Different receptor mechanisms underlying phytocannabinoid- versus synthetic cannabinoid-induced tetrad effects: Opposite roles of CB1/CB2 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 CB1 receptors. Given recent findings of CB2 and GPR55 receptors in the brain, we examined whether these receptors are also involved in cannabinoid action. Experimental Approach We compared Delta(9)-tetrahydrocannabinol (Delta(9)-THC)-, WIN55212-2-, or XLR11-induced tetrad effects between wild-type (WT) and each genotype of CB1-, CB2- 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 Delta(9)-THC, WIN55212-2 or XLR11 produced dose-dependent tetrad effects in WT mice. Genetic deletion or pharmacological blockade of CB1 receptors abolished the tetrad effects produced by all three cannabinoids. Unexpectedly, genetic deletion of CB2 receptor abolished analgesia and catalepsy produced by Delta(9)-THC or WIN55212-2, but not by XLR11. Microinjections of Delta(9)-THC into the lateral ventricles also produced tetrad effects in WT, but not in CB1-KO mice. CB2-KO mice displayed a reduction in intraventricular Delta(9)-THC-induced analgesia and catalepsy. In contrast to CB1 and CB2 receptors, genetic deletion of GPR55 receptors caused enhanced responses to Delta(9)-THC or WIN55212-2. Antagonisim of CB1, CB2 or GPR55 receptors produced alterations similar to those observed in each genotype mouse line. Conclusions and Implications These findings suggest that in addition to CB1, both CB2 and GPR55 receptors are also involved in some pharmacological effects produced by cannabinoids. CB1/CB2, in contrast to GPR55, receptors appears to play opposite roles in cannabinoid action.