The potent emetogenic effects of the endocannabinoid, 2-AG (2-arachidonoylglycerol) are blocked by delta(9)-tetrahydrocannabinol and other cannnabinoids

J Pharmacol Exp Ther. 2002 Jan;300(1):34-42. doi: 10.1124/jpet.300.1.34.


Cannabinoids, including the endogenous cannabinoid or endocannabinoid, anandamide, modulate several gastrointestinal functions. To date, the gastrointestinal effects of the second putative endocannabinoid 2-arachidonoylglycerol (2-AG) have not been studied. In the present study using a shrew (Cryptotis parva) emetic model, 2-AG (0.25-10 mg/kg, i.p.) potently and dose-dependently increased vomiting frequency (ED(50) = 1.13 mg/kg) and the number of animals vomiting (ED(50) = 0.48 mg/kg). In contrast, neither anandamide (2.5-20 mg/kg) nor methanandamide (5-10 mg/kg) induced a dose-dependent emetogenic response, but both could partially block the induced emetic effects. Delta(9)-Tetrahydrocannabinol and its synthetic analogs reduced 2-AG-induced vomiting with the rank order potency: CP 55,940 > WIN 55,212-2 > Delta(9)-tetrahydrocannabinol. The nonpsychoactive cannabinoid, cannabidiol, was inactive. Nonemetic doses of SR 141716A (1-5 mg/kg) also blocked 2-AG-induced vomiting. The 2-AG metabolite arachidonic acid also caused vomiting. Indomethacin, a cyclooxygenase inhibitor, blocked the emetogenic effects of both arachidonic acid and 2-AG. CP 55,940 also blocked the emetic effects of arachidonic acid. 2-AG (0.25-10 mg/kg) reduced spontaneous locomotor activity (ED(50) = 11 mg/kg) and rearing frequency (ED(50) = 4.3 mg/kg) in the shrew, whereas such doses of both anandamide and methanandamide had no effect on locomotor parameters. The present study indicates that: 1) 2-AG is an efficacious endogenous emetogenic cannabinoid involved in vomiting circuits, 2) the emetic action of 2-AG and the antiemetic effects of tested cannabinoids are mediated via CB(1) receptors, and 3) the emetic effects of 2-AG occur in lower doses relative to its locomotor suppressant actions.

Publication types

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

MeSH terms

  • Animals
  • Antiemetics / pharmacology*
  • Arachidonic Acids / pharmacology
  • Cannabinoid Receptor Modulators
  • Cannabinoids / pharmacology*
  • Cyclohexanols / pharmacology
  • Dose-Response Relationship, Drug
  • Dronabinol / pharmacology*
  • Emetics / antagonists & inhibitors*
  • Emetics / pharmacology
  • Endocannabinoids
  • Female
  • Glycerides / antagonists & inhibitors*
  • Glycerides / pharmacology
  • Humans
  • Male
  • Motor Activity / drug effects
  • Piperidines / pharmacology
  • Polyunsaturated Alkamides
  • Pyrazoles / pharmacology
  • Receptors, Cannabinoid
  • Receptors, Drug / antagonists & inhibitors
  • Rimonabant
  • Shrews


  • Antiemetics
  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Cannabinoids
  • Cyclohexanols
  • Emetics
  • Endocannabinoids
  • Glycerides
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyrazoles
  • Receptors, Cannabinoid
  • Receptors, Drug
  • methanandamide
  • Dronabinol
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • glyceryl 2-arachidonate
  • Rimonabant
  • anandamide