Gao Yuan-Yuan, Hong Xiao-Ya, Wang Hong-Jun
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu, 221004, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, No.209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
J Mol Neurosci. 2016 Oct;60(2):258-66. doi: 10.1007/s12031-016-0792-x. Epub 2016 Jul 9.
Neuropathic pain results from nerve injury and is one of the most refractory disorders. Recently, many studies reported that glial cell-derived neurotrophic factor (GDNF) exhibited potent analgesic effects, but the underlying mechanisms still remain unknown. In addition to the classical GDNF-GFRα1-Ret pathway, GDNF can bind to adhesion proteins such as E-cadherin and NCAM via GFRα1 in a Ret-independent way. In this study, we aimed to examine whether the adhesion protein nectin-1 and its downstream protein c-Src are involved in neuropathic pain. We found that nectin-1 was expressed in the superficial dorsal horn of the spinal cord and that it was increased after chronic constrictive injury (CCI). Intrathecal administration of nectin-1 siRNA attenuated neuropathic pain induced by CCI via interference of the expression of nectin-1. Furthermore, we found that GDNF can downregulate the phosphorylation level of nectin-1-associated c-Src without changing the expression level of nectin-1. In summary, these data suggest that nectin-1 is involved in neuropathic pain, and that GDNF exerts analgesic effects by directly or indirectly regulating nectin-1/c-Src signaling. These findings may lead to a new target for the treatment of neuropathic pain.
神经性疼痛由神经损伤引起，是最难治疗的疾病之一。最近，许多研究报道胶质细胞源性神经营养因子（GDNF）具有强大的镇痛作用，但其潜在机制仍不清楚。除了经典的GDNF-GFRα1-Ret途径外，GDNF还可以通过GFRα1以不依赖Ret的方式与E-钙黏蛋白和神经细胞黏附分子等黏附蛋白结合。在本研究中，我们旨在研究黏附蛋白nectin-1及其下游蛋白c-Src是否参与神经性疼痛。我们发现nectin-1在脊髓背角浅层表达，并且在慢性压迫性损伤（CCI）后增加。鞘内注射nectin-1 siRNA通过干扰nectin-1的表达减轻了CCI诱导的神经性疼痛。此外，我们发现GDNF可以下调与nectin-1相关的c-Src的磷酸化水平，而不改变nectin-1的表达水平。总之，这些数据表明nectin-1参与神经性疼痛，并且GDNF通过直接或间接调节nectin-1/c-Src信号发挥镇痛作用。这些发现可能为神经性疼痛的治疗带来新的靶点。
