TY - JOUR
T1 - An entourage effect
T2 - inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity
AU - Ben-Shabat, Shimon
AU - Fride, Ester
AU - Sheskin, Tzviel
AU - Tamiri, Tsippy
AU - Rhee, Man Hee
AU - Vogel, Zvi
AU - Bisogno, Tiziana
AU - De Petrocellis, Luciano
AU - Di Marzo, Vincenzo
AU - Mechoulam, Raphael
N1 - Funding Information:
This work was supported by NIDA grant DA 9789 (to R.M.), a grant by the Israel Science Foundation (to Z.V. and R.M.), and a grant RG26/95 from The Human Frontier Science Program Organization (to V.D.M.). R.M. is associated with the David Bloom Centre for Pharmacy at the Hebrew University.
PY - 1998/7/17
Y1 - 1998/7/17
N2 - 2-Arachidonoyl-glycerol (2-Ara-Gl) 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-Gl 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-Gl, 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. Copyright (C) 1998 Elsevier Science B.V.
AB - 2-Arachidonoyl-glycerol (2-Ara-Gl) 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-Gl 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-Gl, 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. Copyright (C) 1998 Elsevier Science B.V.
KW - 2-Arachidonoyl-glycerol inactivation
KW - Anandamide
KW - Cannabinoid receptor
KW - Endocannabinoid
UR - http://www.scopus.com/inward/record.url?scp=0031830516&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(98)00392-6
DO - 10.1016/S0014-2999(98)00392-6
M3 - Article
AN - SCOPUS:0031830516
SN - 0014-2999
VL - 353
SP - 23
EP - 31
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -