CB1 receptor transgenic mice in the cannabinoid triad: a novel approach to assess in vivo efficacy of CB1 ligands.

Abstract

The abuse of structurally diverse synthetic cannabinoids has resulted in untoward effects in users and concomitant spike in emergency room visits, which signify a significant public health concern. Synthetic cannabinoids bind and activate cannabinoid CB1 receptors, which are responsible for the psychomimetic effects of the primary active constituent of marijuana, D9‐tetrahydrocannabinol (THC). While THC is classified as a partial agonist, many of the synthetic cannabinoids have been identified as full agonists. While various in vitro methods assess CB1 receptor efficacy (e.g. [35S]GTPgS binding, cAMP production), only drug discrimination procedures are currently utilized to determine in vivo efficacy. Here, we assess efficacy utilizing a cumulative dose‐response procedure of several cannabinoids (WIN55,212‐2, CP55,940, CP47,497, and THC) on CB1 receptor‐mediated pharmacological effects (i.e., catalepsy, hypothermia, and thermal antinociception) in CB1 (+/+), (+/‐), and (‐/‐) mice. As expected, these compounds produced little or no effects in CB1 (‐/‐) mice, consistent with the premise that these effects are CB1 receptor mediated. Each of these compounds produced maximum effects in CB1 (+/+) mice, but (+/‐) mice displayed differential sensitivity to these CB1 receptor agonists that was positively associated with their in vitro efficacy. Analysis of potency ratios between CB1 (+/+) and (+/‐) mice revealed a rank order of efficacy (from highest to lowest) of WIN55,212‐2 > CP55,940 > CP47,497 > THC. Together, these experiments demonstrate a quick and accurate method to determine in vivo efficacy, and this design correlates well with prior in vitro efficacy determinations in [35S]GTPgS binding assays.