CB2 Cannabinoid receptors as a therapeutic target-what does the future hold?

Abstract

The past decades have seen an exponential rise in our understanding of the endocannabinoid system, comprising CB1 and CB2 cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. The primary focus of this review is the CB2 receptor. CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential for treating various pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor-based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this review, we summarize our present knowledge of CB2 receptor signaling, localization, and regulation. We discuss the availability of genetic tools (and their limitations) to study CB2 receptors and also provide an update on preclinical data on CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clinical pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclinical and clinical data.

Fig. 1.

Activation of CB₂ receptors by natural or synthetic ligands favors a range of receptor conformations that can variably affect different signaling pathways in the following ways: 1) inhibition of adenylyl cyclase, decreased cAMP production, and less activation of cAMP-dependent protein kinase (PKA), culminating in inhibition of A-type potassium channels and inhibition of some gene expression; 2) activation of Akt/protein kinase B, stimulating cell survival, migration, and growth; 3) activation of the MAPK cascade, favoring cell survival and modulating gene expression; 4) inhibition of specific calcium channels and enhanced opening of G protein–gated inwardly rectifying potassium (GIRK) channels; 5) stimulation of de novo synthesis of ceramide and inhibition of the MAPK cascade, promoting apoptosis; 6) recruitment of β-arrestin to the activated CB₂ receptor, resulting in desensitization and/or internalization of the receptor and potential activation of arrestin-specific signaling; and 7) decreased PKA activity, which increases Raf-1 to stimulate the MAPK cascade, positively regulating the expression of many genes. + indicates activation of pathway by CB₂ receptor agonists; – indicates inhibition/downregulation of pathway by CB₂ receptor agonists; +/− indicates a variable outcome.