Roles of Transient Receptor Potential Melastatin 2 Expressed on Immune Cells in Neuropathic Pain

Abstract

Neuropathic pain is a pathological pain condition that often results from peripheral nerve injury. Several lines of evidence suggest that neuroin‰ammation mediated by the interaction between immune cells and neurons plays an important role in the pathogenesis of neuropathic pain. Transient receptor potential melastatin 2 (TRPM2) is a nonselective Ca 2＋ -permeable cation channel that acts as a sensor for reactive oxygen species. Recent evidence suggests that TRPM2 expressed on immune cells plays an important role in immune and in‰ammatory responses. In this study, we examined the roles of TRPM2 expressed on immune and glial cells in neuropathic pain. TRPM2 deˆciency attenuated pain behaviors (mechanical allodynia, thermal hyperalgesia and spontaneous pain behaviors) in various kinds of in‰amma-tory and neuropathic pain, but not in nociceptive pain models. In peripheral nerve injury-induced neuropathic pain models, TRPM2 deˆciency diminished inˆltration of neutrophils mediated through CXCL2 production from macrophages around the injured peripheral nerve and activation of spinal microglia, suggesting that TRPM2 expressed on macrophages and microglia aggravates peripheral and spinal pronociceptive in‰ammatory responses. Furthermore, we examined the inˆltration of peripheral immune cells into the injured nerve and spinal cord using bone marrow chimeric mice by crossing wildtype and TRPM2-knockout mice. The results suggest that TRPM2 plays an important role in the inˆltration of peripheral immune cells, particularly macrophages, into the spinal cord, rather than into the injured nerves. The spinal inˆltration of macrophages mediated by TRPM2 may contribute to the pathogenesis of neuropathic pain.