AIM: To study the mechanism of oxysophoridine (OSR) in relieving neuropathic pain (NP). METHODS: The analgesic effect of OSR was observed by measuring mechanical pain sensitivity. By combining OSR with agonists and antagonists related to synthesis and metabolism of gamma aminobutyric acid (GABA), the mechanism related to analgesic effects of OSR and GABA nervous system is studied. The expression of c-Fos immunopositive cells and the expression of c-Fos and Glutamic acid decarboxylase (Glutamic acid decarboxylase 67) in brain and spinal cord were detected by immunofluorescence staining. Co-expression of GAD67, GABA transporter 1 (gamma-Aminobutyric acid Transporter 1, GAT-1) immunopositive cells. RESULTS: Compared with Sham group, spared nerve injury (SNI) group showed increased mechanical pain sensitivity, increased expression of c-Fos immunopositive cells, decreased and increased co-expression of c-Fos and GAD67 and GAT-1 immunopositive cells, respectively. Compared with SNI group, mechanical algesia in OSR 500 and 1 000 mg/kg groups was decreased, algesia in OSR 250 mg/kg combined with antagonist group was decreased, and algesia in OSR 500 mg/kg combined with agonist group was increased. The co-expression of c-Fos and GAD67 immunopositive cells in the brain and spinal cord of OSR 500 mg/kg group increased, while the co-expression of c-Fos and GAT-1 decreased. CONCLUSION: OSR has a good analgesic effect on NP mice induced by SNI. The mechanism is that OSR increases the content of central GABA by up-regulating GABAergic neurons in brain and spinal cord.