms for the detection of alkaline pH by sensory neurons are not well understood, although it is well accepted that acidic pH monitoring can be attributed to several ion channels, including TRPV1 and ASICs. We found that alkaline pH activates TRPA1 and that the TRPA1 activation is involved in nociception, using Ca(2+)-imaging and patch-clamp methods. In addition, intracellular alkalization activated TRPA1 at the whole-cell level, and single-channel openings were observed in the inside-out configuration. Furthermore, intraplantar injection of ammonium chloride into the mouse hind paw caused pain-related behaviors, which were not observed in TRPA1-deficient mice. These results suggest that alkaline pH causes pain sensation through activation of TRPA1.

  8. Activity-dependent dephosphorylation of paxillin contributed to nociceptive plasticity in spinal cord dorsal horn.

    PubMed

    Wang, Xin-Tai; Zheng, Rui; Suo, Zhan-Wei; Liu, Yan-Ni; Zhang, Zi-Yang; Ma, Zheng-An; Xue, Ye; Xue, Man; Yang, Xian; Hu, Xiao-Dong

    2016-03-01

    The enzymatic activity of protein tyrosine kinase Src is subjected to the regulation by C-terminal Src kinase (CSK) and protein tyrosine phosphatases (PTPs). Aberrant Src activation in the spinal cord dorsal horn is pivotal for the induction and development of nociceptive behavioral sensitization. In this study, we found that paxillin, one of the well-characterized cell adhesion components involved in cell migration and survival, integrated CSK and PTPs' signaling to regulate Src-dependent nociceptive plasticity. Paxillin localized at excitatory glutamatergic synapses in the spinal dorsal horn of mice, and the phosphorylation of Tyr118 on paxillin was necessary to associate with and target CSK at synapses. After peripheral tissue injury, the enhanced neuronal activity stimulated N-methyl-D-aspartate (NMDA) subtype glutamate receptors, which initiated PTPs' signaling to catalyze Tyr118 dephosphorylation. The reduced Tyr118 phosphorylation disrupted paxillin interaction with CSK, leading to the dispersal of CSK out of synapses. With the loss of CSK-mediated inhibition, Src activity was persistently increased. The active Src potentiated the synaptic transmission specifically mediated by GluN2B subunit-containing NMDA receptors. The active Src also facilitated the induction of long-term potentiation of C fiber-evoked field potentials and exaggerated painful responses. In complete Freund's adjuvant-injected mice, viral expression of phosphomimicking paxillin mutant to resume CSK synaptic localization repressed Src hyperactivity. Meanwhile, this phosphomimicking paxillin mutant blunted NMDA receptor-mediated synaptic transmission and alleviated chronic inflammatory pain. These data showed that PTPs-mediated dephosphorylation of paxillin at Tyr118 was involved in the modification of nociceptive plasticity through CSK-Src signaling.

  9. Transcutaneous spinal cord direct current stimulation inhibits the lower limb nociceptive flexion reflex in human beings.

    PubMed

    Cogiamanian, Filippo; Vergari, Maurizio; Schiaffi, Elena; Marceglia, Sara; Ardolino, Gianluca; Barbieri, Sergio; Priori, Alberto

    2011-02-01

    Aiming at developing a new, noninvasive approach to spinal cord neuromodulation, we evaluated whether transcutaneous direct current (DC) stimulation induces long-lasting changes in the central pain pathways in human beings. A double-blind crossover design was used to investigate the effects of anodal direct current (2mA, 15min) applied on the skin overlying the thoracic spinal cord on the lower-limb flexion reflex in a group of 11 healthy volunteers. To investigate whether transcutaneous spinal cord DC stimulation (tsDCS) acts indirectly on the nociceptive reflex by modulating excitability in mono-oligosynaptic segmental reflex pathways, we also evaluated the H-reflex size from soleus muscle after tibial nerve stimulation. In our healthy subjects, anodal thoracic tsDCS reduced the total lower-limb flexion reflex area by 40.25% immediately after stimulation (T0) and by 46.9% 30min after stimulation offset (T30). When we analyzed the 2 lower-limb flexion reflex components (RII tactile and RIII nociceptive) separately, we found that anodal tsDCS induced a significant reduction in RIII area with a slight but not significant effect on RII area. After anodal tsDCS, the RIII area decreased by 27% at T0 and by 28% at T30. Both sham and active tsDCS left all the tested H-reflex variables unchanged. None of our subjects reported adverse effects after active stimulation. These results suggest that tsDCS holds promise as a tool that is complementary or alternative to drugs and invasive spinal cord electrical stimulation for managing pain. Thoracic transcutaneous direct current stimulation induces depression of nociceptive lower limb flexion reflex in human beings that persists after stimulation offset; this form of stimulation holds promise as a tool that is complementary or alternative to drugs and invasive spinal cord electrical stimulation for managing pain.

  10. Decoding Subjective Intensity of Nociceptive Pain from Pre-stimulus and Post-stimulus Brain Activities

    PubMed Central

    Tu, Yiheng; Tan, Ao; Bai, Yanru; Hung, Yeung Sam; Zhang, Zhiguo

    2016-01-01

    Pain is a highly subjective experience. Self-report is the gold standard for pain assessment in clinical practice, but it may not be available or reliable in some populations. Neuroimaging data, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), have the potential to be used to provide physiology-based and quantitative nociceptive pain assessment tools that complements self-report. However, existing neuroimaging-based nociceptive pain assessments only rely on the information in pain-evoked brain activities, but neglect the fact that the perceived intensity of pain is also encoded by ongoing brain activities prior to painful stimulation. Here, we proposed to use machine learning algorithms to decode pain intensity from both pre-stimulus ongoing and post-stimulus evoked brain activities. Neural features that were correlated with intensity of laser-evoked nociceptive pain were extracted from high-dimensional pre- and post-stimulus EEG and fMRI activities using partial least-squares regression (PLSR). Further, we used support vector machine (SVM) to predict the intensity of pain from pain-related time-frequency EEG patterns and BOLD-fMRI patterns. Results showed that combining predictive information in pre- and post-stimulus brain activities can achieve significantly better performance in classifying high-pain and low-pain and in predicting the rating of perceived pain than only using post-stimulus brain activities. Therefore, the proposed pain prediction method holds great potential in basic research and clinical applications. PMID:27148029

  11. Psychophysics of a Nociceptive Test in the Mouse: Ambient Temperature as a Key Factor for Variation

    PubMed Central

    Pincedé, Ivanne; Pollin, Bernard; Meert, Theo; Plaghki, Léon; Le Bars, Daniel

    2012-01-01

    Background The mouse is increasingly used in biomedical research, notably in behavioral neurosciences for the development of tests or models of pain. Our goal was to provide the scientific community with an outstanding tool that allows the determination of psychophysical descriptors of a nociceptive reaction, which are inaccessible with conventional methods: namely the true threshold, true latency, conduction velocity of the peripheral fibers that trigger the response and latency of the central decision-making process. Methodology/Principal Findings Basically, the procedures involved heating of the tail with a CO2 laser, recording of tail temperature with an infrared camera and stopping the heating when the animal reacted. The method is based mainly on the measurement of three observable variables, namely the initial temperature, the heating rate and the temperature reached at the actual moment of the reaction following random variations in noxious radiant heat. The initial temperature of the tail, which itself depends on the ambient temperature, very markedly influenced the behavioral threshold, the behavioral latency and the conduction velocity of the peripheral fibers but not the latency of the central decision-making. Conclusions/Significance We have validated a psychophysical approach to nociceptive reactions for the mouse, which has already been described for rats and Humans. It enables the determination of four variables, which contribute to the overall latency of the response. The usefulness of such an approach was demonstrated by providing new fundamental findings regarding the influence of ambient temperature on nociceptive processes. We conclude by challenging the validity of using as “pain index" the reaction time of a behavioral response to an increasing heat stimulus and emphasize the need for a very careful control of the ambient temperature, as a prevailing environmental source of variation, during any behavioral testing of mice. PMID:22629325

  12. Opiates Modulate Noxious Chemical Nociception through a Complex Monoaminergic/Peptidergic Cascade

    PubMed Central

    Mills, Holly; Ortega, Amanda; Law, Wenjing; Hapiak, Vera; Summers, Philip; Clark, Tobias

    2016-01-01

    The ability to detect noxious stimuli, process the nociceptive signal, and elicit an appropriate behavioral response is essential for survival. In Caenorhabditis elegans, opioid receptor agonists, such as morphine, mimic serotonin, and suppress the overall withdrawal from noxious stimuli through a pathway requiring the opioid-like receptor, NPR-17. This serotonin- or morphine-dependent modulation can be rescued in npr-17-null animals by the expression of npr-17 or a human κ opioid receptor in the two ASI sensory neurons, with ASI opioid signaling selectively inhibiting ASI neuropeptide release. Serotonergic modulation requires peptides encoded by both nlp-3 and nlp-24, and either nlp-3 or nlp-24 overexpression mimics morphine and suppresses withdrawal. Peptides encoded by nlp-3 act differentially, with only NLP-3.3 mimicking morphine, whereas other nlp-3 peptides antagonize NLP-3.3 modulation. Together, these results demonstrate that opiates modulate nociception in Caenorhabditis elegans through a complex monoaminergic/peptidergic cascade, and suggest that this model may be useful for dissecting opiate signaling in mammals. SIGNIFICANCE STATEMENT Opiates are used extensively to treat chronic pain. In Caenorhabditis elegans, opioid receptor agonists suppress the overall withdrawal from noxious chemical stimuli through a pathway requiring an opioid-like receptor and two distinct neuropeptide-encoding genes, with individual peptides from the same gene functioning antagonistically to modulate nociception. Endogenous opioid signaling functions as part of a complex, monoaminergic/peptidergic signaling cascade and appears to selectively inhibit neuropeptide release, mediated by a α-adrenergic-like receptor, from two sensory neurons. Importantly, receptor null animals can be rescued by the expression of the human κ opioid receptor, and injection of human opioid receptor ligands mimics exogenous opiates, highlighting the utility of this model for dissecting opiate

