Synthetic cannabinoids (SCs) represent an emerging new class of abused drugs that widely differ from each other and from the phytocannabinoid Δ9-tetrahydrocannabinol (THC) in cannabinoid-1 receptor (CB1R) selectivity, potency, and efficacy. As these pharmacological parameters offer critical information to understand drug action, the present study investigated in vivo CB1R efficacy and selectivity of THC, two well-characterized SCs (WIN55,212-2 and CP55,940), and three abused SCs possessing largely unknown pharmacology (JWH-073, CP47,497, and A-834,735-D) in CB1 (+/+), (+/-), and (-/-) mice. Whereas (+/+) mice displayed dose-dependent effects in three CB1R-sensitive assays (i.e., catalepsy, hypothermia and antinociception), these effects were essentially eliminated in CB1R (-/-) mice. CB1 (+/-) mice, which express 50% CB1Rs as (+/+) mice, showed reduced hypothermic and antinociceptive potencies of all drugs and reduced Emax values for THC, CP47,497, and JWH-073. An in vivo metric of relative efficacy (i.e., potency ratios between (+/+) and (+/-) mice) strongly correlated with in vitro efficacy assessed by agonist-stimulated [35S]GTPγS binding in spinal cord tissue (r=0.95 and 0.84 for antinociception and hypothermia, respectively). Conversely, CB1 (+/+) and (+/-) mice displayed similar catalepsy dose-response relationships for each respective cannabinoid. This pattern of findings suggests that low efficacy CB1R agonists show substantial Emax and potency reductions in pharmacological measures mediated by low receptor reserve compared with an effect mediated by high receptor reserve. Thus, evaluating antinociception and hypothermia in CB1R transgenic mice offers a useful in vivo approach to determine CB1R selectivity, potency, and efficacy of emerging SCs, which shows strong congruence with in vitro efficacy.
- The American Society for Pharmacology and Experimental Therapeutics