Background: Neuropathic pain is characterized by hyperalgesia, allodynia, and inflammation and it is often resistant to treatment. The formyl peptide receptor 2 (ALX/FPR2), a G-protein-coupled receptor, has been implicated in resolving inflammation, making its agonist, Resolvin D1 (RvD1), a potential therapeutic agent. Previous studies suggest that RvD1 alleviates neuropathic pain via anti-inflammatory effects, but its mechanisms remain unclear, particularly in relation to microglial activation and the brain-derived neurotrophic factor (BDNF)/TrkB signaling pathway.

Objective: To investigate the analgesic effects of RvD1 in a spared nerve injury (SNI) model of neuropathic pain and explore its mechanisms through the regulation of neuroinflammation and the BDNF/TrkB signaling pathway.

Methods: SNI mice received intrathecal RvD1 at varying doses (10-40 ng) to determine its efficacy in reducing mechanical allodynia and thermal sensitivity. The anti-inflammatory effects of RvD1 were assessed using ELISA, immunofluorescence, and western blotting to measure the expression of pro-inflammatory cytokines and BDNF. The involvement of ALX/FPR2 and TrkB receptors was further examined using antagonists Boc2 and K252a.

Results: RvD1 significantly reduced mechanical and thermal allodynia in SNI mice in a dose-dependent manner. RvD1 also decreased microglial activation and expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and BDNF in both in vivo and in vitro models. These effects were reversed by Boc2 and K252a, confirming that the analgesic actions of RvD1 are mediated via the ALX/FPR2 receptor and inhibition of BDNF/TrkB signaling.

Conclusions: RvD1 alleviates neuropathic pain by reducing neuroinflammation through the ALX/FPR2 receptor and suppressing BDNF/TrkB signaling. These findings suggest RvD1 as a promising therapeutic agent for neuropathic pain management.