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However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of four opioid receptor genes (<jats:italic>Oprm1<\/jats:italic>, <jats:italic>Oprd1<\/jats:italic>, <jats:italic>Oprl1<\/jats:italic> and <jats:italic>Oprk1<\/jats:italic>) and the cannabinoid CB1 receptor (<jats:italic>Cnr1<\/jats:italic>) gene in the DRG regulate nociception. In this study, we determined the role of REST in controlling their expression in the DRG induced by spared nerve injury (SNI). SNI induced chronic pain hypersensitivity in wild-type mice and was accompanied by increased levels of <jats:italic>Rest<\/jats:italic> transcript and protein. Transcriptomic analyses of wild-type mouse DRGs suggested that SNI upregulates the expression of <jats:italic>Rest<\/jats:italic> transcripts and downregulates the transcripts of all four opioid receptor genes and the <jats:italic>Cnr1<\/jats:italic> gene. Quantitative reverse transcription polymerase chain reaction analyses of these tissues validated these results. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions of <jats:italic>Oprm1<\/jats:italic> and <jats:italic>Cnr1<\/jats:italic>. Chromatin immunoprecipitation analyses indicated the presence of REST at these promoters. Full-length <jats:italic>Rest<\/jats:italic> conditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression of <jats:italic>Oprd1<\/jats:italic> and <jats:italic>Cnr1<\/jats:italic> in mouse DRG. Our results suggest that nerve injury represses the transcription of at least the <jats:italic>Oprd1<\/jats:italic> and <jats:italic>Cnr1<\/jats:italic> genes via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain. Thus, inhibiting REST activity could potentially reduce chronic neuropathic pain and augment opioid\/cannabinoid analgesic actions by increasing the transcription of <jats:italic>Oprd1<\/jats:italic> and <jats:italic>Cnr1<\/jats:italic> genes in DRG neurons.<\/jats:p>","DOI":"10.1038\/s41598-024-74487-1","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T09:20:28Z","timestamp":1730712028000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Nerve injury inhibits Oprd1 and Cnr1 transcription through REST in primary sensory neurons"],"prefix":"10.1038","volume":"14","author":[{"given":"Ashok","family":"Subedi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asieh","family":"Etemad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aadhya","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuying","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biji","family":"Chatterjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha M.","family":"McLeod","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yungang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DiAngelo","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Sirito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay K.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra L.","family":"Grimm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Coarfa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Lin","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadhan","family":"Majumder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,4]]},"reference":[{"key":"74487_CR1","doi-asserted-by":"publisher","unstructured":"Finnerup, N. 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