AN ENTOURAGE EFFECT - INACTIVE ENDOGENOUS FATTY-ACID GLYCEROL ESTERS ENHANCE 2-ARACHIDONOYL-GLYCEROL CANNABINOID ACTIVITY

2-Arachidonoyl-glycerol (2-Ara-G1) has been isolated from various tiss ues and identified as an endogenous ligand for both cannabinoid recept ors, CB1 and CB2. Here we report that in spleen, as in brain and gut, 2-Ara-G1 is accompanied by several 2-acyl-glycerol esters, two major o nes being 2-linoleoyl-glycerol (2-Lino-G1) and 2-palmitoyl-glycerol (2 -Palm-G1). These two eaters do not bind to the cannabinoid receptors, nor do they inhibit adenylyl cyclase via either CB1 or CB2; however, t hey significantly potentiate the apparent binding of 2-Ara-G1 and its apparent capacity to inhibit adenylyl cyclase. Together these eaters a lso significantly potentiate 2-Ara-G1 inhibition of motor behavior, im mobility on a ring, analgesia on a hot plate and hypothermia caused by 2-Ara-G1 in mice. 2-Lino-G1, but not 2-Palm-G1, significantly inhibit s the inactivation of 2-Ara-G1 by neuronal and basophilic cells. These data indicate that the biological activity of 2-Ara-G1 can be increas ed by related, endogenous 2-acyl-glycerols, which alone show no signif icant activity in any of the tests employed, This effect ('entourage e ffect') may represent a novel route for molecular regulation of endoge nous cannabinoid activity. (C) 1998 Elsevier Science B.V. All rights r eserved.