The cannabinoid receptors

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Abstract

Cannabinoid receptors were named because they have affinity for the agonist Δ9-tetrahydrocannabinol (Δ9-THC), a ligand found in organic extracts from Cannabis sativa. The two types of cannabinoid receptors, CB1 and CB2, are G protein coupled receptors that are coupled through the Gi/o family of proteins to signal transduction mechanisms that include inhibition of adenylyl cyclase, activation of mitogen-activated protein kinase, regulation of calcium and potassium channels (CB1 only), and other signal transduction pathways. A class of the eicosanoid ligands are relevant to lipid-mediated cellular signaling because they serve as endogenous agonists for cannabinoid receptors, and are thus referred to as endocannabinoids. Those compounds identified to date include the eicosanoids arachidonoylethanolamide (anandamide), 2-arachidonoylglycerol and 2-arachidonylglyceryl ether (noladin ether). Several excellent reviews on endocannabinoids and their synthesis, metabolism and function have appeared in recent years [1], [2], [3], [4]. This paper will describe the biological activities, pharmacology, and signal transduction mechanisms for the cannabinoid receptors, with particular emphasis on the responses to the eicosanoid ligands.

Section snippets

Eicosanoids as cannabinoid receptor agonists

Endocannabinoids comprise a family of eicosanoid and related unsaturated fatty acid derivatives that stimulate cannabinoid receptors: arachidonoylethanolamide (anandamide) [5], homo-γ-linolenoylethanolamide, docosatetraenoylethanolamide [6], 2-arachidonoylglycerol [7], [8] and 2-arachidonylglyceryl ether (noladin ether) [9]. Many analogs of anandamide have been developed such that a structure–activity relationship profile is beginning to emerge, and some of these analogs are of experimental use

Biological actions attributable to CB1 receptors

Therapeutic applications for Δ9-THC have been exploited in analgesia, attenuation of the nausea and vomiting in cancer chemotherapy, and appetite stimulation in wasting syndromes (see Pertwee [17], [18] and Porter and Felder [19] for reviews). However, the pharmaceutical industry has hesitated to promote these agents due to the untoward side effects of alterations in cognition and memory, dysphoria/euphoria, and sedation (see Abood and Martin [20], Ameri [21], and Chaperone and Thiébot [22] for

Biological actions attributable to CB2 receptors

In situ hybridization, immunocytochemical and autoradiographic evidence demonstrates the presence of CB2 receptors in spleen, thymus, tonsils, bone marrow, pancreas, splenic macrophage/monocyte preparations, mast cells, peripheral blood leukocytes, and in a variety of cultured immune cell models, including the myeloid cell line U937 and undifferentiated and differentiated granulocyte-like or macrophage-like HL60 cells (see recent reviews by Berdyshev [99] and Cabral [100]). Cannabinoid drugs

Speculation regarding alternative receptors for eicosanoid ligands

Eicosanoid drugs have been shown to stimulate activities beyond those expected from CB1 receptor activation alone. SR141716 failed to block the effects of anandamide in the tetrad model for mouse behaviors [37]. Oddly, it was capable of blocking the effects of several anandamide analogs that had been developed for their metabolic stability [37]. Furthermore, some anandamide analogs were effective in the mouse tetrad model, but exhibited low affinity for CB1 receptors [13]. One explanation for

Summary

Two mammalian cannabinoid receptors, CB1 and CB2, have been pharmacologically characterized and anatomically localized. Endogenous lipid mediators of the eicosanoid class, notably arachidonoylethanolamide (anandamide), 2-arachidonoylglycerol and 2-arachidonylglyceryl ether (noladin ether), bind to both cannabinoid receptor types and evoke responses. CB1 receptors are found predominantly in the central and peripheral nervous system, where they have been implicated in presynaptic inhibition of

Acknowledgements

Dr. Howlett as well as many of the investigators cited herein were supported by the National Institute on Drug Abuse.

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