Sex differences in nerve injury-induced neuropathic pain via REST in primary sensory neurons

REST is a transcriptional repressor that regulates neuronal gene expression and neural cell identity. Recent studies have examined whether sex influences neuropathic pain (NP), yet findings remain inconsistent. Spared Nerve Injury (SNI) induced NP is associated with increased Rest expression in the dorsal root ganglion (DRG), where REST represses Oprd1 and Cnr1 transcription-a mechanism we previously defined in male mice. To determine whether this pathway operates similarly in females, we analyzed SNI-induced pressure, mechanical, and thermal hypersensitivity in female wild-type and Rest cKO mice, along with DRG expression of Rest, Oprd1, and Cnr1. Female wild-type mice exhibited robust SNI-induced hypersensitivity comparable to males and showed increased Rest with concomitant decreases in Oprd1 and Cnr1 mRNA levels in the DRG. Rest cKO in primary sensory neurons attenuated hypersensitivity and rescued Oprd1 and Cnr1 expression in females, paralleling effects seen in males; however, the rescue of hypersensitivity occurred significantly later in females. These findings suggest that REST-mediated repression of Oprd1 and Cnr1 contributes to NP in both sexes, but that its functional impact may be modulated by additional, as-yet-undefined sex-specific regulatory mechanisms. Thus, these results suggest that a systems-level approach will be required to fully define how sex shapes NP mechanisms.