脊髓背角CB1受体/HCN4通道相互作用参与神经病理性疼痛调节的机制研究

大麻素CB1 受体（CB1R）和超极化激活环核苷酸门控（HCN）通道分别在脊髓水平参与伤害性信息调制，CB1R 和HCN4通道均选择性表达于背角抑制性中间神经元。CB1R激动后可引起AC/cAMP/PKA、p38MAPK、Ca2+等信号分子水平改变，而HCN4通道对于膜电位和胞内多种信使分子变化极其敏感。因此，我们推测CB1R和HCN4通道存在相互作用，共同调节病理性疼痛。本项目拟在以往对神经递质/受体研究的基础上，采用坐骨神经缩窄性损伤（CCI）模型，综合应用行为学、形态学、分子生物学及电生理学方法，观察脊髓背角CB1R和HCN4通道在神经痛发生中的作用；培养背角神经元，观察CB1R和HCN4通道功能的相互调节作用及其机理；最后求证二者相互作用，共同调节脊髓薄片胶状质突触传递效能。该研究将会为人们深入理解疼痛提供一个新的模式系统，开发以HCN4通道为靶点的新型镇痛药提供必须的理论基础。

Spinal Cannabinoid receptor 1(CB1R) and Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels play a critical role in neuropathic pain. HCN4 channels and CB1R express in neurons respectively. CB1R activation causes changes of intracellular messenger molecules and membrane potential. HCN4 channels are highly sensitive to these changes. However, we don't clear wether the interaction between spinal HCN4 channels and CB1R is involved in pain maintenance. This proposal will use some methods including morphology, ethology, molecular biology and electrophysiology to investigate the behavioral responses and the expression of HCN4 channels and CB1R in dorsal horn; to speculate the roles of interaction between HCN4 channels and CB1R in dorsal horn neurons and its signal transduction pathways; to investigate whether the interaction between HCN4 channels and CB1R affect neuronal excitability and synaptic transmission. The research work will provide some evidence for developing effective analgesics bases on HCN4 as new therapeutic targets, and provide new ideas and methods for clinical treatment of pathological pain.