VDAC1 Upregulation Induces Hyperexcitability of Nociceptive Sensory Neurons Via Enhanced Mitochondrial Atp Efflux in Neuropathic Pain

Neuropathic pain results from aberrant sensory processing following nerve injury. Voltage-dependent anion channels (VDACs), a family of ATP gatekeepers in the outer mitochondrial membrane, are central to cellular metabolism and action potential generation, yet their roles in peripheral neuropathic pain remain poorly defined. Here, we demonstrate that among the VDAC isoforms, VDAC1 is predominantly expressed in dorsal root ganglion (DRG) nociceptive neurons and is markedly upregulated in a mouse model of chronic constriction injury (CCI). Functionally, VDAC1 promotes neuropathic pain by increasing mitochondrial ATP permeability, thereby elevating cytoplasmic ATP levels and enhancing neuronal excitability. Genetic or pharmacological inhibition of VDAC1 reduced cytoplasmic ATP, suppresses neuronal hyperexcitability, and alleviates pain behaviors. Collectively, these findings indicate the role of VDAC1 in ATP dynamics and neuronal excitability, highlighting it as a potential therapeutic target for neuropathic pain.