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 Delta(9)-tetrahydrocannabinol, anan damide and 2-arachidonoylglycerol, and 2) may interact with proteins involv ed in the biosynthesis, action and inactivation of endocannabinoids. Due to its pharmacological actions and its accumulation in damaged cells, P EA may have a physio-pathological role as an analgesic, anti-oxidant and an ti-inflammatory mediator. However, its mechanism of action is puzzling. In fact, PEA does not bind to CB1 and CB2 receptors transfected into host cell s, 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 S R144528, a CB2 antagonist. PEA may act as an "entourage" compound for endoc annabinoids, i.e. it may enhance their action for example by inhibiting the ir inactivation. Oleamide is a sleep inducing lipid whose mechanism of action is far from be ing 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 an andamide have common as well as distinct pathways of action. The 5-HT2A rec eptor appears to be a target for oleamide but the possibility of the existe nce of specific receptors for this compound is open. The biosynthesis and t issue distribution of oleamide remain to be assessed in order to both subst antiate its role as a sleep-inducing factor and investigate its participati on in other physiopathological situations.