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

Abstract

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.

• Authors: Nissar A Darmani
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 300 Issue 1 Pg. 34-42 (Jan 2002) ISSN: 0022-3565 [Print] United States
• PMID: 11752094 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

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