Upregulation of FMRP Is Involved in Neuropathic Pain by Regulating GluN2B Activation in Rat Spinal Cord

Abstract

Fragile X mental retardation protein (FMRP) has been proposed to play a potential role in the pathogenesis of autonomy and nociceptive paresthesia. However, the involvement of spinal FMRP in neuropathic pain remains unexplored. Using a rat model of neuropathic pain induced by chronic constriction injury (CCI), our investigation demonstrated an upregulation of FMRP at 3, 7, and 14 days post-CCI operation in the spinal dorsal horn (SDH). Immunofluorescence staining revealed predominant FMRP expression in spinal neurons, which colocalized with Glutamate Ionotropic Receptor NMDA Type Subunit 2B (GluN2B). The Co-immunoprecipitation results suggested an interaction between spinal FMRP and GluN2B. Genetic knockout of the Fmr1 gene or transient interference with the FMRP protein alleviated CCI-induced pain hypersensitivity and suppressed the increase in spinal GluN2B expression. Conversely, intrathecal administration of the GluN2B-specific inhibitor Ifenprodil significantly suppressed the CCI-induced increase in spinal FMRP expression. In conclusion, our findings highlight the pivotal role of spinal FMRP in developing neuropathic pain and modulating GluN2B levels within the SDH. Furthermore, our results suggest a reciprocal regulatory relationship, indicating that GluN2B may also influence FMRP expression. This study provides insights into the molecular mechanisms underlying neuropathic pain, suggesting the potential for therapeutic intervention targeting the FMRP-GluN2B axis in pain management.