Different receptor mechanisms underlying phytocannabinoid- versus synthetic cannabinoid-induced tetrad effects: Opposite roles of CB₁ /CB₂ versus GPR55 receptors.

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 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 Δ⁹ -tetrahydrocannabinol (Δ⁹ -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 Δ⁹ -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 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 intraventricular Δ⁹ -THC-induced analgesia and catalepsy. In contrast to CB₁ and CB₂ receptors, genetic deletion of GPR55 receptors caused enhanced responses to Δ⁹ -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.

SUBMITTER: Wang XF 

PROVIDER: S-EPMC7070166 | biostudies-literature |

REPOSITORIES: biostudies-literature