The palmitoylethanolamide and oleamide enigmas : are these two fatty acid amides cannabimimetic?

Palmitoylethanolamide (PEA) and oleamide are two fatty acid amides which 1) share some cannabimimetic actions with delta9-tetrahydrocannabinol, anandamide and 2-arachidonoylglycerol, and 2) may interact with proteins involved in the biosynthesis, action and inactivation of endocannabinoids. Due to its pharmacological actions and its accumulation in damaged cells, PEA may have a physio-pathological role as an analgesic, anti-oxidant and anti-inflammatory mediator. However, its mechanism of action is puzzling. In fact, PEA does not bind to CB1 and CB2 receptors transfected into host cells, but might be a ligand for a putative CBn receptor present in the RBL-2H3 cell line. On the other hand, the analgesic effect of PEA is reversed by SR144528, a CB2 antagonist. PEA may act as an entourage compound for endocannabinoids, i.e. it may enhance their action for example by inhibiting their inactivation. Oleamide is a sleep inducing lipid whose mechanism of action is far from being understood. Although it does not bind with high affinity to CB1 or CB2 receptors, it exhibits some cannabimimetic actions which could be explained at least in part by entourage effects. It is likely that oleamide and anandamide have common as well as distinct pathways of action. The 5-HT2A receptor appears to be a target for oleamide but the possibility of the existence of specific receptors for this compound is open. The biosynthesis and tissue distribution of oleamide remain to be assessed in order to both substantiate its role as a sleep-inducing factor and investigate its participation in other physiopathological situations.