Peripheral nerve injury-induced upregulation of FKBP5 in the spinal dorsal horn via activating NF-κB pathway aggravates neuropathic pain in rats.

Emerging evidence reveals that the FK506 binding protein 51 (FKBP5) is an important mediator in the pathogenesis of inflammatory diseases. The aim of current study is to investigate the role of FKBP5 in neuropathic pain and the underlying mechanisms. Neuropathic pain was induced by lumbar 5 spinal nerve ligation (L5 SNL) in rats. The paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and microinjection of AAV-FKBP5-shRNA or AAV-EGFP-FKBP5 into the L5 spinal dorsal horn were carried out to explore the role and the mechanisms of FKBP5 in neuropathic pain. Our results showed that SNL increased FKBP5 expression in spinal neurons and glial cells, activated nucleus factor κB (NF-κB) in spinal astrocytes, and enhanced production of TNF-α and IL-1β in the spinal dorsal horn. Repeated intrathecal injection of SAFit2, an inhibitor of FKBP5, or microinjection of AAV-EGFP-FKBP5 shRNA into the L5 spinal dorsal horn inhibited FKBP5 expression, repressed NF-κB signaling, reduced TNF-α and IL-1β production, and alleviated mechanical allodynia and thermal hyperalgesia following SNL. The established neuropathic pain was partially reversed by the treatment of intrathecal administration of SAFit2 after SNL. Moreover, overexpression of FKBP5 in the L5 spinal dorsal horn by AAV-EGFP-FKBP5 activated NF-κB, increased production of TNF-α and IL-1β, and induced abnormal pain in naïve rats. Collectively, our results indicate that the SNL-induced upregulation of FKBP5 may partially through NF-κB signaling-mediated neuroinflammation in the spinal dorsal horn contributes to the pathogenesis of neuropathic pain. Pharmacological targeting of FKBP5 might be a potential therapeutic strategy for treating neuropathic pain.