IN VIVO INHIBITION STUDIES OF FAAH

脂肪酸酰胺水解酶（FAAH）是几种脂肪酸酰胺（FAA）的主要分解代谢酶，包括内源性大麻素n-花生四烯醇乙醇胺（anandamide）、睡眠诱导剂油酰胺、抑制食物的化合物n-油基乙醇胺（OEA）和外周镇痛剂n-棕榈酰乙醇胺（PEA）。缺乏FAAH的基因工程小鼠[FAAH（-/-）小鼠]的创建为评估该酶的功能提供了一个强大的模型。与野生型小鼠相比，这些小鼠表现出cbl介导的疼痛敏感性降低，并伴有CNS和外周内源性anandamide水平的大幅增加。在本申请（项目III）中提出的研究中，我们将评估一系列高选择性和可逆性FAAH抑制剂的体内效应。这些FAAH抑制剂为进一步了解FAAH/FAA系统的生理功能提供了补充工具。具体而言，我们将重点关注以下目标：1)确定选择性、有效、强效、可逆的FAAH

Fatty acid amide hydrolase (FAAH) is the enzyme predominantly responsible for the catabolism of several fatty acid amides (FAA), including the endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide), the sleep-inducing agent oleamide, the food-suppressing compound N-oleoylethanolamine (OEA), and the peripheral pain-suppressing agent N-palmitoylethanolamine (PEA). The creation of genetically engineered mice that lack FAAH [ FAAH(-/-) mice] has provided a powerful model to evaluate the function of this enzyme. These mice exhibit a CBl-mediated reduction in pain sensitivity, accompanied by substantial increases in endogenous anandamide levels in the CNS and periphery compared to wild type mice. In the studies proposed in this application (Project III), we will evaluate the in vivo effects of a series of highly selective and reversible FAAH inhibitors. These FAAH inhibitors provide complementary tools to further our understanding of the physiological functions of the FAAH/FAA system. Specifically, we will focus on the following goals: 1) identify selective, efficacious, potent, reversible FAAH inhibitors suitable for in vivo analysis; 2) characterize selected FAAH inhibitors and FAAH mutant mice in behavioral assays for pain, cognition, emotional behavior, and drug dependence; 3) correlate changes of anandamide and other FAAs in CNS areas associated with the behavioral changes; and 4) elucidate molecular mechanisms of action for FAAH inhibitors. While this Project is focused on investigating the function of FAAH in whole animals, these studies will be tightly linked to studies described in Projects I and II of the Program Project, in which the structural, biochemical, and cellular characterization of FAAH will be used to design highly selective inhibitors of this enzyme and create mutant mice that express FAAH variants with altered functional properties. Implications of this work should not only increase our understanding of the role that the FAAH-FAA system plays in a variety of neurobehavioral processes, but also may lead to the development of a new class of therapeutic drugs for the treatment of pain, anxiety, and substance abuse.