慢性痛和肥胖是当今社会高度普遍的两大疾病，且发病率日益增加。越来越多的证据表明，慢性痛和肥胖之间存在着显著联系，两者的结合会使患者的生活质量更加恶化，但其共病机制尚不清楚。多个基于人类基因组关联研究和转基因动物的基础研究均表明Ⅲ型腺苷酸环化酶（AC3）与肥胖的发生密切相关。我们实验室最近的工作表明，AC3在初级感觉神经元中特异性表达在CGRP阳性的中小直径神经元，高度提示AC3可能参与疼痛的调制。基于下丘脑是调控能量代谢的重要脑区并广泛表达AC3，我们推测，下丘脑中AC3可能是肥胖和慢性痛共病的重要调控激酶。本项目将通过多种转基因小鼠品系，结合病毒注射、光遗传学、化学遗传学和行为药理学，深入探讨下丘脑不同核团、不同细胞类型中表达的AC3对肥胖和慢性痛共病的影响及其可能的分子机制。本研究的实施将为揭示肥胖和慢性痛共病的神经机制提供新的视角，并为肥胖和慢性痛的综合治疗提供新的靶点和理论依据。

Chronic pain and obesity are two of the most prevalent diseases in our society and are increasing rapidly. Accumulating evidence strongly suggests that pain and obesity are significantly related to each other and the combination of obesity and pain may worsen a patient's quality of life more than each condition per self. However, the underlying mechanism remains unclear. Evidence from human genetic studies using genome-wide association analysis and basic researches from transgenic mice suggested that AC3 is highly related to obesity. Recent study from our lab indicated that AC3 is predominantly expressed in the small to medium sized CGRP-positive DRG neurons, implying AC3 enzyme might potentially function in nociception. Since hypothalamus is an important brain area regulating metabolism and AC3 is expressed throughout the hypothalamus, we speculate that AC3 in hypothalamus may be an important regulatory kinase for the comorbidity of obesity and chronic pain. This project will extensively explore the expression of AC3, in different nuclei and cell types of hypothalamus using a variety of transgenic mouse lines, combined with virus injection, optogenetics, DREADD and animal behavioral methods. Also, a possible upstream mechanism of AC signaling will be examined. The present project will provide important insights concerning molecular events contributing to comorbidity of chronic pain and obesity and may identify a specific drug target for the comprehensive treatments of obesity and chronic pain.