Abstract

Cannabinoids, including the bioactive constituents of the marijuana plant, their synthetic analogs, and endogenous lipids with cannabinoid-like activity, produce their biological effects by interacting with specific receptors. To date, two G protein-coupled cannabinoid receptors have been identified by molecular cloning, CB₁ receptors mainly expressed in the brain and mediating most of the neurobehavioral effects of cannabinoids and CB₂ receptors expressed by immune and hematopoietic tissues. Recent findings indicate that some cannabinoid effects are not mediated by either CB₁ or CB₂ receptors, and in some cases there is compelling evidence to implicate additional receptors in these actions. These include transient receptor potential vanilloid 1 (TRPV₁) receptors and as-yet-unidentified receptors implicated in the endothelium-dependent vasodilator effect of certain cannabinoids and in the presynaptic inhibition of glutamatergic neurotransmission in the hippocampus. The case for these additional receptors is being reviewed here.

Keywords: Endocannabinoids; Cannabinoid receptors; Endothelium; Vasodilation; Hippocampus

Abbreviations: 2-AG, 2-arachidonoylglycerol; abn-cbd, abnormal cannabidiol; BK_Ca, large conductance calcium-activated potassium channel; CGRP, calcitonin gene-related peptide; DSI or DSE, depolarization-induced suppression of inhibition or excitation; EDHF, endothelium-derived hyperpolarizing factor; GPCR, G protein-coupled receptor; HUVEC, human umbilical vein endothelial cell; IPSC or EPSC, inhibitory or excitatory postsynaptic current; LPS, lipopolysaccharide; NO, nitric oxide; PEA, palmitoylethanolamine; PTX, pertussis toxin; THC, Δ⁹-tetrahydrocannabinol; TRPV receptor, transient receptor potential vanilloid receptor

Article Outline

1. Introduction

2. CB₁ and CB₂ receptors

3. Non-CB₁/non-CB₂ endothelial cannabinoid receptor

3.1. Pharmacology of the endothelial cannabinoid receptor

3.2. Signaling by the endothelial cannabinoid receptor

3.3. Possible physiological functions of the endothelial cannabinoid receptor

4. Atypical cannabinoid receptors in the central nervous system

4.1. Pharmacology of the non-CB₁ hippocampal cannabinoid receptor

4.2. Function of hippocampal non-CB₁ receptors

5. Role of transient receptor potential vanilloid 1 receptors in endocannabinoid action

6. Evidence for additional cannabinoid-sensitive receptors

7. Conclusions

References