Bone metastasis-induced pain is a debilitating condition that remains a pervasive clinical challenge, with effective treatments still lacking. Although ClC-3 chloride channels are known to play an important role in synaptic transmission within the central nervous system, their expression and function in peripheral sensory neurons are poorly understood. Here, we found that the downregulation of ClC-3 in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and contributed to bone metastasis-induced pain. Overexpressing Clc-3 in DRG neurons attenuated tumor-induced neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats, whereas knocking down Clc-3 induced neuronal hyperexcitability and pain hypersensitivity in naïve rats. Mechanistically, tumor-associated production of insulin-like growth factor 1 (IGF1) activated the receptor IGF1R on DRGs, leading to an upregulation of histone deacetylase 2 (HDAC2), thereby suppressing the transcription of Clc-3 gene. Activation of the IGF1/IGF1R-AKT signaling pathway promotes HDAC2-mediated epigenetic silencing of Clc-3, thereby enhancing neuronal excitability and pain hypersensitivity in tumor-bearing rats. Our findings reveal a new and targetable mechanism underlying bone metastasis-induced pain, offering promising therapeutic avenues for pain management in cancer patients.
Zhang et al. (Sun,) studied this question.