At least part of this crosstalk between the analgesic pathways may be mediated by the overlap in the structural features of endocannabinoids and EFAs (Figure 3). There are two cannabinoid receptors, CB1 expressed in the brain and CB2 which is more prevalent in the immune system and in microglial cells of the CNS although they were historically viewed as absent from this tissue [69]. The two major ligands of the cannabinoid receptors are arachidonylethanolamine (AEA known as anandamide) and 2-arachidonylglycerol (2-AG). These are an amide and an ester of arachidonic acid. The endocannabinoids are rapidly hydrolyzed by the actions of the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) [70]. Early on endocannabinoid epoxidation was suggested to be an activation pathway leading to epoxide metabolites with greater stability than the parent amides or to the formation of unique oxygenated metabolites with potent signaling capacities [71]. More importantly, epoxygenated endocannabinoids have recently been identified and their potential biological roles characterized [72, 73]. Epoxyeicosatrienoic acid ethanolamides (EET-AE) are endogenously produced by select isozymes of P450 in the brain [74]. The 5,6-EET-EA