  13. An altered spinal serotonergic system contributes to increased thermal nociception in an animal model of depression.

    PubMed

    Rodríguez-Gaztelumendi, Antonio; Rojo, María Luisa; Pazos, Angel; Díaz, Alvaro

    2014-06-01

    The olfactory bulbectomized (OB) rat, an animal model of chronic depression with comorbid anxiety, exhibits a profound dysregulation of the brain serotonergic signalling, a neurotransmission system involved in pain transmission and modulation. We here report an increased nociceptive response of OB rats in the tail flick test which is reverted after chronic, but not acute, administration of fluoxetine. Autoradiographic studies demonstrated down-regulation of 5-HT transporters ([(3)H]citalopram binding) and decreased functionality of 5-HT1A receptors (8-OH-DPAT-stimulated [(35)S]GTPγS binding) in the dorsal horn of the lumbar spinal cord in OB rats. Acute administration of fluoxetine (5-40 mg/kg i.p.) did not modify tail flick latencies in OB rats. However, chronic fluoxetine (10 mg/kg/day s.c., 14 days; osmotic minipumps) progressively attenuated OB-associated thermal hyperalgesia, and a total normalization of the nociceptive response was achieved at the end of the treatment with the antidepressant. In these animals, autoradiographic studies revealed further down-regulation of 5-HT transporters and normalization in the functionality of 5-HT1A receptors on the spinal cord. On the other hand, acute morphine (0.5-10 mg/kg s.c.) produced a similar analgesic effect in OB and sham and OB rats, and no changes were detected in the density ([(3)H]DAMGO binding) and functionality (DAMGO-stimulated [(35)S]GTPγS binding) of spinal μ-opioid receptors in OB rats before and after chronic fluoxetine. Our findings demonstrate the participation of the spinal serotonergic system in the increased thermal nociception exhibited by the OB rat and the antinociceptive effect of chronic fluoxetine in this animal model of depression.

  14. Postnatal temporal, spatial and modality tuning of nociceptive cutaneous flexion reflexes in human infants.

    PubMed

    Cornelissen, Laura; Fabrizi, Lorenzo; Patten, Deborah; Worley, Alan; Meek, Judith; Boyd, Stewart; Slater, Rebeccah; Fitzgerald, Maria

    2013-01-01

    Cutaneous flexion reflexes are amongst the first behavioural responses to develop and are essential for the protection and survival of the newborn organism. Despite this, there has been no detailed, quantitative study of their maturation in human neonates. Here we use surface electromyographic (EMG) recording of biceps femoris activity in preterm (<37 weeks gestation, GA) and term (≥ 37 weeks GA) human infants, less than 14 days old, in response to tactile, punctate and clinically required skin-breaking lance stimulation of the heel. We show that all infants display a robust and long duration flexion reflex (>4 seconds) to a single noxious skin lance which decreases significantly with gestational age. This reflex is not restricted to the stimulated limb: heel lance evokes equal ipsilateral and contralateral reflexes in preterm and term infants. We further show that infant flexion withdrawal reflexes are not always nociceptive specific: in 29% of preterm infants, tactile stimulation evokes EMG activity that is indistinguishable from noxious stimulation. In 40% of term infants, tactile responses are also present but significantly smaller than nociceptive reflexes. Infant flexion reflexes are also evoked by application of calibrated punctate von Frey hairs (vFh), 0.8-17.2 g, to the heel. Von Frey hair thresholds increase significantly with gestational age and the magnitude of vFh evoked reflexes are significantly greater in preterm than term infants. Furthermore flexion reflexes in both groups are sensitized by repeated vFh stimulation. Thus human infant flexion reflexes differ in temporal, modality and spatial characteristics from those in adults. Reflex magnitude and tactile sensitivity decreases and nociceptive specificity and spatial organisation increases with gestational age. Strong, relatively non-specific, reflex sensitivity in early life may be important for driving postnatal activity dependent maturation of targeted spinal cord sensory circuits.

  15. Peripheral and spinal mechanisms of nociception in a rat reserpine-induced pain model.

    PubMed

    Taguchi, Toru; Katanosaka, Kimiaki; Yasui, Masaya; Hayashi, Koei; Yamashita, Mai; Wakatsuki, Koji; Kiyama, Hiroshi; Yamanaka, Akihiro; Mizumura, Kazue

    2015-03-01

    Chronic widespread pain is a serious medical problem, yet the mechanisms of nociception and pain are poorly understood. Using a reserpine-induced pain model originally reported as a putative animal model for fibromyalgia, this study was undertaken to examine the following: (1) expression of several ion channels responsible for pain, mechanotransduction, and generation/propagation of action potentials in the dorsal root ganglion (DRG), (2) activities of peripheral nociceptive afferents, and (3) alterations in spinal microglial cells. A significant increase in mRNA expression of the acid-sensing ion channel (ASIC)-3 was detected in the DRG, and the behavioral mechanical hyperalgesia was significantly reversed by subcutaneous injection of APETx2, a selective blocker of ASIC3. Single-fiber recordings in vitro revealed facilitated mechanical responses of mechanoresponsive C-fibers both in the skin and muscle although the proportion of mechanoresponsive C-nociceptors was paradoxically decreased. In the spinal dorsal horn, microglial cells labeled with Iba1 immunoreactivity was activated, especially in laminae I-II where the nociceptive input is mainly processed compared with the other laminae. The activated microglia and behavioral hyperalgesia were significantly tranquilized by intraperitoneal injection of minocycline. These results suggest that the increase in ASIC3 in the DRG facilitated mechanical response of the remaining C-nociceptors and that activated spinal microglia may direct to intensify pain in this model. Pain may be further amplified by reserpine-induced dysfunction of the descending pain inhibitory system and by the decrease in peripheral drive to this system resulting from a reduced proportion of mechanoresponsive C-nociceptors.

  16. Development of mechanical and thermal nociceptive threshold testing devices in unrestrained birds (broiler chickens).

    PubMed

    Hothersall, B; Caplen, G; Nicol, C J; Taylor, P M; Waterman-Pearson, A E; Weeks, C A; Murrell, J C

    2011-09-30

    Behavioural signs of pain are difficult to quantify and interpret in animals. Nociceptive threshold testing is therefore a useful method for examining the perception and processing of noxious stimuli underlying pain states. Devices were developed to measure response thresholds to quantified, ramped mechanical and thermal nociceptive stimuli applied to the leg or keel of unrestrained birds. Up to 9N mechanical force was delivered via a single round-ended 2mm pin using a pneumatic actuator at 0.4Ns(-1). Heat was applied through a small copper element at 0.8°Cs(-1) to a maximum of 50°C. The repeatability and reliability of threshold measures were validated using 10-12 broiler chickens (aged 49-66 days) per site and modality. Mechanical threshold, or skin and threshold temperature, were recorded over three sessions across a 36h period. Both stimulus types elicited clear, reproducible behavioural responses. Mechanical threshold means and 95% confidence intervals were 3.0 (2.8-3.2)N for keel and 2.0 (1.8-2.1)N for leg sites. Keel thermal tests gave a mean skin temperature of 39.3 (39.1-39.5)°C, and threshold of 46.8 (46.6-47.1)°C. Leg skin temperature was 35.7 (35.6-35.9)°C and threshold 42.5 (42.2-42.8)°C. Threshold measures were consistent within and across sessions and birds showed individual repeatability across tests within sessions. Individual birds' mechanical keel thresholds were also repeatable across sessions. The apparatus gave reliable, reproducible measurements of thresholds to noxious mechanical and thermal stimuli. The range recorded was comparable with previously published nociceptor thresholds in dissected chicken nerve filament fibres, and the method appears suitable for studying nociceptive processes in broiler chickens.

  17. Modification of formalin-induced nociception by different histamine receptor agonists and antagonists.

    PubMed

    Farzin, Davood; Nosrati, Farnaz

    2007-01-15

    The present study evaluated the effects of different histamine receptor agonists and antagonists on the nociceptive response in the mouse formalin test. Intracerebroventricular (20-40 microg/mouse i.c.v.) or subcutaneous (1-10 mg/kg s.c.) injection of HTMT (H(1) receptor agonist) elicited a dose-related hyperalgesia in the early and late phases. Conversely, intraperitoneal (20 and 30 mg/kg i.p.) injection of dexchlorpheniramine (H(1) receptor antagonist) was antinociceptive in both phases. At a dose ineffective per se, dexchlorpheniramine (10 mg/kg i.p.) antagonized the hyperalgesia induced by HTMT (40 mug/mouse i.c.v. or 10 mg/kg s.c.). Dimaprit (H(2) receptor agonist, 30 mg/kg i.p.) and ranitidine (H(2) receptor antagonist, 20 and 40 mg/kg i.p.) reduced the nociceptive responses in the early and late phases. No significant change in the antinociceptive activity was found following the combination of dimaprit (30 mg/kg i.p.) with ranitidine (10 mg/kg i.p.). The antinociceptive effect of dimaprit (30 mg/kg i.p.) was prevented by naloxone (5 mg/kg i.p.) in the early phase or by imetit (H(3) receptor agonist, 25 mg/kg i.p.) in both early and late phases. The histamine H(3) receptor agonist imetit was hyperalgesic following i.p. administration of 50 mg/kg. Imetit-induced hyperalgesia was completely prevented by treatment with a dose ineffective per se of thioperamide (H(3) receptor antagonist, 5 mg/kg i.p.). The results suggest that histamine H(1) and H(3) receptor activations increase sensitivity to nociceptive stimulus in the formalin test.

