{"title":"瞬时受体电位通道Trpv1和Trpm8在糖尿病周围神经病变中的作用。","authors":"Mallikarjuna R Pabbidi, Louis S Premkumar","doi":"","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>1.1.Transient Receptor Potential (Vanilloid 1) TRPV1 and (Melastatin 8) TRPM8 are heat and cold sensing non-selective cation channels, respectively. We sought to correlate the modulation of TRPV1- and TRPM8-mediated membrane currents and altered thermal sensitivity in Diabetic Peripheral Neuropathy (DPN).</p><p><strong>Method: </strong>1.2.Streptozotocin (STZ)-induced diabetic mice were used and thermal (heat and cold) pain sensitivities were determined using hot plate and acetone drop test, respectively. Membrane currents were recorded using patch-clamp techniques.</p><p><strong>Results: </strong>1.3.First, we tested thermal pain sensitivities to implicate a possible role of TRPV1 and TRPM8 in DPN. Paw withdrawal latency on a hot plate test was decreased, and acetone-induced cold sensitivity was enhanced in diabetic mice as compared to non-diabetic mice. Dorsal Root Ganglion (DRG) neurons dissociated from diabetic hyperalgesic mice exhibited an increase in TRPV1-mediated current and a decrease in TRPM8-mediated currents as compared to non-diabetic mice. Then, we determined the modulation of TRPV1- and TRPM8-mediated currents using HEK cells heterologously expressing TRPV1 by promoting PKC- and PKA-mediated phosphorylation. Both Phorbol 12,13-Dibutyrate (PDBu), a PKC activator and forskolin, a PKA activator upregulated TRPV1-mediated currents but downregulated TRPM8-mediated currents. In diabetic mice, intraplantar injection of capsaicin, a TRPV1 agonist-induced nocifensive behavior but the severity of this behavior was significantly lower when co-administered with menthol, a TRPM8 agonist.</p><p><strong>Conclusions: </strong>1.4.These findings suggest that diabetic thermal hyperalgesia mediated by up-regulation of TRPV1 function may be further aggravated by the downregulation of TRPM8 function. Targeting TRPV1 may be a useful approach to alleviate pain associated with DPN.</p>","PeriodicalId":73707,"journal":{"name":"Journal of diabetes and treatment","volume":"2017 4","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317870/pdf/nihms-1002094.pdf","citationCount":"0","resultStr":"{\"title\":\"Role of Transient Receptor Potential Channels Trpv1 and Trpm8 in Diabetic Peripheral Neuropathy.\",\"authors\":\"Mallikarjuna R Pabbidi, Louis S Premkumar\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>1.1.Transient Receptor Potential (Vanilloid 1) TRPV1 and (Melastatin 8) TRPM8 are heat and cold sensing non-selective cation channels, respectively. We sought to correlate the modulation of TRPV1- and TRPM8-mediated membrane currents and altered thermal sensitivity in Diabetic Peripheral Neuropathy (DPN).</p><p><strong>Method: </strong>1.2.Streptozotocin (STZ)-induced diabetic mice were used and thermal (heat and cold) pain sensitivities were determined using hot plate and acetone drop test, respectively. Membrane currents were recorded using patch-clamp techniques.</p><p><strong>Results: </strong>1.3.First, we tested thermal pain sensitivities to implicate a possible role of TRPV1 and TRPM8 in DPN. Paw withdrawal latency on a hot plate test was decreased, and acetone-induced cold sensitivity was enhanced in diabetic mice as compared to non-diabetic mice. Dorsal Root Ganglion (DRG) neurons dissociated from diabetic hyperalgesic mice exhibited an increase in TRPV1-mediated current and a decrease in TRPM8-mediated currents as compared to non-diabetic mice. Then, we determined the modulation of TRPV1- and TRPM8-mediated currents using HEK cells heterologously expressing TRPV1 by promoting PKC- and PKA-mediated phosphorylation. Both Phorbol 12,13-Dibutyrate (PDBu), a PKC activator and forskolin, a PKA activator upregulated TRPV1-mediated currents but downregulated TRPM8-mediated currents. In diabetic mice, intraplantar injection of capsaicin, a TRPV1 agonist-induced nocifensive behavior but the severity of this behavior was significantly lower when co-administered with menthol, a TRPM8 agonist.</p><p><strong>Conclusions: </strong>1.4.These findings suggest that diabetic thermal hyperalgesia mediated by up-regulation of TRPV1 function may be further aggravated by the downregulation of TRPM8 function. Targeting TRPV1 may be a useful approach to alleviate pain associated with DPN.</p>\",\"PeriodicalId\":73707,\"journal\":{\"name\":\"Journal of diabetes and treatment\",\"volume\":\"2017 4\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2017-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317870/pdf/nihms-1002094.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of diabetes and treatment\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2017/10/17 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of diabetes and treatment","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2017/10/17 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
Role of Transient Receptor Potential Channels Trpv1 and Trpm8 in Diabetic Peripheral Neuropathy.
Objective: 1.1.Transient Receptor Potential (Vanilloid 1) TRPV1 and (Melastatin 8) TRPM8 are heat and cold sensing non-selective cation channels, respectively. We sought to correlate the modulation of TRPV1- and TRPM8-mediated membrane currents and altered thermal sensitivity in Diabetic Peripheral Neuropathy (DPN).
Method: 1.2.Streptozotocin (STZ)-induced diabetic mice were used and thermal (heat and cold) pain sensitivities were determined using hot plate and acetone drop test, respectively. Membrane currents were recorded using patch-clamp techniques.
Results: 1.3.First, we tested thermal pain sensitivities to implicate a possible role of TRPV1 and TRPM8 in DPN. Paw withdrawal latency on a hot plate test was decreased, and acetone-induced cold sensitivity was enhanced in diabetic mice as compared to non-diabetic mice. Dorsal Root Ganglion (DRG) neurons dissociated from diabetic hyperalgesic mice exhibited an increase in TRPV1-mediated current and a decrease in TRPM8-mediated currents as compared to non-diabetic mice. Then, we determined the modulation of TRPV1- and TRPM8-mediated currents using HEK cells heterologously expressing TRPV1 by promoting PKC- and PKA-mediated phosphorylation. Both Phorbol 12,13-Dibutyrate (PDBu), a PKC activator and forskolin, a PKA activator upregulated TRPV1-mediated currents but downregulated TRPM8-mediated currents. In diabetic mice, intraplantar injection of capsaicin, a TRPV1 agonist-induced nocifensive behavior but the severity of this behavior was significantly lower when co-administered with menthol, a TRPM8 agonist.
Conclusions: 1.4.These findings suggest that diabetic thermal hyperalgesia mediated by up-regulation of TRPV1 function may be further aggravated by the downregulation of TRPM8 function. Targeting TRPV1 may be a useful approach to alleviate pain associated with DPN.