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

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.
AuthorsNissar A Darmani
JournalThe 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
PMID11752094 (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
  • rimonabant
  • 2-arachidonylglycerol
  • Dronabinol
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • anandamide
  • 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)
  • Shrews

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