  18. Cellular and subcellular localization of CXCL12 and CXCR4 in rat nociceptive structures: physiological relevance.

    PubMed

    Reaux-Le Goazigo, Annabelle; Rivat, Cyril; Kitabgi, Patrick; Pohl, Michel; Melik Parsadaniantz, Stéphane

    2012-09-01

    Initial studies implicated the chemokine CXC motif ligand 12 (CXCL12) and its cognate CXC motif receptor 4 (CXCR4) in pain modulation. However, there has been no description of the distribution, transport and axonal sorting of CXCL12 and CXCR4 in rat nociceptive structures, and their direct participation in nociception modulation has not been demonstrated. Here, we report that acute intrathecal administration of CXCL12 induced mechanical hypersensitivity in naive rats. This effect was prevented by a CXCR4-neutralizing antibody. To determine the morphological basis of this behavioural response, we used light and electron microscopic immunohistochemistry to map CXCL12- and CXCR4-immunoreactive elements in dorsal root ganglia, lumbar spinal cord, sciatic nerve and skin. Light microscopy analysis revealed CXCL12 and CXCR4 immunoreactivity in calcitonin gene related peptide-containing peptidergic primary sensory neurons, which were both conveyed to central and peripheral sensory nerve terminals. Electron microscopy clearly demonstrated CXCL12 and CXCR4 immunoreactivity in primary sensory nerve terminals in the dorsal horn; both were sorted into small clear vesicles and large dense-core vesicles. This suggests that CXCL12 and CXCR4 are trafficked from nerve cell bodies to the dorsal horn. Double immunogold labelling for CXCL12 and calcitonin gene related peptide revealed partial vesicular colocalization in axonal terminals. We report, for the first time, that CXCR4 receptors are mainly located on the neuronal plasma membrane, where they are present at pre-synaptic and post-synaptic sites of central terminals. Receptor inactivation experiments, behavioural studies and morphological analyses provide strong evidence that the CXCL12/CXCR4 system is involved in modulation of nociceptive signalling.

  19. Effects of nociceptive stimuli on the pulmonary circulation in the ovine fetus.

    PubMed

    Houfflin-Debarge, V; Delelis, A; Jaillard, S; Larrue, B; Deruelle, P; Ducloy, A S; Puech, F; Storme, L

    2005-02-01

    The fetus is able to exhibit a stress response to painful events, and stress hormones have been shown to modulate pulmonary vascular tone. At birth, the increased level of stress hormones plays a significant role in the adaptation to postnatal life. We therefore hypothesized that pain may alter pulmonary circulation in the perinatal period. The hemodynamic response to subcutaneous injection of formalin, which is used in experimental studies as nociceptive stimulus, was evaluated in chronically prepared, fetal lambs. Fetal lambs were operated on at 128 days gestation. Catheters were placed into the ascending aorta, superior vena cava, and main pulmonary artery. An ultrasonic flow transducer was placed around the left pulmonary artery. Three subcutaneous catheters were placed in the lambs' limb. The hemodynamic responses to subcutaneous injection of formalin, to formalin after fetal analgesia by sufentanil, and to sufentanil alone were recorded. Cortisol and catecholamine concentrations were also measured. Pulmonary vascular resistances (PVR) increased by 42% (P < 0.0001) after formalin injection. Cortisol increased by 54% (P = 0.05). During sufentanil infusion, PVR did not change significantly after formalin. Cortisol increased by 56% (P < 0.05). PVR did not change during sufentanil infusion. Norepinephrine levels did not change during any of the protocols. Our results indicate that nociceptive stimuli may increase the pulmonary vascular tone. This response is not mediated by an increase in circulating catecholamine levels. Analgesia prevents this effect. We speculate that this pulmonary vascular response to nociceptive stimulation may explain some hypoxemic events observed in newborn infants during painful intensive care procedures.

  20. Trafficking of Na+/Ca2+ Exchanger to the Site of Persistent Inflammation in Nociceptive Afferents

    PubMed Central

    Scheff, Nicole N.

    2015-01-01

    Persistent inflammation results in an increase in the amplitude and duration of depolarization-evoked Ca2+ transients in putative nociceptive afferents. Previous data indicated that these changes were the result of neither increased neuronal excitability nor an increase in the amplitude of depolarization. Subsequent data also ruled out an increase in voltage-gated Ca2+ currents and recruitment of Ca2+-induced Ca2+ release. Parametric studies indicated that the inflammation-induced increase in the duration of the evoked Ca2+ transient required a relatively large and long-lasting increase in the concentration of intracellular Ca2+ implicating the Na+/Ca2+ exchanger (NCX), a major Ca2+ extrusion mechanism activated with high intracellular Ca2+ loads. The contribution of NCX to the inflammation-induced increase in the evoked Ca2+ transient in rat sensory neurons was tested using fura-2 AM imaging and electrophysiological recordings. Changes in NCX expression and protein were assessed with real-time PCR and Western blot analysis, respectively. An inflammation-induced decrease in NCX activity was observed in a subpopulation of putative nociceptive neurons innervating the site of inflammation. The time course of the decrease in NCX activity paralleled that of the inflammation-induced changes in nociceptive behavior. The change in NCX3 in the cell body was associated with a decrease in NCX3 protein in the ganglia, an increase in the peripheral nerve (sciatic) yet no change in the central root. This single response to inflammation is associated with changes in at least three different segments of the primary afferent, all of which are likely to contribute to the dynamic response to persistent inflammation. PMID:26041911

  1. Trafficking of Na+/Ca2+ exchanger to the site of persistent inflammation in nociceptive afferents.

    PubMed

    Scheff, Nicole N; Gold, Michael S

    2015-06-03

    Persistent inflammation results in an increase in the amplitude and duration of depolarization-evoked Ca(2+) transients in putative nociceptive afferents. Previous data indicated that these changes were the result of neither increased neuronal excitability nor an increase in the amplitude of depolarization. Subsequent data also ruled out an increase in voltage-gated Ca(2+) currents and recruitment of Ca(2+)-induced Ca(2+) release. Parametric studies indicated that the inflammation-induced increase in the duration of the evoked Ca(2+) transient required a relatively large and long-lasting increase in the concentration of intracellular Ca(2+) implicating the Na(+)/Ca(2+) exchanger (NCX), a major Ca(2+) extrusion mechanism activated with high intracellular Ca(2+) loads. The contribution of NCX to the inflammation-induced increase in the evoked Ca(2+) transient in rat sensory neurons was tested using fura-2 AM imaging and electrophysiological recordings. Changes in NCX expression and protein were assessed with real-time PCR and Western blot analysis, respectively. An inflammation-induced decrease in NCX activity was observed in a subpopulation of putative nociceptive neurons innervating the site of inflammation. The time course of the decrease in NCX activity paralleled that of the inflammation-induced changes in nociceptive behavior. The change in NCX3 in the cell body was associated with a decrease in NCX3 protein in the ganglia, an increase in the peripheral nerve (sciatic) yet no change in the central root. This single response to inflammation is associated with changes in at least three different segments of the primary afferent, all of which are likely to contribute to the dynamic response to persistent inflammation.

  2. Conversion to eslicarbazepine acetate monotherapy

    PubMed Central

    French, Jacqueline; Jacobson, Mercedes P.; Pazdera, Ladislav; Gough, Mallory; Cheng, Hailong; Grinnell, Todd; Blum, David

    2016-01-01

    Objective: To assess the efficacy and safety of eslicarbazepine acetate (ESL) monotherapy. Methods: This post hoc pooled analysis of 2 randomized double-blind studies (093-045 and -046) included adults with partial-onset seizures medically uncontrolled by 1 or 2 antiepileptic drugs (AEDs). Following the baseline period (8 weeks), eligible patients were randomized 2:1 to receive ESL 1,600 mg or 1,200 mg once daily for 18 weeks; the primary endpoint was study exit by meeting predefined exit criteria (signifying worsening seizure control). In each study, treatment was considered effective if the upper 95% confidence limit for exit rate was lower than the historical control threshold (65.3%). Results: Pooled exit rates were as follows: ESL 1,600 mg = 20.6% (95% confidence interval: 15.6%–26.8%); ESL 1,200 mg = 30.8% (23.0%–40.5%). Use of 2 baseline AEDs or rescue medication, US location, epilepsy duration ≥20 years, and higher maximum baseline seizure frequency were associated with higher exit risks. Median percent reductions in standardized seizure frequency between baseline and the 18-week double-blind period were as follows: ESL 1,600 mg = 43.2%; ESL 1,200 mg = 35.7%; baseline carbamazepine use was associated with smaller reductions. Safety profiles were similar between ESL doses. Conclusions: Exit rates for ESL monotherapy (1,600 mg and 1,200 mg once daily) were lower than the historical control threshold, irrespective of baseline AED use and region, with no additional safety concerns identified. Clinical factors and location clearly influence treatment responses in conversion-to-monotherapy trials. Classification of evidence: This pooled analysis provides Class IV evidence that for adults with medically uncontrolled partial-onset seizures, ESL monotherapy is well tolerated and effective. PMID:26911639

