Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB 1 /CB 2 versus GPR55 receptors

Background and Purpose Cannabis or cannabinoids produce characteristic tetrad effects—analgesia, hypothermia, catalepsy and suppressed locomotion, which are believed to be mediated by the activation of cannabinoid CB 1 receptors. Given recent findings of CB 2 and GPR55 receptors in the brain, we examined whether these receptors are also involved in cannabinoid action. Experimental Approach We compared Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC)‐, WIN55212‐2‐, or XLR11‐induced tetrad effects between wild‐type (WT) and each genotype of CB 1 ‐, CB 2 ‐ or GPR55‐knockout (KO) mice and then observed the effects of antagonists of these receptors on these tetrad effects in WT mice. Key Results Systemic administration of Δ 9 ‐THC, WIN55212‐2 or XLR11 produced dose‐dependent tetrad effects in WT mice. Genetic deletion or pharmacological blockade of CB 1 receptors abolished the tetrad effects produced by all three cannabinoids. Unexpectedly, genetic deletion of CB 2 receptor abolished analgesia and catalepsy produced by Δ 9 ‐THC or WIN55212‐2, but not by XLR11. Microinjections of Δ 9 ‐THC into the lateral ventricles also produced tetrad effects in WT, but not in CB 1 ‐KO mice. CB 2 ‐KO mice displayed a reduction in intraventricular Δ 9 ‐THC‐induced analgesia and catalepsy. In contrast to CB 1 and CB 2 receptors, genetic deletion of GPR55 receptors caused enhanced responses to Δ 9 ‐THC or WIN55212‐2. Antagonisim of CB 1 , CB 2 or GPR55 receptors produced alterations similar to those observed in each genotype mouse line. Conclusions and Implications These findings suggest that in addition to CB 1 , both CB 2 and GPR55 receptors are also involved in some pharmacological effects produced by cannabinoids. CB 1 /CB 2 , in contrast to GPR55, receptors appears to play opposite roles in cannabinoid action.