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。

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.