Research for identifying pain molecules in the spinal cord

Neuropathic pain, a debilitating chronic pain condition, is a common consequence of damage to the nervous system that can be induced by cancer, diabetes mellitus, infection, autoimmune diseases, or traumatic injury. The underlying mechanisms remain unclear, and currently available treatments are frequently ineffective. Thus, effective treatment of neuropathic pain is a major clinical challenge. A growing body of evidence indicates that peripheral nerve injury (PNI) converts spinal microglia into reactive cells that are required for the development and maintenance of neuropathic pain. Therefore, to identify pain molecules in spinal glial cells would advance our understanding of the pathogenesis of neuropathic pain and would provide a new target for treating this pain. Results of our laboratory have demonstrated that following PNI, P2X4 receptors (P2X4Rs) are upregulated in spinal microglia and are necessary for neuropathic pain. We have further found the upregulation of the transcription factor interferon regulatory factor 8 (IRF8) in microglia after PNI. IRF8-knockout mice exhibited reductions in upregulation of genes associated with the activated processes of microglia, including P2X4R, and in PNI-induced tactile allodynia. Our study has recently identified IRF5 as a target of IRF8 and as being required for upregulation of P2X4R expression through its binding to the promoter region of the P2rx4 gene. These results provide a new mechanism for neuropathic pain and its therapeutic targets.