TY - JOUR T1 - The Potent Emetogenic Effects of the Endocannabinoid, 2-AG (2-Arachidonoylglycerol) Are Blocked by Δ<sup>9</sup>-Tetrahydrocannabinol and Other Cannnabinoids JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 34 LP - 42 DO - 10.1124/jpet.300.1.34 VL - 300 IS - 1 AU - Nissar A. Darmani Y1 - 2002/01/01 UR - http://jpet.aspetjournals.org/content/300/1/34.abstract N2 - 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 (ED50 = 1.13 mg/kg) and the number of animals vomiting (ED50 = 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. Δ9-Tetrahydrocannabinol and its synthetic analogs reduced 2-AG-induced vomiting with the rank order potency: CP 55,940 &gt; WIN 55,212-2 &gt; Δ9-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 (ED50 = 11 mg/kg) and rearing frequency (ED50 = 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 CB1 receptors, and 3) the emetic effects of 2-AG occur in lower doses relative to its locomotor suppressant actions. Δ9-THCΔ9-tetrahydrocannabinol2-AG2-arachidonoylglycerolANOVAanalysis of variance ER -