TY - JOUR T1 - Stratification of Cannabinoid 1 Receptor (CB<sub>1</sub>R) Agonist Efficacy: Manipulation of CB<sub>1</sub>R Density through Use of Transgenic Mice Reveals Congruence between In Vivo and In Vitro Assays JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 329 LP - 339 DO - 10.1124/jpet.116.233163 VL - 359 IS - 2 AU - T. W. Grim AU - A. J. Morales AU - M. M. Gonek AU - J. L. Wiley AU - B. F. Thomas AU - G. W. Endres AU - L. J. Sim-Selley AU - D. E. Selley AU - S. S. Negus AU - A. H. Lichtman Y1 - 2016/11/01 UR - http://jpet.aspetjournals.org/content/359/2/329.abstract N2 - Synthetic cannabinoids (SCs) are an emerging class of abused drugs that differ from each other and the phytocannabinoid ∆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 CB1R 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 CB1Rs (i.e., decreased receptor reserve). Notably, CB1 (+/−) mice displayed profound rightward and downward shifts in the antinociception and hypothermia dose-response curves of low-efficacy compared with high-efficacy cannabinoids. In vitro efficacy, quantified using agonist-stimulated [35S]GTPγS binding in spinal cord tissue, significantly correlated with the relative efficacies of antinociception (r = 0.87) and hypothermia (r = 0.94) 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. ER -