LAUSR

Glial cells play important roles in the development and maintenance of neuropathic pain. In particular, activated microglia in the spinal cord facilitate the hyper‐excitability of dorsal horn neurons after peripheral nerve injury via pro‐inflammatory molecules. In this study, we investigated the possible involvement of the anti‐inflammatory cytokine, interleukin‐4 (IL‐4), in neuropathic pain. We did not detect the expression of IL‐4 mRNA in the rat dorsal root ganglion or spinal cord; however, peripheral nerve injury induced the expression of IL‐4 receptor (IL‐4R) alpha mRNA in the spinal cord. A histological analysis revealed that nerve injury induced IL‐4R alpha mRNA in activated spinal microglia ipsilateral to the injury site. Additionally, the increases in IL‐4R alpha were coincident with the increased expression of phosphorylated signal transducer and activator of transcription 6 (pSTAT6) in spinal microglia. Intrathecal administration of recombinant IL‐4 suppressed mechanical hypersensitivity in neuropathic rats, and the analgesic effect of IL‐4 was accompanied by further enhancement of pSTAT6 expression in spinal microglia. Taken together, these results suggest that the adaptive responses of microglia to nerve injury involve both inflammatory and anti‐inflammatory signaling, including IL‐4R alpha and pSTAT6. These findings support that utilizing the endogenous anti‐nociceptive activity of IL‐4R alpha may modify the cell lineage of pro‐nociceptive microglia, thus providing a novel therapeutic strategy for neuropathic pain.