The Serine Hydrolases: Positioned at the Axis of Endocannabinoid-Eicosanoid Signaling

The endocannabinoid system (ECS) is an important physiological regulatory system and drugs that target this system have effects on a number of critical biological systems including synaptic transmission and immune response. The ECS is also the target for cannabinoid constituents from the cannabis plant including behaviorally active tetrahydrocannabinol that interacts with cannabinoid 1 and cannabinoid 2 receptors. There is a tremendous interest in targeting the ECS to treat disease particularly using indirect agonists such as enzyme inhibitors. These inhibitors block the metabolism of endocannabinoids, the endogenous signaling lipids for the ECS, and may avoid the side-effects of directly activating cannabinoid receptors. However, despite significant promise in pre-clinical studies, clinical trials of enzyme inhibitors have halted due to either a lack of efficacy or toxicity. These outcomes reflect the complexities of endocannabinoid lipid signaling in the central nervous system (CNS) and our current lack of knowledge on the outcomes of manipulating the ECS. This research addresses these important areas by: 1) Provision of fundamental knowledge regarding manipulation of endocannabinoid signaling in the CNS. 2) Identifying the risks or benefits of using drugs that indirectly enhance endocannabinoid levels for therapeutic targeting of the ECS in CNS disease.