<p>A lesion or disease of the somatosensory nervous system causes neuropathic pain (NP). Previous experiments have demonstrated that aloperine (ALO) exhibits antiallodynic effects on neuropathic pain in mice; however, the mechanism underlying its analgesic action remains unclear. This study investigated the analgesic mechanism of ALO on neuropathic pain in mice using a chronic constriction injury (CCI) model. Experiments were conducted using the ALO and p38MAPK inhibitor SB 203580. In vivo experiments demonstrated that ALO played an analgesic role by inhibiting p38MAPK phosphorylation, and it improved mechanical allodynia, cold allodynia, and hot hyperalgesia in CCI mice, as well as having a protective effect on injured sciatic nerves. The combined administration of a subthreshold dose of ALO (20&#xa0;mg/kg) with the p38MAPK inhibitor SB203580 (20&#xa0;mg/kg) produced significant analgesic effects, suggesting that ALO likely shares a common target with SB203580, namely p38MAPK. Fluorescence double staining indicated that the antiallodynic effect of ALO may be related to its inhibition of the p38MAPK/FKN/CX3CR1 pathway in the spinal cord, and it may play a role in regulating the expression of p38MAPK in microglial cells. In vitro studies have shown that ALO can reduce the activation of BV₂ cells, inhibit p38MAPK phosphorylation in microglia, and play a role in regulating the p38MAPK protein. In conclusion, our results suggest that the analgesic mechanism of aloperine is associated with its inhibition of the FKN/CX3CR1 pathway, which is regulated by p38MAPK phosphorylation in spinal microglia. This study provides new potential targets for the analgesic mechanism of aloperine.</p> Graphical Abstract <p></p>