  3. Protective Effect of Huoxiang Zhengqi Oral Liquid on Intestinal Mucosal Mechanical Barrier of Rats with Postinfectious Irritable Bowel Syndrome Induced by Acetic Acid

    PubMed Central

    Liu, Yao; Liu, Wei; Peng, Qiu-Xian; Peng, Jiang-Li; Yu, Lin-Zhong; Hu, Jian-Lan

    2014-01-01

    In this study, a rat model with acetic acid-induced PI-IBS was used to study the role of HXZQ oral liquid in repairing the colonic epithelial barrier and reducing intestinal permeability. Pathomorphism of colonic tissue, epithelial ultrastructure, DAO activity in serum, and the protein expression of ZO-1 and occludin were examined to investigate protective effect mechanisms of HXZQ on intestinal mucosa barrier and then present experimental support for its use for prevention and cure of PI-IBS. PMID:25254052

  4. Central distribution of nociceptive intradental afferent nerve fibers in the rat.

    PubMed

    Bombardi, C; Chiocchetti, R; Brunetti, O; Grandis, A; Lucchi, M L; Bortolami, R

    2006-08-01

    The central distribution of intradental afferent nerve fibers was investigated by combining electron microscopic observations with a selective method for inducing degeneration of the A delta- and C-type afferent fibers. Degenerating terminals were found on the proprioceptive mesencephalic trigeminal neurons and on dendrites in the neuropil of the trigeminal motor nucleus after application of capsaicin to the rat's lower incisor tooth pulp. The results give anatomical evidence of new sites of central projection of intradental A delta- and C-type fibers whereby the nociceptive information from the tooth pulp can affect jaw muscle activity.

  5. TRPA1 has a key role in the somatic pro-nociceptive actions of hydrogen sulfide.

    PubMed

    Andersson, David A; Gentry, Clive; Bevan, Stuart

    2012-01-01

    Hydrogen sulfide (H(2)S), which is produced endogenously from L-cysteine, is an irritant with pro-nociceptive actions. We have used measurements of intracellular calcium concentration, electrophysiology and behavioral measurements to show that the somatic pronociceptive actions of H(2)S require TRPA1. A H(2)S donor, NaHS, activated TRPA1 expressed in CHO cells and stimulated DRG neurons isolated from Trpa1(+/+) but not Trpa1(-/-) mice. TRPA1 activation by NaHS was pH dependent with increased activity at acidic pH. The midpoint of the relationship between NaHS EC(50) values and external pH was pH 7.21, close to the expected dissociation constant for H(2)S (pK(a) 7.04). NaHS evoked single channel currents in inside-out and cell-attached membrane patches consistent with an intracellular site of action. In behavioral experiments, intraplantar administration of NaHS and L-cysteine evoked mechanical and cold hypersensitivities in Trpa1(+/+) but not in Trpa1(-/-) mice. The sensitizing effects of L-cysteine in wild-type mice were inhibited by a cystathionine β-synthase inhibitor, D,L-propargylglycine (PAG), which inhibits H(2)S formation. Mechanical hypersensitivity evoked by intraplantar injections of LPS was prevented by PAG and the TRPA1 antagonist AP-18 and was absent in Trpa1(-/-) mice, indicating that H(2)S mediated stimulation of TRPA1 is necessary for the local pronociceptive effects of LPS. The pro-nociceptive effects of intraplantar NaHS were retained in Trpv1(-/-) mice ruling out TRPV1 as a molecular target. In behavioral studies, NaHS mediated sensitization was also inhibited by a T-type calcium channel inhibitor, mibefradil. In contrast to the effects of NaHS on somatic sensitivity, intracolonic NaHS administration evoked similar nociceptive effects in Trpa1(+/+) and Trpa1(-/-) mice, suggesting that the visceral pro-nociceptive effects of H(2)S are independent of TRPA1. In electrophysiological studies, the depolarizing actions of H(2)S on isolated DRG neurons

  6. Fragrance material review on 4-methylbenzyl acetate.

    PubMed

    McGinty, D; Letizia, C S; Api, A M

    2012-09-01

    A toxicologic and dermatologic review of 4-methylbenzyl acetate when used as a fragrance ingredient is presented. 4-Methylbenzyl acetate is a member of the fragrance structural group Aryl Alkyl Alcohol Simple Acid Esters (AAASAE). The AAASAE fragrance ingredients are prepared by reacting an aryl alkyl alcohol with a simple carboxylic acid (a chain of 1-4 carbons) to generate formate, acetate, propionate, butyrate, isobutyrate and carbonate esters. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 4-methylbenzyl acetate were evaluated, then summarized, and includes: physical properties, skin irritation, skin sensitization, and elicitation data. A safety assessment of the entire AAASAE will be published simultaneously with this document. Please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all AAASAE in fragrances.

  7. Affective disturbance associated with premenstrual dysphoric disorder does not disrupt emotional modulation of pain and spinal nociception.

    PubMed

    Rhudy, Jamie L; Bartley, Emily J; Palit, Shreela; Kuhn, Bethany L; Kerr, Kara L; Martin, Satin L; DelVentura, Jennifer L; Terry, Ellen L

    2014-10-01

    In healthy individuals, emotions modulate pain and spinal nociception according to a valence linear trend (ie, pain/nociception is highest during negative emotions and lowest during positive emotions). However, emerging evidence suggests that emotional modulation of pain (but not spinal nociception) is disrupted in fibromyalgia and disorders associated with chronic pain risk (eg, major depression, insomnia). The present study attempted to extend this work and to examine whether women with premenstrual dysphoric disorder (PMDD), a cyclical syndrome associated with debilitating affective symptoms during the late-luteal (premenstrual) phase of the menstrual cycle, is also associated with disrupted emotional modulation of pain. To do so, an affective picture-viewing procedure was used to study emotional modulation of pain and spinal nociception in 14 women with PMDD and 14 control women during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (verified by salivary hormone levels and luteinizing hormone tests). At each phase, mutilation, neutral, and erotic pictures were presented to manipulate emotion. During picture viewing, suprathreshold electrocutaneous stimuli were presented to evoke pain and the nociceptive flexion reflex (NFR; a physiological measure of spinal nociception). Statistically powerful linear mixed model analyses confirmed that pictures evoked the intended emotional states in both groups across all menstrual phases. Furthermore, emotion modulated pain and NFR according to a valence linear trend in both groups and across all menstrual phases. Thus, PMDD-related affective disturbance is not associated with a failure to emotionally modulate pain, suggesting that PMDD does not share this pain phenotype with major depression, insomnia, and fibromyalgia.

  8. An in vitro assay system for studying synapse formation between nociceptive dorsal root ganglion and dorsal horn neurons

    PubMed Central

    Joseph, Donald J.; Choudhury, Papiya; MacDermott, Amy B.

    2010-01-01

    Synapses between nociceptive dorsal root ganglion (DRG) neurons and spinal cord dorsal horn neurons represent the first loci for transmission of painful stimuli. Our knowledge of the molecular organization and development of these synapses is sparse due, partly, to a lack of a reliable model system that reconstitutes synaptogenesis between these two neuronal populations. To address this issue, we have established an in vitro assay system consisting of separately purified DRG neurons and dorsal horn neurons on astrocyte micro-islands. Using immunocytochemistry, we have found that 97%, 93%, 98%, 96%, and 94% of DRG neurons on these microislands express markers often associated with nociceptive neurons including Substance P, TRPV1, calcitonin-gene related peptide (CGRP), TrKA, and peripherin, respectively. Triple labeling with these nociceptive-like markers, synaptic vesicle marker Vglut2 and using MAP2 as a dendritic marker revealed the presence of nociceptive-like markers at synaptic terminals. Using this immunocytochemical approach, we counted contact points as overlapping MAP2/Vglut2 puncta and showed that they increased with time in culture. Single and dual patch clamp recordings showed that overlapping Vglut2/MAP2 puncta observed after a few days in culture are likely to be functional synapses between DRG and dorsal horn neurons in our in vitro assay system. Taken together, these data suggest our co-culture microisland model system consists of mostly nociceptive-like DRG neurons that express presynaptic markers and form functional synapses with their dorsal horn partners. Thus, this model system may have direct application for studies on factors regulating development of nociceptive DRG/dorsal horn synapses. PMID:20385165

  9. Differential roles of spinal cholera toxin- and pertussis toxin-sensitive G proteins in nociceptive responses caused by formalin, capsaicin, and substance P in mice.

