Exploring the mechanism of ropivacaine in alleviating neuropathic pain via the mTOR-PKM2/STAT3-H4K12 lactylation axis

Neuropathic pain (NP) is one of the most challenging pathological conditions, with few therapeutic options, and the quality of life of patients is grossly affected. Nevertheless, the success of the existing clinical treatment is not satisfactory, and the exploration of new intervention strategies is the most urgent issue. Over the past few years, the functions of microglial metabolic reprogramming and epigenetic control in chronic neuroinflammation have been slowly understood. The current research paper was conducted to explore the hypothesis that ropivacaine alleviates NP by modulating the mTOR-PKM2/STAT3-H4K12la axis. The mouse model of chronic constriction injury (CCI) and the BV-2 microglia cell model culture were used in a series of experiments. The experimental evidence showed that the behavioral indices of pain, diffusion of metabolic axis-related proteins and proinflammatory cytokine contents were significantly increased in the CCI model, and the intervention with ropivacaine was effective in reducing these pathological alterations in the CCI model. Similarly, on the mechanistic level, ropivacaine has the potential to regulate the overactivation of the mTOR-PKM2/STAT3 signaling pathway, lessen microglial activation and oxidative stress, and eventually decrease H4K12la levels. This study elucidated the potential mechanism underlying the NP-alleviating effect of ropivacaine: ropivacaine mitigates neuroinflammation and pain responses by inhibiting the mTOR-PKM2/STAT3 signaling axis and reducing the level of histone H4K12 lactylation in microglia. The findings have a new conceptual foundation on the expansion of clinical usage of ropivacaine in chronic pain management.