MicroRNA-96 is required to prevent allodynia by repressing voltage-gated sodium channels in spinal cord

Voltage-gated sodium channels (Na_vs) 1.7, 1.8, and 1.9 are predominately expressed in peripheral sensory neurons and are critical for action potential propagation in nociceptors. Unexpectedly, we found that expression of SCN9A, SCN10A, SCN11A, and SCN2A, the alpha subunit of Na_v1.7, Na_v1.8, Na_v1.9 and Na_v1.2, respectively, are up-regulated in spinal dorsal horn (SDH) neurons of miR-96 knockout mice. These mice also have de-repression of CACNA2D1/2 in DRG and display thermal and mechanical allodynia that could be attenuated by intrathecal or intraperitoneal injection of Na_v1.7 or Na_v1.8 blockers or Gabapentin. Moreover, Gad2::CreERT2 conditional miR-96 knockout mice phenocopied global knockout mice, implicating inhibitory neurons; nerve injury induced significant loss of miR-96 in SDH GABAergic and Glutamatergic neurons in mice which negatively correlated to up-regulation of Na_v1.7, Na_v1.8, Na_v1.9 and Scn2a, this dis-regulation of miR-96 and Na_vs in SDH neurons contributed to neuropathic pain which can be alleviated by intrathecal injection of Na_v1.7 or Na_v1.8 blockers. In conclusion, miR-96 is required to avoid allodynia through limiting the expression of VGCCs and Na_vs in DRG and Na_vs in SDH in naïve and nerve injury-induced neuropathic pain mice. Our findings suggest that central nervous system penetrating Na_v1.7 and Na_v1.8 blockers may be efficacious for pain relief.