    PubMed

    Chung, K M; Lee, K C; Choi, S S; Suh, H W

    2001-03-15

    The aim of the present study is to characterize the roles of spinal cholera toxin (CTX)- and pertussis toxin (PTX)-sensitive G proteins in the regulation of various nociceptive responses. The effects of intrathecal (i.t.) pretreatments with CTX and PTX on the formalin (subcutaneous)-, capsaicin (i.t.)-, and substance P (SP; i.t.)-induced nociceptive behaviours were examined in mice. Pretreatment with CTX (i.t.; 24 h before) significantly and dose-dependently (0.05-0.5 microg) suppressed both the first and second phases of the formalin-induced nociceptive behaviour. On the other hand, pretreatment with PTX (i.t., 6 days before) at the same doses (0.05-N0.5 microg) did not affect the formalin-induced response. Capsaicin (i.t., 0.5 microg)- and SP (i.t., 0.7 microg)-induced nociceptive behaviours were attenuated by the pretreatment with CTX. In addition, SP-induced nociceptive response was also attenuated by the pretreatment with PTX. However, the capsaicin-induced nociceptive response was not influenced by PTX pretreatment. These findings suggest that, at the spinal cord level, CTX-sensitive G-proteins are involved in the formalin-, capsaicin-, and SP-induced nociceptive behavioural responses, whereas PTX-sensitive G proteins are involved in SP-induced nociceptive response.

  10. Oxalic acid-induced modifications of postglycation activity of lysozyme and its glycoforms.

    PubMed

    Gao, Hong Ying; Yaylayan, Varoujan A; Yeboah, Faustinus

    2010-05-26

    The role of selected carboxylic acids and their potential to influence the glycation pattern and the enzymatic activity of lysozyme using glucose and ribose were investigated independently of the pH of the reaction medium. The model systems were incubated with and without selected carboxylic acids (maleic, acetic, oxalic, and citraconic) at 50 degrees C for 12 or 24 and 48 h at constant pH of 6.5. The effect of carboxylic acids on the glycation of lysozyme was studied by electrospray ionization mass spectrometry (ESI-MS) and by the measurement of the residual enzyme activity of lysozyme in the glycated samples. Of the carboxylic acids evaluated, oxalic acid showed the highest antiglycation activity. The residual lysozyme activity in both oxalic acid-glucose and oxalic acid-ribose systems was >80% compared with 46 and 36% activity in the controls of glucose and ribose systems, respectively. On the other hand, maleic, acetic, and citraconic acid containing systems with both sugars did not exhibit any enhanced enzyme activity relative to the controls. The results of this study show that oxalic acid was unique among the carboxylic acids evaluated with respect to its ability to interact with sugars and inhibit glycation.

  11. [Experimental study of proflavine acetate phototransformation processes].

    PubMed

    Zholdakova, Z I; Sinitsyna, O O; Lebedev, A T; Kharchevnikova, N V

    2009-01-01

    Changes in proflavine acetate phototransformation processes upon exposure to visible-range irradiation were studied by high performance liquid chromatography. Proflavine acetate was offered as a photosensitizer during photodynamic water disinfection. Dye transformation products upon time-varying exposure to irradiation were identified. By using structure-activity relationships and information from toxicity databases, the authors evaluated the hazard of the identified products and identified the most hazardous ones.

  12. Tachykinin inhibition of acid-induced gastric hyperaemia in the rat.

    PubMed Central

    Heinemann, A.; Jocic, M.; Herzeg, G.; Holzer, P.

    1996-01-01

    1. Primary afferent neurones releasing the vasodilator, calcitonin gene-related peptide, mediate the gastric hyperaemic response to acid back-diffusion. The tachykinins neurokinin A (NKA) and substance P (SP) are located in the same neurones and are co-released with calcitonin gene-related peptide. In this study we investigated the effect and possible role of tachykinins in the acid-evoked gastric vasodilatation in urethane-anaesthetized rats. 2. Gastric acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCl, increased gastric mucosal blood flow by 60-90%, as determined by the hydrogen clearance technique. NKA and SP (0.14-3.78 nmol min-1 kg-1, infused intra-aortically) inhibited the gastric mucosal hyperaemic response to acid back-diffusion in a dose-dependent manner, an effect that was accompanied by aggravation of ethanol/acid-induced macroscopic haemorrhagic lesions. 3. The inhibitory effect of NKA (1.26 nmol min-1 kg-1) on the acid-induced gastric mucosal vasodilatation was prevented by the tachykinin NK2 receptor antagonists, MEN 10,627 (200 nmol kg-1) but left unaltered by the NK1 receptor antagonist, SR 140,333 (300 nmol kg-1) and the mast-cell stabilizer, ketotifen (4.6 mumol kg-1). 4. Under basal conditions, with 0.05 M HCl being perfused through the stomach, NKA (1.26 nmol min-1 kg-1) reduced gastric mucosal blood flow by about 25%, an effect that was abolished by SR 140,333 but not MEN 10,627 or ketotifen. 5. SR 140,333, MEN 10,627 or ketotifen had no significant effect on basal gastric mucosal blood flow nor did they modify the gastric mucosal hyperaemic reaction to acid back-diffusion. 6. The effect of NKA (1.26 nmol min-1 kg-1) in causing vasoconstriction and inhibiting the vasodilator response to acid back-diffusion was also seen when blood flow in the left gastric artery was measured with the ultrasonic transit time shift technique. 7. Arginine vasopressin (AVP, 0.1 nmol min-1 kg-1) induced gastric

  13. Pistacia lentiscus resin regulates intestinal damage and inflammation in trinitrobenzene sulfonic acid-induced colitis.

    PubMed

    Gioxari, Aristea; Kaliora, Andriana C; Papalois, Apostolos; Agrogiannis, George; Triantafillidis, John K; Andrikopoulos, Nikolaos K

    2011-11-01

    Mastic (Pistacia lentiscus) of the Anacardiaceae family has exhibited anti-inflammatory and antioxidant properties in patients with Crohn's disease. This study was based on the hypothesis that mastic inhibits intestinal damage in inflammatory bowel disease, regulating inflammation and oxidative stress in intestinal epithelium. Four different dosages of P. lentiscus powder in the form of powder were administered orally to trinitrobenzene sulfonic acid-induced colitic rats. Eighty-four male Wistar rats were randomly assigned to seven groups: A, control; B, colitic; C-F, colitic rats daily supplemented with P. lentiscus powder at (C) 50 mg/kg, (D) 100 mg/kg, (E) 200 mg/kg, and (F) 300 mg/kg of body weight; and G, colitic rats treated daily with cortisone (25 μg/kg of body weight). Colonic damage was assessed microscopically. The cytokines tumor necrosis factor-α, intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-6, IL-8, and IL-10 and malonaldehyde were measured in colonic specimens. Results were expressed as mean ± SE values. Histological amelioration of colitis (P≤.001) and significant differences in colonic indices occurred after 3 days of treatment. Daily administration of 100 mg of P. lentiscus powder/kg of body weight decreased all inflammatory cytokines (P≤.05), whereas 50 mg of P. lentiscus powder/kg of body weight and cortisone treatment reduced only ICAM-1 (P≤.05 and P≤.01, respectively). Malonaldehyde was significantly suppressed in all treated groups (P≤.01). IL-10 remained unchanged. Cytokines and malonaldehyde remained unaltered after 6 days of treatment. Thus P. lentiscus powder could possibly have a therapeutic role in Crohn's disease, regulating oxidant/antioxidant balance and modulating inflammation.

  14. Praeruptorin D and E attenuate lipopolysaccharide/hydrochloric acid induced acute lung injury in mice.

    PubMed

    Yu, Peng-Jiu; Li, Jing-Rong; Zhu, Zheng-Guang; Kong, Huan-Yu; Jin, Hong; Zhang, Jun-Yan; Tian, Yuan-Xin; Li, Zhong-Huang; Wu, Xiao-Yun; Zhang, Jia-Jie; Wu, Shu-Guang

    2013-06-15

    Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury.

  15. Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

    SciTech Connect

    Woolbright, Benjamin L.; Dorko, Kenneth; Antoine, Daniel J.; Clarke, Joanna I.; Gholami, Parviz; Li, Feng; Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson; Fan, Fang; Jenkins, Rosalind E.; Park, B. Kevin; Hagenbuch, Bruno; Olyaee, Mojtaba; Jaeschke, Hartmut

    2015-03-15

    Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury

  16. Human sweet taste receptor mediates acid-induced sweetness of miraculin.

    PubMed

    Koizumi, Ayako; Tsuchiya, Asami; Nakajima, Ken-ichiro; Ito, Keisuke; Terada, Tohru; Shimizu-Ibuka, Akiko; Briand, Loïc; Asakura, Tomiko; Misaka, Takumi; Abe, Keiko

    2011-10-04

    Miraculin (MCL) is a homodimeric protein isolated from the red berries of Richadella dulcifica. MCL, although flat in taste at neutral pH, has taste-modifying activity to convert sour stimuli to sweetness. Once MCL is held on the tongue, strong sweetness is sensed over 1 h each time we taste a sour solution. Nevertheless, no molecular mechanism underlying the taste-modifying activity has been clarified. In this study, we succeeded in quantitatively evaluating the acid-induced sweetness of MCL using a cell-based assay system and found that MCL activated hT1R2-hT1R3 pH-dependently as the pH decreased from 6.5 to 4.8, and that the receptor activation occurred every time an acid solution was applied. Although MCL per se is sensory-inactive at pH 6.7 or higher, it suppressed the response of hT1R2-hT1R3 to other sweeteners at neutral pH and enhanced the response at weakly acidic pH. Using human/mouse chimeric receptors and molecular modeling, we revealed that the amino-terminal domain of hT1R2 is required for the response to MCL. Our data suggest that MCL binds hT1R2-hT1R3 as an antagonist at neutral pH and functionally changes into an agonist at acidic pH, and we conclude this may cause its taste-modifying activity.

