Abstract
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.