Targeting Microglia–Neuron Crosstalk to Regulate Neuronal Excitability: Novel Translational Approaches for Chronic Pain Intervention

Chronic pain is a complex and widespread pathological state that severely impairs the quality of life of millions worldwide and imposes a heavy socioeconomic burden. Current therapeutic regimens often fail to provide adequate relief, frequently accompanied by dose-limiting side effects. Emerging evidence suggests that the bidirectional crosstalk between microglia and neurons plays a fundamental role in the development and maintenance of chronic pain. This interaction contributes to central sensitization and enhanced neuronal excitability. This review elucidates the molecular mechanisms underlying microglia–neuron communication. with particular emphasis on its modulation of neuronal excitability. We also discuss innovative translational strategies such as gene therapy, cell therapy, and nanomedicine. Modulating these neuroimmune interfaces represents a promising frontier for developing more precise and efficacious analgesic interventions.