Molly K Martin, Raider Rodriguez, Giselle Guerrero, Garrett D Sheehan, Rasheen Powell, Amanda H Klein, Arin Bhattacharjee
{"title":"通过药理作用使 NaV1.8 通道降解,从而减轻神经性疼痛。","authors":"Molly K Martin, Raider Rodriguez, Giselle Guerrero, Garrett D Sheehan, Rasheen Powell, Amanda H Klein, Arin Bhattacharjee","doi":"10.1097/j.pain.0000000000003470","DOIUrl":null,"url":null,"abstract":"<p><strong>Abstract: </strong>In phase II clinical trials, Na V 1.8 channels were identified as viable targets to treat acute pain. Results were modest, however, and Na V 1.8 pore blockers must be given systemically, potentially leading to adverse effects, especially during prolonged use. A local, long-lasting approach is desirable, yet local anesthetics are neither specific nor long-lasting. In lieu of a pore blocker approach, we show a pharmacological method targeting the scaffolding and degradation of Na V 1.8 channels, which attenuated neuropathic pain behavior in mice. Na V 1.8 channels interact with the WW domain-containing scaffold protein called Magi-1. WW domains are typically found in ubiquitin ligases, and Na V 1.8 channels are susceptible to degradation by ubiquitin ligases. Here, we show Na V 1.8 and MAGI-1 colocalized in human tissues. We demonstrate that a lipidated peptide derived from the Na V 1.8 WW binding domain, at sub-micromolar concentrations, inhibited rodent dorsal root ganglion neuronal firing. The peptide reduced Na V 1.8 channel immunoreactivity and tetrodotoxin-resistant currents in human dorsal root ganglion neurons. We found that the lipidated peptide attenuated neuropathic pain behaviors in mice for multiple weeks after a single injection. Our results reveal that the Na V 1.8-targeted lipidated peptide provides local and sustained analgesia, serving as a viable alternative to Na V 1.8 pore blockers.</p>","PeriodicalId":19921,"journal":{"name":"PAIN®","volume":" ","pages":"1191-1203"},"PeriodicalIF":5.9000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003070/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pharmacologically enabling the degradation of Na V 1.8 channels to reduce neuropathic pain.\",\"authors\":\"Molly K Martin, Raider Rodriguez, Giselle Guerrero, Garrett D Sheehan, Rasheen Powell, Amanda H Klein, Arin Bhattacharjee\",\"doi\":\"10.1097/j.pain.0000000000003470\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Abstract: </strong>In phase II clinical trials, Na V 1.8 channels were identified as viable targets to treat acute pain. Results were modest, however, and Na V 1.8 pore blockers must be given systemically, potentially leading to adverse effects, especially during prolonged use. A local, long-lasting approach is desirable, yet local anesthetics are neither specific nor long-lasting. In lieu of a pore blocker approach, we show a pharmacological method targeting the scaffolding and degradation of Na V 1.8 channels, which attenuated neuropathic pain behavior in mice. Na V 1.8 channels interact with the WW domain-containing scaffold protein called Magi-1. WW domains are typically found in ubiquitin ligases, and Na V 1.8 channels are susceptible to degradation by ubiquitin ligases. Here, we show Na V 1.8 and MAGI-1 colocalized in human tissues. We demonstrate that a lipidated peptide derived from the Na V 1.8 WW binding domain, at sub-micromolar concentrations, inhibited rodent dorsal root ganglion neuronal firing. The peptide reduced Na V 1.8 channel immunoreactivity and tetrodotoxin-resistant currents in human dorsal root ganglion neurons. We found that the lipidated peptide attenuated neuropathic pain behaviors in mice for multiple weeks after a single injection. Our results reveal that the Na V 1.8-targeted lipidated peptide provides local and sustained analgesia, serving as a viable alternative to Na V 1.8 pore blockers.</p>\",\"PeriodicalId\":19921,\"journal\":{\"name\":\"PAIN®\",\"volume\":\" \",\"pages\":\"1191-1203\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003070/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"PAIN®\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/j.pain.0000000000003470\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/8 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ANESTHESIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"PAIN®","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/j.pain.0000000000003470","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/8 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ANESTHESIOLOGY","Score":null,"Total":0}
Pharmacologically enabling the degradation of Na V 1.8 channels to reduce neuropathic pain.
Abstract: In phase II clinical trials, Na V 1.8 channels were identified as viable targets to treat acute pain. Results were modest, however, and Na V 1.8 pore blockers must be given systemically, potentially leading to adverse effects, especially during prolonged use. A local, long-lasting approach is desirable, yet local anesthetics are neither specific nor long-lasting. In lieu of a pore blocker approach, we show a pharmacological method targeting the scaffolding and degradation of Na V 1.8 channels, which attenuated neuropathic pain behavior in mice. Na V 1.8 channels interact with the WW domain-containing scaffold protein called Magi-1. WW domains are typically found in ubiquitin ligases, and Na V 1.8 channels are susceptible to degradation by ubiquitin ligases. Here, we show Na V 1.8 and MAGI-1 colocalized in human tissues. We demonstrate that a lipidated peptide derived from the Na V 1.8 WW binding domain, at sub-micromolar concentrations, inhibited rodent dorsal root ganglion neuronal firing. The peptide reduced Na V 1.8 channel immunoreactivity and tetrodotoxin-resistant currents in human dorsal root ganglion neurons. We found that the lipidated peptide attenuated neuropathic pain behaviors in mice for multiple weeks after a single injection. Our results reveal that the Na V 1.8-targeted lipidated peptide provides local and sustained analgesia, serving as a viable alternative to Na V 1.8 pore blockers.
期刊介绍:
PAIN® is the official publication of the International Association for the Study of Pain and publishes original research on the nature,mechanisms and treatment of pain.PAIN® provides a forum for the dissemination of research in the basic and clinical sciences of multidisciplinary interest.