Nerve Injury Inhibits Oprd1 and Cnr1 Transcription Through REST in Primary Sensory Neurons

Authors

Ashok Subedi
Asieh Etemad
Aadhya Tiwari
Yuying Huang
Biji Chatterjee
Samantha M McLeod
Yungang Lu
DiAngelo Gonzalez
Krishna Ghosh
Mario Sirito
Sanjay K Singh
Elisa Ruiz
Sandra L Grimm
Cristian Coarfa
Hui-Lin Pan
Sadhan Majumder

Publication Date

11-4-2024

Journal

Scientific Reports

DOI

10.1038/s41598-024-74487-1

PMID

39496614

PMCID

PMC11535536

PubMedCentral® Posted Date

11-4-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Receptor, Cannabinoid, CB1, Ganglia, Spinal, Mice, Sensory Receptor Cells, Repressor Proteins, Neuralgia, Peripheral Nerve Injuries, Male, Receptors, Opioid, delta, Receptors, Opioid, mu, Mice, Knockout, Gene Expression Regulation, Mice, Inbred C57BL, Transcription, Genetic, Promoter Regions, Genetic, REST, Dorsal root ganglion, Chronic pain, Opioid receptors, Cannabinoid CB1 receptor, Therapeutic target, Neuroscience, Chronic pain

Abstract

The 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 four opioid receptor genes (Oprm1, Oprd1, Oprl1 and Oprk1) and the cannabinoid CB1 receptor (Cnr1) 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 Rest transcript and protein. Transcriptomic analyses of wild-type mouse DRGs suggested that SNI upregulates the expression of Rest transcripts and downregulates the transcripts of all four opioid receptor genes and the Cnr1 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 Oprm1 and Cnr1. Chromatin immunoprecipitation analyses indicated the presence of REST at these promoters. Full-length Rest conditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression of Oprd1 and Cnr1 in mouse DRG. Our results suggest that nerve injury represses the transcription of at least the Oprd1 and Cnr1 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 Oprd1 and Cnr1 genes in DRG neurons.

Comments

Associated Data