Spinal KCC2 Mediates the Modulation Effect of HDAC2 on Bone Cancer Pain in Rats

Background: Bone cancer pain is a global medical concern with limited treat-ment options that significantly reduce the quality of life for cancer patients. Therefore, identifying a promising therapeutic target for bone cancer pain is urgently needed. Objective: Our previous research indicated that KCC2 may be associated with the modula-tion of HDAC2 in a rat model of bone cancer pain. The current study aimed to investigate whether KCC2 in the lumbar spinal cord is a key downstream molecule in the modulation of HDAC2 related to bone cancer pain. Methods: In this study, we assessed the expression levels of KCC2 and HDAC2 in the lumbar spinal cord of rats with bone cancer pain using Western blotting and RT-PCR. Mechanical hyperalgesia was evaluated using Von Frey hairs, and immunofluores-cence was employed to localize KCC2 in central nervous system cells. Results: The expression of KCC2 was down-regulated in a time-dependent manner in the lumbar spinal cord of rats with bone cancer pain. Furthermore, the use of an RNA-interfering lentivirus targeting HDAC2 restored KCC2 expression and alleviated mechani-cal hyperalgesia in these rats. Notably, the analgesic effect of the HDAC2-targeting lenti-virus was completely reversed by the KCC2 inhibitor VU0240551. result: The expression of KCC2 was down-regulated in a time-dependent manner in the lumbar spinal cord of bone cancer pain rats. Furthermore, the use of an RNA-interfering lentivirus targeting HDAC2 restored KCC2 expression and alleviated mechanical hyperalgesia in these rats. Notably, the analgesic effect of the HDAC2-targeting lentivirus was completely reversed by the KCC2 inhibitor VU0240551. Conclusion: KCC2 in the lumbar spinal cord mediated the modulation of HDAC2 in rat models of bone cancer pain, suggesting that KCC2 could be a promising therapeutic target for treating bone cancer pain.