There are at least two types of cannabinoid receptors (CB₁ and CB₂). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ⁹-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB₁, non-CB₂ established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB₁ and/or CB₂ receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB₃” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB₁, non-CB₂ pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB₃ receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB₁ receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB₁/CB₂ receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB₁, non-CB₂ cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

The presence and function of CB₂receptors in central nervous system (CNS) neurons are controversial. We report the expression of CB₂receptor messenger RNA and protein localization on brainstem neurons. These functional CB₂receptors in the brainstem were activated by a CB₂receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB₁receptors. CB₂receptors represent an alternative site of action of endocannabinoids that opens the possibility of nonpsychotropic therapeutic interventions using enhanced endocannabinoid levels in localized brain areas.