• Article

Stratification of Cannabinoid 1 Receptor (CB1R) Agonist Efficacy


Grim, T. W., Morales, A. J., Gonek, M. M., Wiley, J. L., Thomas, B. F., Endres, G. W., ... Lichtman, A. H. (2016). Stratification of Cannabinoid 1 Receptor (CB1R) Agonist Efficacy: Manipulation of CB1R Density through Use of Transgenic Mice Reveals Congruence between In Vivo and In Vitro Assays. Journal of Pharmacology and Experimental Therapeutics, 359(2), 329-339. DOI: 10.1124/jpet.116.233163


Synthetic cannabinoids (SCs) are an emerging class of abused drugs that differ from each other and the phytocannabinoid Delta(9)-tetrahydrocannabinol (THC) in their safety and cannabinoid-1 receptor (CB1R) pharmacology. As efficacy represents a critical parameter to understanding drug action, the present study investigated this metric by assessing in vivo and in vitro actions of THC, two well-characterized SCs (WIN55,212-2 and CP55,940), and three abused SCs (JWH-073, CP47,497, and A-834,735-D) in CB1 (+/+), (+/-), and (-/-) mice. All drugs produced maximal cannabimimetic in vivo effects (catalepsy, hypothermia, antinociception) in CB1 (+/+) mice, but these actions were essentially eliminated in CB1 (-/-) mice, indicating a CB 1 R mechanism of action. CB1R efficacy was inferred by comparing potencies between CB1 (+/+) and (+/-) mice [+/+ ED50 /+/- ED50], the latter of which has a 50% reduction of CB(1)Rs (i. e., decreased receptor reserve). Notably, CB1 (+/-) mice displayed profound rightward and downward shifts in the antinociception and hypothermia dose-response curves of lowefficacy compared with high-efficacy cannabinoids. In vitro efficacy, quantified using agonist-stimulated [S-35] GTPgS binding in spinal cord tissue, significantly correlated with the relative efficacies of antinociception (r50.87) and hypothermia (r50.94) in CB1 (+/-) mice relative to CB1 (+/+) mice. Conversely, drug potencies for cataleptic effects did not differ between these genotypes and did not correlate with the in vitro efficacy measure. These results suggest that evaluation of antinociception and hypothermia in CB1 transgenic mice offers a useful in vivo approach to determine CB1R selectivity and efficacy of emerging SCs, which shows strong congruence with in vitro efficacy.