An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity

Eur J Pharmacol. 1998 Jul 17;353(1):23-31. doi: 10.1016/s0014-2999(98)00392-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclase Inhibitors
  • Analgesics / chemistry
  • Analgesics / isolation & purification
  • Analgesics / metabolism
  • Analgesics / pharmacology
  • Animals
  • Arachidonic Acids*
  • COS Cells
  • Cannabinoids / metabolism*
  • Cell Line
  • Drug Synergism
  • Endocannabinoids
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gas Chromatography-Mass Spectrometry
  • Glycerides / chemistry
  • Glycerides / isolation & purification
  • Glycerides / metabolism*
  • Glycerides / pharmacology
  • Hydrolysis
  • Hypothermia / chemically induced
  • Ligands
  • Mice
  • Motor Activity / drug effects
  • Pain Measurement
  • Receptors, Cannabinoid
  • Receptors, Drug / metabolism*
  • Spleen / chemistry
  • Spleen / immunology


  • Adenylyl Cyclase Inhibitors
  • Analgesics
  • Arachidonic Acids
  • Cannabinoids
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • Ligands
  • Receptors, Cannabinoid
  • Receptors, Drug
  • 2-palmitoylglycerol
  • 2-linoleoylglycerol
  • glyceryl 2-arachidonate