Nerve injury inhibitsOprd1andCnr1transcription through REST in primary sensory neurons

Abstract

AbstractThe transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of 4 opioid receptor (Oprm1,Oprd1,Oprl1,Oprk1)and the cannabinoid CB1 receptor (Cnr1) genes in the DRG regulate nociception. In this study, we determined the role of REST in the control of their expression in the DRG induced by spared nerve injury (SNI) in both male and female mice. Transcriptomic analyses of male mouse DRGs followed by quantitative reverse transcription polymerase chain reaction analyses of both male and female mouse DRGs showed that SNI upregulated expression ofRestand downregulated mRNA levels of all 4 opioid receptor andCnr1genes, butOprm1was upregulated in female mice. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions ofOprm1andCnr1. Chromatin immunoprecipitation analyses indicated differing levels of REST at these promoters in male and female mice. Full-lengthRestconditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression ofOprd1andCnr1in the DRG in both male and female mice. Our results suggest that nerve injury represses the transcription ofOprd1andCnr1via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain.