内脏痛是临床上极为普遍的症状，目前的药物不能满足临床需求，开发新型内脏痛镇痛药物非常必要。KCNQ钾通道非选择性激动剂对躯体痛、神经痛、痛风痛、内脏痛的镇痛效应已获证实。近年来研究发现KCNQ钾通道在内脏平滑肌和内脏感觉神经元中广泛分布，特别是该亚家族第四个成员KCNQ4通道在多种内脏器官和组织中呈现特异性高表达。KCNQ4通道在中枢神经系统中基本不表达，特异性靶向KCNQ4可以避免激动其它亚型的副作用。因此，本项目拟采用本实验室发现的KCNQ4相对选择性激动剂为探针，在内脏痛动物模型上考察其镇痛效应，构建KCNQ4基因敲除或KCNQ4靶标器官条件性敲除小鼠，考察KCNQ4通道作为内脏痛镇痛靶点的可行性，并阐明其作用机制。进而结合高通量筛选、电生理、化合物结构改造等方法发现新型KCNQ4选择性激动剂，综合考虑体内镇痛效应、代谢、毒性等，发展新型内脏痛镇痛候选化合物。

Visceral pain is a very common clinical symptom. Development of new treatments is urgerntly needed. KCNQ potassium channels play essential roles in regulation of neuronal excitability and have been attractive targets for body pain, neuropathylogical pain and gout pain, etc. KCNQ channels are also widely expressed in visceral smooth muscle and visceral sensory neurons. Among the five isoforms of KCNQ subfamily, KCNQ4, the fourth member, shows highest expression level in visceral tissues. Therefore, we speculate that KCNQ4 might be a potential drug target for visceral pain. Using the identfied KCNQ4 activators as probes, combining visceral pain models and gene knock out technique, we plan to investigate the drugablity of KCNQ4 channels for treatment of visceral pain and develop new drug candidates.