Nerve injury inhibits Oprd1 and Cnr1 transcription through REST in primary sensory neurons.

Autor: Subedi A; Department of Genetics, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA.; Baylor College of Medicine, 77030, Houston, TX, USA., Etemad A; Department of Genetics, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., Tiwari A; Department of Genetics, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., Huang Y; Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., Chatterjee B; Department of Genetics, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., McLeod SM; Department of Genetics, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., Lu Y; Department of Genetics, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA.; Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., Gonzalez D; Department of Genetics, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., Ghosh K; Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., Sirito M; Department of Genetics, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., Singh SK; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA., Ruiz E; Department of Molecular and Cell Biology, Baylor College of Medicine, 77030, Houston, TX, USA., Grimm SL; Department of Molecular and Cell Biology, Baylor College of Medicine, 77030, Houston, TX, USA., Coarfa C; Department of Molecular and Cell Biology, Baylor College of Medicine, 77030, Houston, TX, USA., Pan HL; Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA. huilinpan@mdanderson.org., Majumder S; Department of Genetics, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA. smajumder@mdanderson.org.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Nov 04; Vol. 14 (1), pp. 26612. Date of Electronic Publication: 2024 Nov 04.
DOI: 10.1038/s41598-024-74487-1
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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