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 generally believed to be mediated by the activation of cannabinoid CB1 receptors (CB1Rs). Given recent findings of CB2 and GPR55 receptors in the brain, we examined whether CB2 and GPR55 receptors are also involved in cannabinoid action.

EXPERIMENTAL APPROACH:

We first compared Δ⁹ -THC-, WIN55212-2-, or XLR11-induced tetrad effects between wild-type (WT) and each genotype of CB1-, CB2-, or GPR55-knockout mice, and then observed the effects of antagonists of these receptors on cannabinoid-induced tetrad effects in WT mice.

KEY RESULTS:

Systemic administration of Δ⁹ -THC, WIN55212-2, or XLR11 produced dose-dependent tetrad effects in WT mice. Genetic deletion or pharmacological blockade of CB1Rs abolished the tetrad effects produced by all three cannabinoids. Unexpectedly, genetic deletion of CB2Rs also abolished analgesia and catalepsy produced by Δ⁹ -THC or WIN55212-2, but not by XLR11. Microinjections of Δ⁹ -THC into the lateral ventricles also produced tetrad effects in WT, but not in CB1-KO, mice. CB2-KO mice displayed a reduction in intra-ventricle Δ⁹ -THC-induced analgesia and catalepsy. In contrast to CB1Rs and CB2Rs, genetic deletion of GPR55s caused enhanced responses to Δ⁹ -THC or WIN55212-2. Pharmacological blockade 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 CB1Rs, both CB2Rs and GPR55s are also involved in some pharmacological effects produced by cannabinoids. CB1/CB2Rs, in contrast to GPR55 receptors, appear to play opposite roles in cannabinoid action.

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