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.

Activation of CB₁receptors by plant cannabinoids or the endogenous ligand, anandamide, causes hypotension via a sympathoinhibitory action in anaesthetized rats. In mouse isolated vas deferens, activation of CB₁receptors inhibits the electrically evoked twitch response. To determine if these effects are related to presynaptic inhibition of noradrenaline (NA) release, we examined the effects of Δ⁹‐tetrahydrocannabinol (‡⁹‐THC), anandamide and the CB¹antagonist, SR141716A, on exocytotic NA release in rat isolated atria and vasa deferentia. In isolated atria and vasa deferentia preloaded with [³H]‐NA, electrical field stimulation caused [³H]‐NA release, which was abolished by tetrodotoxin 0.5 μmand concentration‐dependently inhibited by ‡⁹‐THC or anandamide, 0.3–10 μm. The inhibitory effect of ‡⁹‐THC and anandamide was competitively antagonized by SR141716A, 1–10 μm. Tyramine, 1 μm, also induced [³H]‐NA release, which was unaffected by tetrodotoxin, ‡⁹‐THC or anandamide in either atria or vasa deferentia. CB₁receptor mRNA is present in the superior cervical ganglion, as well as in whole brain, cerebellum, hypothalamus, spleen, and vas deferens and absent in medulla oblongata and atria, as demonstrated by reverse transcription‐polymerase chain reaction. There was no evidence of the presence of CB^1Areceptor mRNA in ganglia, brain, or cerebellum. These results suggest that activation of presynaptic CB¹receptors located on peripheral sympathetic nerve terminals mediate sympathoinhibitory effectsin vitroand in vivo.

The cannabinoid receptor 1 (CB₁) and CB₂ cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR55 is also a cannabinoid receptor remains unclear as a result of conflicting pharmacological studies. GPR55 has been reported to be activated by exogenous and endogenous cannabinoid compounds but surprisingly also by the endogenous non-cannabinoid mediator lysophosphatidylinositol (LPI). We examined the effects of a representative panel of cannabinoid ligands and LPI on GPR55 using a β-arrestin-green fluorescent protein biosensor as a direct readout of agonist-mediated receptor activation. Our data demonstrate that AM251 and SR141716A (rimonabant), which are cannabinoid antagonists, and the lipid LPI, which is not a cannabinoid receptor ligand, are GPR55 agonists. They possess comparable efficacy in inducing β-arrestin trafficking and, moreover, activate the G-protein-dependent signaling of protein kinase CβII. Conversely, the potent synthetic cannabinoid agonist CP55,940 acts as a GPR55 antagonist/partial agonist. CP55,940 blocks GPR55 internalization, the formation of β-arrestin GPR55 complexes, and the phosphorylation of ERK1/2; CP55,940 produces only a slight amount of protein kinase CβII membrane recruitment but does not stimulate membrane remodeling like LPI, AM251, or rimonabant. Our studies provide a paradigm for measuring the responsiveness of GPR55 to a variety of ligand scaffolds comprising cannabinoid and novel compounds and suggest that at best GPR55 is an atypical cannabinoid responder. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy.