Restoration of mitochondrial function alleviates trigeminal neuropathic pain in mice

Craniofacial pain is prevalent and a debilitating condition. Managing craniofacial pain is particularly challenging due to its multifaceted nature. Among the most severe forms of craniofacial pain is trigeminal neuralgia, often described as one of the most excruciating pain syndromes encountered in clinical practice. Utilizing a mouse model of trigeminal neuropathic pain, we found severe mitochondrial impairment in the injured trigeminal ganglion (TG), spanning transcription and translation to functionality. Our findings demonstrated that rejuvenating mitochondria by boosting NAD⁺ levels enhanced mitochondrial fitness and significantly ameliorated trigeminal neuropathic pain. Additionally, we showed that the analgesic effects of nicotinamide riboside (NR) supplementation mainly depend on Sirt1. Importantly, our multi-omics studies revealed that activated Sirt1 by NR suppresses a broad range of key pain genes and exerts anti-inflammatory effects in the TG. Together, we present a comprehensive view of how mitochondrial dysfunction is involved in trigeminal neuropathic pain. Therefore, targeting mitochondrial dysfunction offers a novel and promising approach to craniofacial pain management.