Resveratrol alleviates neuropathic pain associated with restoration of mitochondrial fission-fusion balance in CCI mice.

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. We established a chronic constriction injury (CCI) model in male mice. Starting on the seventh day after the injury, resveratrol (1 mg/kg) or vehicle was administered via intrathecal injection for three consecutive days. 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. Resveratrol significantly reduced CCI-induced mechanical hypersensitivity and restored thermal latency. In DRG, 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. Resveratrol mitigates CCI-induced NP associated with restoring the balance of mitochondrial fission and fusion proteins and reducing oxidative stress in DRG. These results provide credence to the idea of mitochondrial dynamics as a potential NP target. However, this study did not establish a causal relationship between these molecular changes and resveratrol’s analgesic effects through direct manipulation of proteins. Further validation is needed through experiments targeting key proteins involved in mitochondrial fission and fusion. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-41965-7.