Common alterations in parallel metabolomic profiling of serum and spinal cord and mechanistic studies on neuropathic pain following PPARα administration

Neuropathic pain (NP) is usually treated with analgesics and symptomatic therapy with poor efficacy and numerous side effects, highlighting the urgent need for effective treatment strategies. Recent studies have reported an important role for peroxisome proliferator-activated receptor alpha (PPAR alpha) in regulating metabolism as well as inflammatory responses. Through pain behavioral assessment, we found that activation of PPAR alpha prevented chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. In addition, PPAR alpha ameliorated inflammatory cell infiltration at the injury site and decreased microglial activation, NOD-like receptor protein 3 (NLRP3) inflammasome production, and spinal dendritic spine density, as well as improved serum and spinal cord metabolic levels in mice. Administration of PPAR alpha antagonists eliminates the analgesic effect of PPAR alpha agonists. PPAR alpha relieves NP by inhibiting neuroinflammation and functional synaptic plasticity as well as modulating metabolic mechanisms, suggesting that PPAR alpha may be a potential molecular target for NP alleviation. However, the effects of PPAR alpha on neuroinflammation and synaptic plasticity should be further explored.