Spinal nerve transection‐induced upregulation of KDM4A in the dorsal root ganglia contributes to the development and maintenance of neuropathic pain via promoting CCL2 expression in rats

Abstract

AbstractStudies indicate that the lysine‐specific demethylase 4A (KDM4A), acts as a key player in neuropathic pain, driving the process through its involvement in promoting neuroinflammation. Emerging evidence reveals that C‐C Motif Chemokine Ligand 2 (CCL2) participates in neuroinflammation, which plays an important role in the development and maintenance of neuropathic pain. However, it remains unclear if KDM4A plays a role in regulating CCL2 in neuropathic pain. This study found that following spinal nerve transection (SNT) of the lumbar 5 nerve root in rats, the expression of KDM4A and CCL2 increased in the ipsilateral L4/5 dorsal root ganglia (DRG). Injecting KDM4A siRNA into the DRGs of rats post‐SNT resulted in a higher paw withdrawal threshold (PWT) and paw‐withdrawal latency (PWL) compared to the KDM4A scRNA group. In addition, prior microinjection of AAV‐EGFP‐KDM4A shRNA also alleviates the decrease in PWT and PWL caused by SNT. Correspondingly, microinjection of AAV‐EGFP‐KDM4A shRNA subsequent to SNT reduced the established mechanical and thermal hyperalgesia. Furthermore, AAV‐EGFP‐KDM4A shRNA injection decreased the expression of CCL2 in DRGs. ChIP‐PCR analysis revealed that increased binding of p‐STAT1 with the CCL2 promoter induced by SNT was inhibited by AAV‐EGFP‐KDM4A shRNA treatment. These findings suggest that KDM4A potentially influences neuropathic pain by regulating CCL2 expression in DRGs.