  17. Human sweet taste receptor mediates acid-induced sweetness of miraculin

    PubMed Central

    Koizumi, Ayako; Tsuchiya, Asami; Nakajima, Ken-ichiro; Ito, Keisuke; Terada, Tohru; Shimizu-Ibuka, Akiko; Briand, Loïc; Asakura, Tomiko; Misaka, Takumi; Abe, Keiko

    2011-01-01

    Miraculin (MCL) is a homodimeric protein isolated from the red berries of Richadella dulcifica. MCL, although flat in taste at neutral pH, has taste-modifying activity to convert sour stimuli to sweetness. Once MCL is held on the tongue, strong sweetness is sensed over 1 h each time we taste a sour solution. Nevertheless, no molecular mechanism underlying the taste-modifying activity has been clarified. In this study, we succeeded in quantitatively evaluating the acid-induced sweetness of MCL using a cell-based assay system and found that MCL activated hT1R2-hT1R3 pH-dependently as the pH decreased from 6.5 to 4.8, and that the receptor activation occurred every time an acid solution was applied. Although MCL per se is sensory-inactive at pH 6.7 or higher, it suppressed the response of hT1R2-hT1R3 to other sweeteners at neutral pH and enhanced the response at weakly acidic pH. Using human/mouse chimeric receptors and molecular modeling, we revealed that the amino-terminal domain of hT1R2 is required for the response to MCL. Our data suggest that MCL binds hT1R2-hT1R3 as an antagonist at neutral pH and functionally changes into an agonist at acidic pH, and we conclude this may cause its taste-modifying activity. PMID:21949380

  18. The cumulus cell layer protects the bovine maturing oocyte against fatty acid-induced lipotoxicity.

    PubMed

    Lolicato, Francesca; Brouwers, Jos F; de Lest, Chris H A van; Wubbolts, Richard; Aardema, Hilde; Priore, Paola; Roelen, Bernard A J; Helms, J Bernd; Gadella, Bart M

    2015-01-01

    Mobilization of fatty acids from adipose tissue during metabolic stress increases the amount of free fatty acids in blood and follicular fluid and is associated with impaired female fertility. In a previous report, we described the effects of the three predominant fatty acids in follicular fluid (saturated palmitate and stearate and unsaturated oleate) on oocyte maturation and quality. In the current study, the effects of elevated fatty acid levels on cumulus cells were investigated. In a dose-dependent manner, the three fatty acids induced lipid storage in cumulus cells accompanied by an enhanced immune labeling of perilipin-2, a marker for lipid droplets. Lipidomic analysis confirmed incorporation of the administered fatty acids into triglyceride, resulting in a 3- to 6-fold increase of triglyceride content. In addition, palmitate selectively induced ceramide formation, which has been implicated in apoptosis. Indeed, of the three fatty acids tested, palmitate induced reactive oxygen species formation, caspase 3 activation, and mitochondria deterioration, leading to degeneration of the cumulus cell layers. This effect could be mimicked by addition of the ceramide-C2 analog and could be inhibited by the ceramide synthase inhibitor fumonisin-B1. Interfering with the intactness of the cumulus cell layers, either by mechanical force or by palmitate treatment, resulted in enhanced uptake of lipids in the oocyte and increased radical formation. Our results show that cumulus cells act as a barrier, protecting oocytes from in vitro induced lipotoxic effects. We suggest that this protective function of the cumulus cell layers is important for the developmental competence of the oocyte. The relevance of our findings for assisted reproduction technologies is discussed.

  19. Behavior-associated Neuronal Activation After Kainic Acid-induced Hippocampal Neurotoxicity is Modulated in Time.

    PubMed

    Aguilar-Arredondo, Andrea; López-Hernández, Fernanda; García-Velázquez, Lizbeth; Arias, Clorinda; Zepeda, Angélica

    2017-02-01

    Kainic acid-induced (KA) hippocampal damage leads to neuronal death and further synaptic plasticity. Formation of aberrant as well as of functional connections after such procedure has been documented. However, the impact of such structural plasticity on cell activation along time after damage and in face of a behavioral demand has not been explored. We evaluated if the mRNA and protein levels of plasticity-related protein synaptophysin (Syp and SYP, respectively) and activity-regulated cytoskeleton-associated protein mRNA and protein levels (Arc and Arc, respectively) in the dentate gyrus were differentially modulated in time in response to a spatial-exploratory task after KA-induced hippocampal damage. In addition, we analyzed Arc+/NeuN+ immunopositive cells in the different experimental conditions. We infused KA intrahippocampally to young-adult rats and 10 or 30 days post-lesion (dpl) animals performed a hippocampus-activating spatial-exploratory task. Our results show that Syp mRNA levels significantly increase at 10dpl and return to control levels after 30dpl, whereas SYP protein levels are diminished at 10dpl, but significantly increase at 30dpl, as compared to 10dpl. Arc mRNA and protein levels are both increased at 30dpl as compared to sham. Also the number of NeuN+/Arc+ cells significantly increases at 30dpl in the group with a spatial-exploratory demand. These results provide information on the long-term modifications associated to structural plasticity and neuronal activation in the dentate gyrus after excitotoxic damage and in face of a spatial-exploratory behavior. Anat Rec, 300:425-432, 2017. © 2016 Wiley Periodicals, Inc.

  20. Lysophosphatidic acid induces vasodilation mediated by LPA1 receptors, phospholipase C, and endothelial nitric oxide synthase

    PubMed Central

    Ruisanchez, Éva; Dancs, Péter; Kerék, Margit; Németh, Tamás; Faragó, Bernadett; Balogh, Andrea; Patil, Renukadevi; Jennings, Brett L.; Liliom, Károly; Malik, Kafait U.; Smrcka, Alan V.; Tigyi, Gabor; Benyó, Zoltán

    2014-01-01

    Lysophosphatidic acid (LPA) has been implicated as a mediator of several cardiovascular functions, but its potential involvement in the control of vascular tone is obscure. Here, we show that both LPA (18:1) and VPC31143 (a synthetic agonist of LPA1–3 receptors) relax intact mouse thoracic aorta with similar Emax values (53.9 and 51.9% of phenylephrine-induced precontraction), although the EC50 of LPA- and VPC31143-induced vasorelaxations were different (400 vs. 15 nM, respectively). Mechanical removal of the endothelium or genetic deletion of endothelial nitric oxide synthase (eNOS) not only diminished vasorelaxation by LPA or VPC31143 but converted it to vasoconstriction. Freshly isolated mouse aortic endothelial cells expressed LPA1, LPA2, LPA4 and LPA5 transcripts. The LPA1,3 antagonist Ki16425, the LPA1 antagonist AM095, and the genetic deletion of LPA1, but not that of LPA2, abolished LPA-induced vasorelaxation. Inhibition of the phosphoinositide 3 kinase–protein kinase B/Akt pathway by wortmannin or MK-2206 failed to influence the effect of LPA. However, pharmacological inhibition of phospholipase C (PLC) by U73122 or edelfosine, but not genetic deletion of PLCε, abolished LPA-induced vasorelaxation and indicated that a PLC enzyme, other than PLCε, mediates the response. In summary, the present study identifies LPA as an endothelium-dependent vasodilator substance acting via LPA1, PLC, and eNOS.—Ruisanchez, É., Dancs, P., Kerék, M., Németh, T., Faragó, B., Balogh, A., Patil, R., Jennings, B. L., Liliom, K., Malik, K. U., Smrcka, A. V., Tigyi, G., Benyó, Z. Lysophosphatidic acid induces vasodilation mediated by LPA1 receptors, phospholipase C, and endothelial nitric oxide synthase. PMID:24249637

  1. Transient Receptor Potential Melastatin-3 (TRPM3) Mediates Nociceptive-Like Responses in Hydra vulgaris

    PubMed Central

    Malafoglia, Valentina; Traversetti, Lorenzo; Del Grosso, Floriano; Scalici, Massimiliano; Lauro, Filomena; Russo, Valeria; Persichini, Tiziana; Salvemini, Daniela; Mollace, Vincenzo; Fini, Massimo; Raffaeli, William

    2016-01-01

    The ability of mammals to feel noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors, which express specific membrane receptors, such as the Transient Receptor Potential (TRP) family. Here, we show that one of the most important nociceptive-like pathways is conserved in the freshwater coelenterate Hydra vulgaris, the most primitive organism possessing a nervous system. In particular, we found that H. vulgaris expresses TRPM3, a nociceptor calcium channel involved in the detection of noxious heat in mammals. Furthermore, we detected that both heat shock and TRPM3 specific agonist (i.e., pregnenolone sulfate) induce the modulation of the heat shock protein 70 (HSP70) and the nitric oxide synthase (NOS), two genes activated by TRP-mediated heat painful stimuli in mammals. As expected, these effects are inhibited by a TRPM3 antagonist (i.e., mefenamic acid). Interestingly, the TRPM3 agonist and heat shock also induce the expression of nuclear transcription erythroid 2-related factor (Nrf2) and superoxide dismutase (SOD), known markers of oxidative stress; noteworthy gene expression was also inhibited by the TRPM3 antagonist. As a whole, our results demonstrate the presence of conserved molecular oxidative/nociceptive-like pathways at the primordial level of the animal kingdom. PMID:26974325

