The CB1 and CB2 cannabinoid receptors are members of the G protein-coupled receptor (GPCR) family that are pharmacologically well defined. However, the discovery of additional sites of action for endocannabinoids as well as synthetic cannabinoid compounds suggests the existence of additional cannabinoid receptors. Here we review this evidence, as well as the current nomenclature for classifying a target as a cannabinoid receptor. Basic pharmacological definitions, principles and experimental conditions are discussed in order to place in context the mechanisms underlying cannabinoid receptor activation. Constitutive (agonist-independent) activity is observed with the overexpression of many GPCRs, including cannabinoid receptors. Allosteric modulators can alter the pharmacological responses of cannabinoid receptors. The complex molecular architecture of each of the cannabinoid receptors allows for a single receptor to recognize multiple classes of compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. Importantly, the basic biology of the endocannabinoid system will continue to be revealed by ongoing investigations.
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