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.