Targeting the endocannabinoid system: to enhance or reduce?

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Abstract
Endocannabinoids are lipid chemical mediators that act locally by activating cannabinoid receptors of type 1 (CB1) and type 2 (CB2) receptors. The two most-studied endocannabinoids are anandamide and 2-arachidonoylglycerol (2-AG), which are released from cells immediately after their biosynthesis from phospholipid-derived precursors, and whose action at receptors is controlled by rapid metabolism. The levels of the endocannabinoids and/or the expression of cannabinoid receptors in tissues vary during acute or chronic pathological conditions. These changes are due to increases in intracellular calcium concentration, changes in metabolic enzyme expression and availability of phospholipid precursors. They potentially lead to a modification of the activity of CB1 and CB2 receptors, and occur selectively in tissues and cells involved in the pathology. Anandamide and/or 2-AG are initially biosynthesized and released more, or degraded less, during perturbations of cell homeostasis or acute pathological conditions in an attempt to bring back cell homeostasis to its steady state prior to these perturbations. This seems to occur in a strictly site- and time-specific way. During certain chronic conditions, the levels of endocannabinoids in tissues might be altered in such a way that they start activating cannabinoid receptors for longer, or on cell populations that they were not initially meant to target, or they start interacting with different receptor types. This loss of specificity results in the contribution of endocannabinoids and their receptors to the symptoms and/or progress of certain chronic disorders. This plasticity of endocannabinoid signalling opened the way to the development of drugs that either boost or counteract the action of endocannabinoids, by inhibiting their inactivation or their binding to receptor, respectively. Inhibitors of endocannabinoid degradation via fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), and inhibitors of endocannabinoid cellular reuptake are also known as indirect agonists of endocannabinoid receptors. They have proved useful in animal models of inflammatory and neuropathic pain, inflammatory gastrointestinal diseases, epilepsy, neuromotor disorders, Alzheimer's disease and multiple sclerosis, affective disorders (chronic stress, fear, anxiety and depression), emesis and nausea, colorectal and thyroid cancer, and hypertension. CB1 antagonists/inverse agonists are already on the market for the treatment of obesity and related metabolic dysfunctions. They are also potentially useful against alcohol and nicotine abuse and drug of abuse reinstatement, Parkinson's and Alzheimer's diseases, liver fibrosis, pernicious hypotensive states induced by septic shock and cirrhosis, inflammatory pain and inflammation, osteoporosis and some cardiopathies. CB2 antagonists/inverse agonists are being tested in animals against inflammation and contact dermatitis and some neuroinflammatory disorders. Owing to the local action of endocannabinoids, both enhancers and inhibitors of their activity are specifically acting only when and where anandamide and/or 2-AG are being produced and degraded. Therefore, they should exhibit a relatively safe profile of side effects. In view of the pleiotropic effects of endocannabinoids, it is clear that compounds that manipulate either their lifespan or action need to be administered with caution and by making sure to use the appropriate dosage and to select the right patient in the right disease phase.