Long-term neuropathic pain can lead to anxiety, depression, and other issues, which seriously affect patients' quality of life. For this reason, it is important to find effective treatments. Studies have shown that glial cell-derived neurotrophic factor (GDNF) can relieve neuropathic pain. However, its mechanism of action is unknown. Our previous study of GDNF suggested that the N-cadherin-beta-catenin transmembrane signaling system might play a role in GDNF transmembrane signaling. Based on this, the current study aimed to produce a neuropathic pain model to confirm the activation of the N-cadherin-beta-catenin signaling system in the spinal dorsal horn under pain conditions and to study the impact of GDNF intrathecal injection on central sensitization of dorsal horn neurons. The results showed that N-cadherin expression, as well as the expression of membrane-associated beta-catenin, was reduced in the dorsal horn of the spinal cord in the chronic pain model. Intrathecal injection of GDNF could reactivate the N-cadherin-beta-catenin system, improve central sensitization, and relieve pain. Knockdown of N-cadherin or beta-catenin could significantly reduce the analgesic effect of GDNF. These results provide clear experimental evidence that the N-cadherin-beta-catenin signaling system participates in the analgesic effect of GDNF in neuropathic pain and help identify transmembrane and intracellular signal transduction mechanisms associated with GDNF's analgesic effects. (C) 2019 Elsevier Inc. All rights reserved.