Jiangsu Key Laboratory of Anesthesiology & Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Jiangsu province, 221004, PR China.
Jiangsu Key Laboratory of Anesthesiology & Jiangsu Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Jiangsu province, 221004, PR China.
Brain Res Bull. 2017 Oct;135:149-156. doi: 10.1016/j.brainresbull.2017.10.008. Epub 2017 Oct 12.
Treatment of neuropathic pain (NP) continues to be a clinical challenge and the underlying mechanisms of NP remain elusive. More evidence suggests that glial cell line-derived neurotrophic factor (GDNF) has potent anti-nociceptive effects on NP, but the underlying mechanisms are still largely unknown. Recent data have shown that integrin β1 plays an important part in NP induction, and that the activity of integrin β1 signaling is associated with the phosphorylation of the conserved threonines in the cytoplasmic domain and recruitment of focal adhesion kinase (FAK) to the integrin β1 tail and phosphorylation. We assessed the effect of GDNF on integrinβ1/FAK signaling in NP states. Immunostaining results showed that integrin β1 was mainly observed in the superficial dorsal horn in the spinal cord of rats, and was mostly expressed in intrinsic neurons. Expression of p-integrin β1 and the phosphorylation of integrin β1-associated FAK, but not integrin β1 itself, was up-regulated after chronic constriction injury (CCI), which could be reversed by GDNF, and the effect of GDNF on integrin β1/FAK signaling was inhibited by pre-treatment with RET function-blocking antibody (RET Ab). Moreover, pre-treatment with RET Ab could antagonize the effect of GDNF on inhibiting the NP induced by CCI. These data suggest that GDNF can regulate integrin β1 activity via a RET-related mechanism.
治疗神经性疼痛（NP）仍然是一个临床挑战，NP 的潜在机制仍然难以捉摸。越来越多的证据表明胶质细胞源性神经营养因子（GDNF）对 NP 具有强大的抗伤害作用，但潜在机制在很大程度上仍不清楚。最近的数据表明整合素β1在 NP 诱导中起着重要作用，整合素β1信号的活性与细胞质结构域中保守苏氨酸的磷酸化以及粘着斑激酶（FAK）向整合素β1尾部的募集和磷酸化有关。我们评估了 GDNF 对 NP 状态下整合素β1/FAK 信号的影响。免疫染色结果表明，整合素β1主要在大鼠脊髓背角浅层观察到，主要表达于固有神经元。慢性缩窄性损伤（CCI）后，整合素β1的表达上调，整合素β1相关的 FAK 磷酸化，但整合素β1本身没有上调，GDNF 可逆转这一现象，而 RET 功能阻断抗体（RET Ab）预处理可抑制 GDNF 对整合素β1/FAK 信号的作用。此外，RET Ab 的预处理可以拮抗 GDNF 对抑制 CCI 诱导的 NP 的作用。这些数据表明，GDNF 可以通过 RET 相关机制调节整合素β1的活性。
