An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.
2-Arachidonoyl-glycerol (2-Ara-GI) has been isolated from various tissues and identified as an endogenous ligand for both cannabinoid receptors, CB1 and CB2. Here we report that in spleen, as in brain and gut, 2-Ara-GI is accompanied by several 2-acyl-glycerol esters, two major ones being 2-linoleoyl-glycerol (2-Lino-Gl) and 2-palmitoyl-glycerol (2-Palm-Gl). These two esters do not bind to the cannabinoid receptors, nor do they inhibit adenylyl cyclase via either CB1 or CB2; however, they significantly potentiate the apparent binding of 2-Ara-Gl and its apparent capacity to inhibit adenylyl cyclase. Together these esters also significantly potentiate 2-Ara-Gl inhibition of motor behavior, immobility on a ring, analgesia on a hot plate and hypothermia caused by 2-Ara-Gl in mice. 2-Lino-Gl, but not 2-Palm-GI, significantly inhibits the inactivation of 2-Ara-Gl by neuronal and basophilic cells. These data indicate that the biological activity of 2-Ara-Gl can be increased by related, endogenous 2-acyl-glycerols, which alone show no significant activity in any of the tests employed. This effect ('entourage effect') may represent a novel route for molecular regulation of endogenous cannabinoid activity.
Ben-Shabat
S
S
Department of Natural Products, The Hebrew University Medical Faculty, Jerusalem, Israel.
Fride
E
E
Sheskin
T
T
Tamiri
T
T
Rhee
M H
MH
Vogel
Z
Z
Bisogno
T
T
De Petrocellis
L
L
Di Marzo
V
V
Mechoulam
R
R
D000067956:Adenylyl Cyclase Inhibitors; D000700:Analgesics / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids; D019556:COS Cells; D002186:Cannabinoids / Q000378:metabolism*; D002460:Cell Line; D004357:Drug Synergism; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005989:Glycerides / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D006868:Hydrolysis; D007035:Hypothermia / Q000139:chemically induced; D008024:Ligands; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D013154:Spleen / Q000737:chemistry / Q000276:immunology
D000067956:Adenylyl Cyclase Inhibitors; D000700:Analgesics; D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D008024:Ligands; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C114956:2-palmitoylglycerol; C114955:2-linoleoylglycerol; C094503:glyceryl 2-arachidonate