  2. Transient Receptor Potential Melastatin-3 (TRPM3) Mediates Nociceptive-Like Responses in Hydra vulgaris.

    PubMed

    Malafoglia, Valentina; Traversetti, Lorenzo; Del Grosso, Floriano; Scalici, Massimiliano; Lauro, Filomena; Russo, Valeria; Persichini, Tiziana; Salvemini, Daniela; Mollace, Vincenzo; Fini, Massimo; Raffaeli, William; Muscoli, Carolina; Colasanti, Marco

    2016-01-01

    The ability of mammals to feel noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors, which express specific membrane receptors, such as the Transient Receptor Potential (TRP) family. Here, we show that one of the most important nociceptive-like pathways is conserved in the freshwater coelenterate Hydra vulgaris, the most primitive organism possessing a nervous system. In particular, we found that H. vulgaris expresses TRPM3, a nociceptor calcium channel involved in the detection of noxious heat in mammals. Furthermore, we detected that both heat shock and TRPM3 specific agonist (i.e., pregnenolone sulfate) induce the modulation of the heat shock protein 70 (HSP70) and the nitric oxide synthase (NOS), two genes activated by TRP-mediated heat painful stimuli in mammals. As expected, these effects are inhibited by a TRPM3 antagonist (i.e., mefenamic acid). Interestingly, the TRPM3 agonist and heat shock also induce the expression of nuclear transcription erythroid 2-related factor (Nrf2) and superoxide dismutase (SOD), known markers of oxidative stress; noteworthy gene expression was also inhibited by the TRPM3 antagonist. As a whole, our results demonstrate the presence of conserved molecular oxidative/nociceptive-like pathways at the primordial level of the animal kingdom.

  3. Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

    PubMed Central

    Rouwette, Tom; Avenali, Luca; Sondermann, Julia; Narayanan, Pratibha; Gomez-Varela, David; Schmidt, Manuela

    2015-01-01

    In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles. PMID:26039491

  4. TRPV1 and TRPA1 mediate peripheral nitric oxide-induced nociception in mice.

    PubMed

    Miyamoto, Takashi; Dubin, Adrienne E; Petrus, Matt J; Patapoutian, Ardem

    2009-10-29

    Nitric oxide (NO) can induce acute pain in humans and plays an important role in pain sensitization caused by inflammation and injury in animal models. There is evidence that NO acts both in the central nervous system via a cyclic GMP pathway and in the periphery on sensory neurons through unknown mechanisms. It has recently been suggested that TRPV1 and TRPA1, two polymodal ion channels that sense noxious stimuli impinging on peripheral nociceptors, are activated by NO in heterologous systems. Here, we investigate the relevance of this activation. We demonstrate that NO donors directly activate TRPV1 and TRPA1 in isolated inside-out patch recordings. Cultured primary sensory neurons display both TRPV1- and TRPA1-dependent responses to NO donors. BH4, an essential co-factor for NO production, causes activation of a subset of DRG neurons as assayed by calcium imaging, and this activation is at least partly dependent on nitric oxide synthase activity. We show that BH4-induced calcium influx is ablated in DRG neurons from TRPA1/TRPV1 double knockout mice, suggesting that production of endogenous levels of NO can activate these ion channels. In behavioral assays, peripheral NO-induced nociception is compromised when TRPV1 and TRPA1 are both ablated. These results provide genetic evidence that the peripheral nociceptive action of NO is mediated by both TRPV1 and TRPA1.

  5. St. John's wort reversal of meningeal nociception: a natural therapeutic perspective for migraine pain.

    PubMed

    Galeotti, N; Ghelardini, C

    2013-07-15

    Despite a number of antimigraine drugs belonging to different pharmacological classes are available, there is a huge unmet need for better migraine pharmacotherapy. We here demonstrated the capability of Hypericum perforatum, popularly called St. John's wort (SJW), to relieve meningeal nociception in an animal model induced by administration of the nitric oxide (NO) donors glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). GTN and SNP produced a delayed meningeal inflammation, as showed by the upregulation of interleukin (IL)-1β and inducible NO synthase (iNOS), and a prolonged cold allodynia and heat hyperalgesia with a time-course consistent with NO-induced migraine attacks. A single oral administration of a SJW dried extract (5mg/kg p.o.) counteracted the nociceptive behaviour and the overexpression of IL-1β and iNOS. To clarify the cellular pathways involved, the expression of protein kinase C (PKC) and downstream effectors was detected. NO donors increased expression and phosphorylation of PKCγ, PKCɛ and transcription factors, such as nuclear factor (NF)-κB, cyclic AMP response element binding protein (CREB), Signal Transducer and Activator of Transcription (STAT)-1. All these molecular events were prevented by SJW and hypericin, a SJW main component. In conclusion, SJW counteracted the NO donor-induced pain hypersensitivity and meningeal activation by blocking PKC-mediated pathways involving NF-κB, CREB, STAT1. These results might suggest SJW as an innovative and safe perspective for migraine pain.

  6. Dorsal horn convergent neurones: negative feedback triggered by spatial summation of nociceptive afferents.

    PubMed

    Bouhassira, D; Gall, O; Chitour, D; Le Bars, D

    1995-08-01

    In order to investigate the effects of spatial summation on the spinal transmission of nociceptive information, we compared in intact and spinal anaesthetized rats, responses of lumbar convergent neurones elicited by noxious heat stimuli applied to areas of the body much greater in size than their individual excitatory receptive fields, located distally on the hindpaw. Twenty-four neurones were recorded in each group of animals. For each neurone, 4 successive immersions of increasing areas (1.9-18 cm2) of the ipsilateral hindpaw in a 48 degrees C water bath (15-sec duration) were performed with 10-min intervals in a randomized and balanced order. In intact animals, the responses of convergent neurones progressively decreased when the area of noxious thermal stimulation reached and then exceeded approximately twice the area of their individual excitatory receptive fields. This decrease was highly significant for 18 cm2 which represents approximately 10-fold the mean of the receptive field areas. Such a phenomenon was not observed for neurones recorded in spinal animals although their excitatory receptive field areas were not significantly different. These results suggest that the activation of a large population of nociceptive afferents triggers supraspinally mediated negative feed-back loop modulating the responses of convergent neurones.

  7. Morphine in combination with metabotropic glutamate receptor antagonists on schedule-controlled responding and thermal nociception.

    PubMed

    Fischer, Bradford D; Zimmerman, Eric I; Picker, Mitchell J; Dykstra, Linda A

    2008-02-01

    The present study examined the interactive effects of morphine in combination with metabotropic glutamate (mGlu) receptor antagonists on schedule-controlled responding and thermal nociception. Drug interaction data were examined with isobolographic and dose-addition analysis. Morphine, the mGlu1 receptor antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone], the mGlu5 receptor antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride], and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] all decreased rates of schedule-controlled responding. JNJ16259685/morphine, MPEP/morphine, and LY341495/morphine mixtures produced additive effects on this endpoint. Morphine also produced dose-dependent antinociception in the assay of thermal nociception, whereas JNJ16259685, MPEP, and LY341495 failed to produce an effect. In this assay, JNJ16259685 and LY341495 potentiated the antinociceptive effects of morphine, whereas MPEP/morphine mixtures produced additive effects. These results suggest that an mGlu1 and an mGlu2/3 receptor antagonist, but not an mGlu5 receptor antagonist, selectively enhance the antinociceptive effects of morphine. In addition, these data confirm that the behavioral effects of drug mixtures depend on the endpoint under study.

  8. Hargreaves does not evaluate nociception following a surgical laparotomy in Xenopus leavis frogs.

    PubMed

    Vachon, P

    2014-10-01

    The present study was performed to determine the effectiveness of the Hargreaves test for the evaluation of nociception in frogs, more precisely to determine if cutaneous thresholds to a radiant heat stimulus would increase with analgesics following an abdominal laparotomy performed under general anaesthesia. Non breeding female Xenopus leavis frogs (3 groups (non-anaesthetized, anaesthetized with tricaine methanesulfonate (MS222), with or without an abdominal laparotomy) were used to evaluate the effectiveness of the Hargreaves test. Cutaneous thresholds were evaluated at baseline and following anaesthetic recovery (over 8 h) at six different body locations. Increased reaction times were observed in the gular area only at 1 h post-recovery following a MS222 bath immersion in frogs with (p < 0.02) and without the abdominal laparotomy (p < 0.002). In conclusion, the Hargreaves test does not provide an adequate test to evaluate nociception induced by an abdominal laparotomy and consequently cannot be used to evaluate analgesics in X. leavis frogs.

  9. Frutalin reduces acute and neuropathic nociceptive behaviours in rodent models of orofacial pain.

    PubMed

    Damasceno, Marina B M V; de Melo Júnior, José de Maria A; Santos, Sacha Aubrey A R; Melo, Luana T M; Leite, Laura Hévila I; Vieira-Neto, Antonio E; Moreira, Renato de A; Monteiro-Moreira, Ana Cristina de O; Campos, Adriana R

    2016-08-25

    Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor.

