Electroacupuncture as a promising therapeutic strategy for chronic constriction injury-induced neuropathic pain: Insights into the PPARα/SIRT1/NF-κB axis

BACKGROUND: Electroacupuncture (EA), a therapeutic modality that combines traditional acupuncture with electrical stimulation, is a promising non-pharmacological therapy for alleviating neuropathic pain (NP). However, the molecular mechanisms through which EA exerts its effects in the context of NP remain inadequately understood. METHODS: In this study, a rat model of chronic constriction injury (CCI) was employed to investigate the therapeutic effects of EA on NP and the underlying molecular mechanisms. Pain-related behaviors were assessed via mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), and footprint. RNA sequencing (RNA-Seq) was used to identify key targets. Immuno-fluorescence, Western blot, enzyme-linked immunosorbent assay (ELISA), and RT-qPCR were performed to evaluate the expression of related molecules and pro-inflammatory factors. Neuronal excitability was recorded by whole-cell patch-clamp. RESULTS: We demonstrated that EA stimulation increased the expression of PPARα in spinal dorsal horn (SDH) neurons, which subsequently enhanced silent information regulator transcript 1(SIRT1) levels and reduced the acetylated NF-κB (Ac-NF-κB) /total NF-κB ratio. This cascade suppressed microglial activation and decreased the levels of pro-inflammatory factors (IL-1β, TNF-α, IL-6), thereby reducing neuronal hyperexcitability (sEPSCs, rheobase, and AP firing) and ultimately alleviating pain-related behaviors (including MWT, TWL, and sen-sorimotor function). CONCLUSIONS: Our findings suggest that EA stimulation alleviates NP by regulating the PPARα/SIRT1/NF-κB axis in CCI rats. This study not only provides innovative insights into the mechanisms underlying EA's analgesic effects but also highlights this axis as a promising therapeutic target for NP management.