Possible Efficacy Related Differences Among Cannabinoid Agonists

Currently, there are scant in vivo data showing that cannabinoid (CB) agonists vary in efficacy. Here, we show that the efficacy of two CB agonists ‐ Δ 9 ‐tetrahydrocannabinol (THC) and the 3‐ adamantyl CB AM4054 ‐ can be differentiated with CB antagonists in a warm‐water (52°C) tail withdrawal antinociception assay in CD1 mice and in drug discrimination studies in AM4054‐ trained monkeys. In mice, both THC and AM4054 produced 100% maximum possible effects (MPE) with ED 50 values of 21.0 and 0.28 mg/kg, respectively. Rimonabant, 1–30 mg/kg, similarly antagonized both drugs, producing parallel rightward shifts of the dose‐effect functions, e.g., 3‐ to 10‐fold rightward shifts after 10 mg/kg rimonabant, with recovery in ≤ 24hr. In contrast, pretreatment with 0.1–10 mg/kg AM6538, a pyrazole analog of rimonabant, produced rightward then downward shifts of the agonist dose‐effect functions, and recovery was prolonged. Thus, after 3.2 mg/kg AM6538, THC (up to 300 mg/kg) produced <30%MPE; comparable doses of AM4054 still produced >;65%MPE and, after 10 mg/kg AM6538, antagonism was evident for >;2 days. In squirrel monkeys, AM6538 antagonized the discriminative‐stimulus effects of AM4054 dose‐dependently and, after the highest dose (5.6 mg/kg), for up to 10 days. These results suggest that differences in CB efficacy in vivo can be revealed with long‐acting CB antagonists such as AM6538. [Supported by: DA023142 , DA026795 ]