  10. Translational control of nociception via 4E-binding protein 1

    PubMed Central

    Khoutorsky, Arkady; Bonin, Robert P; Sorge, Robert E; Gkogkas, Christos G; Pawlowski, Sophie Anne; Jafarnejad, Seyed Mehdi; Pitcher, Mark H; Alain, Tommy; Perez-Sanchez, Jimena; Salter, Eric W; Martin, Loren; Ribeiro-da-Silva, Alfredo; De Koninck, Yves; Cervero, Fernando; Mogil, Jeffrey S; Sonenberg, Nahum

    2015-01-01

    Activation of the mechanistic/mammalian target of rapamycin (mTOR) kinase in models of acute and chronic pain is strongly implicated in mediating enhanced translation and hyperalgesia. However, the molecular mechanisms by which mTOR regulates nociception remain unclear. Here we show that deletion of the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a major mTOR downstream effector, which represses eIF4E activity and cap-dependent translation, leads to mechanical, but not thermal pain hypersensitivity. Mice lacking 4E-BP1 exhibit enhanced spinal cord expression of neuroligin 1, a cell-adhesion postsynaptic protein regulating excitatory synapse function, and show increased excitatory synaptic input into spinal neurons, and a lowered threshold for induction of synaptic potentiation. Pharmacological inhibition of eIF4E or genetic reduction of neuroligin 1 levels normalizes the increased excitatory synaptic activity and reverses mechanical hypersensitivity. Thus, translational control by 4E-BP1 downstream of mTOR effects the expression of neuroligin 1 and excitatory synaptic transmission in the spinal cord, and thereby contributes to enhanced mechanical nociception. DOI: http://dx.doi.org/10.7554/eLife.12002.001 PMID:26678009

  11. Heart rate variability in subjects with different hypnotic susceptibility receiving nociceptive stimulation and suggestions of analgesia.

    PubMed

    Balocchi, R; Varanini, M; Menicucci, D; Santarcangelo, E L; Migliorini, S; Fontani, G; Carli, G

    2005-01-01

    The aim of the present study was to investigate the possible hypnotizability-related modulation of heart activity during nociceptive stimulation (pressor pain) and during nociceptive stimulation associated with the suggestion of analgesia in not hypnotized healthy individuals with a high (Highs) and a low (Lows) hypnotic susceptibility. ECG and respirogram were recorded. Standard time and frequency domain indexes were evaluated, together with the sd1 and sd2 values of the Poincaré plot over the RR series. Results showed self reports of analgesia in Highs and a significant increase of the respiratory frequency during stimulation in both groups. Very few significant differences between groups and among conditions were detected for mean RR and heart rate variability (HRV) through spectral analysis. and through the Poincaré indexes evaluation. On the contrary, a promising approach seems to be the study of the correlations among standard and Poincaré variables. In particular, different changes in (or even lost of) correlations were enlightened in Highs and Lows, suggesting a different modulation of RR in the two groups, probably due to the very low frequency components of HRV. Different roles of sympathetic and parasympathetic activities during stimulation can be suggested.

  12. Prediction of nociceptive responses during sedation by time-frequency representation.

    PubMed

    Melia, Umberto; Vallverdú, Montserrat; Jospin, Mathieu; Jensen, Erik W; Valencia, Jose Fernando; Clariá, Francesc; Gambus, Pedro L; Caminal, Pere

    2013-01-01

    The level of sedation in patients undergoing medical procedures evolves continuously, such as the effect of the anesthetic and analgesic agents is counteracted by pain stimuli. The monitors of depth of anesthesia, based on the analysis of the electroencephalogram (EEG), have been progressively introduced into the daily practice to provide additional information about the state of the patient. However, the quantification of analgesia still remains an open problem. The purpose of this work is to analyze the capability of prediction of nociceptive responses based on the time-frequency representation (TFR) of EEG signal. Functions of spectral entropy, instantaneous power and instantaneous frequency were calculated in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. Values of prediction probability of Pk above 0.75 and percentages of sensitivity and specificity above 70% and 65% respectively were achieved combining TFR functions with bispectral index (BIS) and with concentrations of propofol (CeProp) and remifentanil (CeRemi).

  13. Acid-Sensing Ion Channels and nociception in the peripheral and central nervous systems.

    PubMed

    Deval, Emmanuel; Lingueglia, Eric

    2015-07-01

    Since their molecular cloning in the late 90's, Acid-Sensing Ion Channels (ASICs) have been shown to be involved in many aspects of nociception, both in peripheral and central neurons. In rodents, the combination of specific or non-specific pharmacological modulators of ASICs, together with in vivo knockdown and/or knockout animals has revealed their contribution to the detection, the modulation and the sensitization of the pain message by primary and secondary sensory neurons. Functional ASICs are homo or heterotrimers of different homologous subunits (ASIC1-3). Channels containing ASIC3 or ASIC1 subunits, appear to be important in peripheral nociceptors, where they are subject to intense regulation, while ASIC1a-containing channels also have a prominent role in central neurons, including spinal cord neurons that modulate and transmit the pain signal to the brain. In humans, experiments performed in healthy volunteers using drugs already used in the clinic and acting as poorly-selective inhibitors of ASICs, together with recent in vitro data obtained from stem cell-derived sensory neurons both support a role for these channels in nociception. These data thus suggest a real translational potential in the development of inhibitory strategies of ASICs for the treatment of pain. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'.

  14. Persistent changes in peripheral and spinal nociceptive processing after early tissue injury

    PubMed Central

    Walker, Suellen; Beggs, Simon; Baccei, Mark L.

    2015-01-01

    It has become clear that tissue damage during a critical period of early life can result in long-term changes in pain sensitivity, but the underlying mechanisms remain to be fully elucidated. Here we review the clinical and preclinical evidence for persistent alterations in nociceptive processing following neonatal tissue injury, which collectively point to the existence of both a widespread hypoalgesia at baseline as well as an exacerbated degree of hyperalgesia following a subsequent insult to the same somatotopic region. We also highlight recent work investigating the effects of early trauma on the organization and function of ascending pain pathways at a cellular and molecular level. These effects of neonatal injury include altered ion channel expression in both primary afferent and spinal cord neurons, shifts in the balance between synaptic excitation and inhibition within the superficial dorsal horn (SDH) network, and a ‘priming’ of microglial responses in the adult SDH. A better understanding of how early tissue damage influences the maturation of nociceptive circuits could yield new insight into strategies to minimize the long-term consequences of essential, but invasive, medical procedures on the developing somatosensory system. PMID:26103453

  15. TMC-1 Mediates Alkaline Sensation in C. elegans through Nociceptive Neurons.

    PubMed

    Wang, Xiang; Li, Guang; Liu, Jie; Liu, Jianfeng; Xu, X Z Shawn

    2016-07-06

    Noxious pH triggers pungent taste and nocifensive behavior. While the mechanisms underlying acidic pH sensation have been extensively characterized, little is known about how animals sense alkaline pH in the environment. TMC genes encode a family of evolutionarily conserved membrane proteins whose functions are largely unknown. Here, we characterize C. elegans TMC-1, which was suggested to form a Na(+)-sensitive channel mediating salt chemosensation. Interestingly, we find that TMC-1 is required for worms to avoid noxious alkaline environment. Alkaline pH evokes an inward current in nociceptive neurons, which is primarily mediated by TMC-1 and to a lesser extent by the TRP channel OSM-9. However, unlike OSM-9, which is sensitive to both acidic and alkaline pH, TMC-1 is only required for alkali-activated current, revealing a specificity for alkaline sensation. Ectopic expression of TMC-1 confers alkaline sensitivity to alkali-insensitive cells. Our results identify an unexpected role for TMCs in alkaline sensation and nociception.

  16. Sensitization of nociceptive spinal neurons contributes to pain in a transgenic model of sickle cell disease.

    PubMed

    Cataldo, Giuseppe; Rajput, Sugandha; Gupta, Kalpna; Simone, Donald A

    2015-04-01

    Chronic pain is a major characteristic feature of sickle cell disease (SCD). The refractory nature of pain and the development of chronic pain syndromes in many patients with SCD suggest that central neural mechanisms contribute to pain in this disease. We used HbSS-BERK sickle mice, which show chronic features of pain similar to those observed in SCD, and determined whether sensitization of nociceptive neurons in the spinal cord contributes to pain and hyperalgesia in SCD. Electrophysiological recordings of action potential activity were obtained from single identified dorsal horn neurons of the spinal cord in anesthetized mice. Compared with control HbAA-BERK mice, nociceptive dorsal horn neurons in sickle mice exhibited enhanced excitability as evidenced by enlarged receptive fields, increased rate of spontaneous activity, lower mechanical thresholds, enhanced responses to mechanical stimuli, and prolonged afterdischarges following mechanical stimulation. These changes were accompanied by increased phosphorylation of mitogen-activated protein kinases (MAPKs) in the spinal cord that are known to contribute to neuronal hyperexcitability, including c-Jun N-terminal kinase (JNK), p44/p42 extracellular signaling-regulated kinase (ERK), and p38. These findings demonstrate that central sensitization contributes to pain in SCD.

  17. Descending effect on spinal nociception by amygdaloid glutamate varies with the submodality of noxious test stimulation.

    PubMed

    Bourbia, Nora; Sagalajev, Boriss; Pertovaara, Antti

    2014-06-06

    Amygdala has an important role in the processing of primary emotions, such as fear. Additionally, amygdala is involved in processing and modulation of pain. While the amygdala, particularly its central nucleus (CeA), has been shown to contribute to pain control, the descending pain regulation by the CeA is still only partly characterized. Here heat and mechanical nociception was tested in both hind limbs of healthy rats with a chronic guide cannula for microinjection of glutamate into the CeA of the left or right hemisphere. The aim was to assess whether the descending pain regulatory effect by glutamate in the amygdala varies with the submodality or the body side of