Endocannabinoids are lipophilic molecules synthesized ‘on demand’, meaning synthesis occurs after neuronal activation, from membrane phospholipids, and are released immediately, without storage in vesicles [5]. Both anandamide and 2-AG are produced by post-synaptic neurons (Figure 1A). Anandamide is produced in a two-step process and its levels are regulated by its degradation by the fatty acid amide hydrolase (FAAH) [41]. Also synthesized is 2-AG, in a two-step process involving the action of phospholipase C (PLC), followed by the hydrolytic activity of diacyl glycerol lipase (DAGL) [35]. The levels of 2-AG are essentially regulated by monoacylglycerol lipase (MAGL) [42]. There is a difference however in the location in which both eCBs are degraded. The hydrolysis of 2-AG occurs in presynaptic neurons by MAGL, after CB1R activation, whereas anandamide is hydrolyzed in postsynaptic neurons by FAAH, which may lead to a termination of anandamide action where it is synthesized [5]. In addition to hydrolysis, 2-AG can also be transformed into other bioactive compounds by cyclooxygenase-2 [43] and lipoxygenase [44]. Further, the metabolism of anandamide by lipoxygenase and cyclo-oxygenase enzymes generates oxygenated products that signal through non-cannabinoid targets [5,45].
