The Potent Emetogenic Effects of the Endocannabinoid, 2-AG (2-Arachidonoylglycerol) Are Blocked by Δ⁹-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 (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 > WIN 55,212-2 > 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.