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 is one of four regioisomer EET-EA formed by these P450 enzymes [74]. 5,6-EET-EA is a potent agonist of CB2 receptors exceeding the binding affinity of the parent anandamide by 1000 fold and with greater stability [72]. While the metabolism of these fatty amides has not been completely described there is evidence of epoxide hydrolase metabolism of 5,6-EET-EA [72]. A different regioisomer 14,15-EET-EA has been found to bind CB1 receptors in rat brain albeit more weakly that anandamide. Interestingly the EETs themselves can directly act on the CB2 receptor [57]. We found that the regioisomeric mixture of EETs can displace CB2 agonist WIN 55212-2 but not the CB1 agonist CP 55940 in radioligand displacement assays. The activity is mostly mediated by the 5,6EET regioisomer, in accordance with results from Snider et al. demonstrating the potency of 5,6-EET-EA [72]. Though the affinity of 19µM for CB2 is weak we tested if either a CB1 or CB2 antagonist would block sEHI mediated anti-hyperalgesia.
