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Possible Efficacy Related Differences Among Cannabinoid Agonists
Author(s) -
Chopda Girish,
Bergman Jack,
Vemuri Kiran,
Makriyannis Alex,
Paronis Carol A
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1097.2
Subject(s) - rimonabant , cannabinoid , pharmacology , agonist , chemistry , in vivo , antagonist , antagonism , cannabinoid receptor , cannabinoid receptor antagonist , medicine , receptor , biology , biochemistry , microbiology and biotechnology
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 ]