N-cadherin/β-catenin信号系统介导 GDNF对神经病理性疼痛镇痛作用的研究

Long-term neuropathic pain can lead to anxiety, depression, and other issues, which seriously affect a patients’ quality of life. For this reason, it is important to find effective treatments. Studies have shown that GDNF can relieve neuropathic pain. However, the mechanism of action is unknown. Our previous study of the analgesic effects of GDNF suggested that the N-cadherin/β-catenin transmembrane signaling system may play a role in GDNF transmembrane signaling and hence in the process of GDNF-mediated analgesia. Based on this, the current study aimed to produce a neuropathic pain model to confirm the activation of the N-cadherin/β-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 effects of GDNF on the activation of the N-cadherin/β-catenin signaling system and on downstream changes in the PI3K-Akt/PKB signaling pathway were explored as well. Block the N-cadherin/β-catenin signaling system to evaluate its impact on the analgesic effect of GDNF. These results provide clear experimental evidence that the N-cadherin/β-catenin signaling system participates in the analgesic effects of GDNF on neuropathic pain and help identify transmembrane and intracellular signal transduction mechanisms associated with GDNF analgesic effects.

长期神经病理性疼痛会导致焦虑、抑郁等疾病发生，严重影响患者生活质量，因此迫切需要寻找有效的治疗药物。GDNF可治疗神经病理性疼痛，但机制不明。我们前期对GDNF镇痛研究提示：作为GDNF跨膜信号传递系统的N-cadherin/β-catenin可能在GDNF镇痛中发挥作用。基于此，本项目拟应用神经病理性疼痛模型，明确疼痛状态下脊髓背角N-cadherin/β-catenin的激活情况；研究鞘内注射GDNF对背角神经元中枢敏化作用的影响，重点探索GDNF激活N-cadherin/β-catenin及导致下游PI3K-Akt/PKB信号通路的改变；阻断N-cadherin/β-catenin观察其对GDNF镇痛作用的影响。预期结果不仅可为N-cadherin/β-catenin信号系统参与GDNF对神经病理性疼痛镇痛作用提供明确的实验证据, 而且有助于阐明GDNF镇痛的跨膜及胞内信号转导机制。

长期神经病理性疼痛会导致焦虑、抑郁等疾病发生，严重影响患者生活质量，因此迫切需要寻找有效的治疗药物。GDNF可治疗神经病理性疼痛，但机制不明。我们前期对GDNF镇痛研究提示：作为GDNF跨膜信号传递系统的N-cadherin/β-catenin可能在GDNF镇痛中发挥作用。基于此，本项目拟应用慢性神经病理性疼痛模型，明确疼痛状态下脊髓背角N-cadherin/β-catenin跨膜系统的激活情况；研究鞘内注射GDNF对脊髓背角神经元中枢敏化作用的影响，重点探索GDNF激活N-cadherin/β-catenin及导致下游信号通路的改变；阻断N-cadherin/β-catenin观察其对GDNF镇痛作用的影响。目前我们实验发现：1.慢性疼痛模型建立后脊髓背角N-cadherin表达减少，N-cadherin/β-catenin跨膜信息传递系统功能降低；2.鞘内注射GDNF能够重新激活N-cadherin/β-catenin系统，改善中枢敏化，缓解疼痛；3.预先敲低N-cadherin/β-catenin的表达能够明显减弱GDNF的镇痛作用。通过上述实验结果我们不仅为N-cadherin/β-catenin信号系统参与GDNF的镇痛作用提供了明确实验证据, 而且有助于阐明GDNF镇痛的跨膜及胞内信号转导机制。