脊髓胰高血糖素样肽-1（GLP-1）受体镇痛作用及其信号通路

Glucagon-like peptide-1 (GLP-1) receptors of spinal cord belong to the B family of G protein-coupled receptor, is a popular target for the treatment of type II diabetes, but there are no pain related-reports so far. We first discovered that administration of GLP-1 receptor agonist of GLP-1, exenatide, KP104 or its derivatives through the spinal cord or subcutaneous can inhibit formalin-induced phase II pain, cancer pain and neuropathic pain, and the analgesic effects can be completely blocked by GLP-1 receptor antagonist, which suggest that activation the GLP-1 receptor of spinal cord can specifically block chronic pain. In this project we will further confirm the GLP-1 receptor of spinal cord as a new target molecule for treatment of chronic pain and explore the signaling pathways and biological characteristics of its analgesic effect. The problems to be solved in this project are as follows: 1) receptor antagonists, siRNA and gene knockout prove that GLP-1 receptor-mediated chronic pain; 2) to explore the analgesic process of GLP-1 receptor agonist signaling pathway, such as adenylatebiological characteristics of the enzyme and β-arrestin - 1 in the GLP-1 receptor analgesic; 3) GLP-1 receptor analgesic effects, such as self-tolerance and any area beyond its and morphine cross-tolerance.

脊髓胰高血糖素样肽-1（GLP-1）受体属于G蛋白偶联受体B家族，是治疗II型糖尿病的热门靶点，迄今未见任何与疼痛有关的报道。我们首次发现脊髓和皮下给予GLP-1受体激动剂GLP-1和exenatide，以及小分子KP104及其衍生物可抑制福尔马林诱导的II相疼痛、肿瘤疼痛和神经源性疼痛；并可被GLP-1受体拮抗剂完全阻断，表明激活脊髓GLP-1受体可特异性阻断慢性疼痛。本课题将进一步证明脊髓GLP-1受体是治疗慢性疼痛的新靶点分子，并探索其镇痛作用信号通路和生物学特征。包括1）采用受体拮抗剂、siRNA和基因敲除等证明GLP-1受体介导慢性疼痛；2）探索在镇痛过程中GLP-1受体激动后信号通路，如腺苷酸环化酶和β-arrestin 1在GLP-1受体镇痛中作用；3）研究GLP-1受体镇痛作用的生物学特征，如自身耐受以及与吗啡之间的交叉耐受。

脊髓胰高血糖素样肽-1（GLP-1）受体属于 G 蛋白偶联受体 B 家族，是治疗 II型糖尿病的热门靶点，但未见任何与疼痛有关的报道。本项目在首次发现脊髓和皮下给予 GLP-1受体激动剂 GLP-1 和 exenatide，以及小分子激动剂均可抑制福尔马林诱导的 II相疼痛、肿瘤疼痛和神经源性疼痛、并可被 GLP-1 受体拮抗剂完全阻断的基础上，深入研究了脊髓小胶质细胞胰高血糖素样肽-1（GLP-1）受体/β-内啡肽镇痛通路。我们采用免疫荧光染色法显示脊髓背角小胶质细胞特异性地表达GLP-1受体，并可被外周神经损伤上调；肽类和小分子GLP-1受体激动剂，对神经源性、肿瘤、糖尿病和类风湿性关节炎等慢性疼痛动物模型产生强烈镇痛作用；采用GLP-1受体拮抗剂、基因knock down和knock out技术证明了GLP-1受体介导慢性疼痛；证明GLP-1受体激动剂与经典镇痛药吗啡不同，它不诱导镇痛耐受性；进一步发现激动GLP-1受体后，会引起脊髓小胶质细胞释放内源性β-内啡肽而起到镇痛作用。该项目研究结果首次揭示了脊髓小胶质细胞GLP-1受体/β-内啡肽镇痛通路，表征了GLP-1受体作为治疗慢性疼痛的靶点分子的生物学特征，而且为小分子类GLP-1受体激动剂的研发提供了药理学基础。而且，脊髓GLP-1受体/β-内啡肽镇痛靶点和镇痛通路的发现和验证，对基于GLP-1受体的新型镇痛药物研发起到促进作用；此外本发现为疼痛生物学、胶质细胞功能和GLP-1受体信号通路研究提供了新理论和新范畴。