IN VIVO INHIBITION STUDIES OF FAAH

脂肪酸酰胺水解酶（FAAH）是主要负责几种脂肪酸酰胺（FAA）的催化的酶，包括内源性大麻素N-花生四烯酸乙醇胺（anandamide）、睡眠诱导剂油酰胺、食物抑制化合物N-油酰乙醇胺（OEA）和外周疼痛抑制剂N-棕榈酰乙醇胺（PEA）。缺乏FAAH的基因工程小鼠[ FAAH（-/-）小鼠]的创建提供了一个强大的模型来评估这种酶的功能。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，伴随着CNS和外周中内源性大麻素水平的显著增加。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抑制剂的体内作用。这些FAAH抑制剂提供了补充工具，以进一步了解FAAH/FAA系统的生理功能。具体而言，我们将集中在以下目标：1）确定选择性，有效，强效，可逆FAAH 本发明的目的在于：2）在疼痛、认知、情绪行为和药物依赖的行为测定中表征选择的FAAH抑制剂和FAAH突变小鼠; 3）使大麻素和其他FAA在与行为变化相关的CNS区域中的变化相关联;和4）阐明FAAH抑制剂的分子作用机制。虽然该项目的重点是研究FAAH在整个动物中的功能，但这些研究将与项目I和项目II中描述的研究紧密相关，其中FAAH的结构，生物化学和细胞表征将用于设计该酶的高选择性抑制剂，并创建表达功能特性改变的FAAH变体的突变小鼠。这项工作的意义不仅应该增加我们对FAAH-FAA系统在各种神经行为过程中所起作用的理解，而且还可能导致一类新的治疗药物的开发，用于治疗疼痛，焦虑和药物滥用。

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.