Resveratrol alleviates neuropathic pain by restoring mitochondrial fission–fusion balance in CCI mice

Background Neuropathic pain (NP) is commonly associated with mitochondrial dysfunction in sensory neurons. Although resveratrol (Res), a natural polyphenolic compound, has demonstrated analgesic properties, its impact on mitochondrial dynamics in NP remains unclear. Methods We established a chronic constriction injury (CCI) model in male mice. Starting on day seven after the injury, resveratrol (1 mg/kg) or a vehicle was injected intravenously for three days in a row. We evaluated pain behaviors and analyzed dorsal root ganglia (DRG) for markers of oxidative stress, mitochondrial respiratory chain complexes, fission (DRP1) and fusion (OPA1) proteins, and mitochondrial morphology/ultrastructure. Results Resveratrol significantly reduced CCI-induced mechanical hypersensitivity and restored thermal latency. In DRG neurons, reactive oxygen species (ROS) accumulation decreased, while superoxide dismutase (SOD) activity increased, indicating reduced oxidative stress. Mitochondrial respiratory chain complexes I–II were restored, while DRP1 expression decreased and OPA1 increased, suggesting a normalization of fission–fusion balance. Resveratrol also increased mitochondrial volume and number. Ultrastructural deficits in mitochondrial area, perimeter, and connectivity were reversed. Conclusion Resveratrol mitigates CCI-induced NP by reducing oxidative stress, restoring respiratory chain function, rebalancing fission–fusion proteins, and repairing mitochondrial structural damage in DRG. These results provide credence to the idea that mitochondrial dynamics as a potential NP target.