Best Practice & Research Clinical Endocrinology & Metabolism
1An introduction to the endocannabinoid system: from the early to the latest concepts
Section snippets
The endocannabinoid system: the ‘early’ view
For centuries the biological and molecular bases of the recreational and medicinal use of preparations from the hemp plant Cannabis sativa have remained unexplained. It took, in fact, much longer to identify the natural components responsible for the pharmacological effects of marijuana and hashish than it had taken to assign a chemical identity to the active principle of opium. The identification of cannabidiol (CBD) first, and of Δ9-tetrahydrocannabinol (THC) shortly after, in the 1960s1, 2
Non-CB1 non-CB2 receptors for endocannabinoids
Especially when compared to the several GPCRs for, e.g., histamine and glutamate, ‘only’ two receptors for endocannabinoids looked like ‘too little of a good thing’. However, homology cloning could not identify other THC receptors with some sequence similarity to CB1 and CB2, and the screening of the several tens of orphan GPCRs, the sequences of which are already available, initially yielded negative results (but see below). On the other hand, several pharmacological studies, reviewed by Di
Endogenous bioactive endocannabinoid-related molecules
Since their discovery as endocannabinoids, it was immediately clear that both anandamide and 2-AG are often accompanied in cells, tissues and biological fluids by congeners that are less active, or even inactive, at cannabinoid receptors. Thus, it is now well established that other long-chain N-acylethanolamines, very probably biosynthesized from molecules similar to NArPE, the N-acyl-phosphatidylethanolamines, and, like anandamide, degraded to the corresponding fatty acid and ethanolamine by
New pathways and enzymes for endocannabinoid biosynthesis and degradation
The start of the new century witnessed the discovery of several alternative enzymes for the biosynthesis of anandamide from NArPE, and for the inactivation of 2-AG to glycerol and arachidonic acid (Fig. 2). Following studies showing that NAPE-PLD ‘knock-out’ mice do not exhibit reduced levels of anandamide in most tissues91, and suggesting multiple pathways for the biosynthesis of this endocannabinoid, anandamide was suggested to be formed from phospho-anandamide, a product of the hydrolysis of
Tools for the study of endocannabinoid biology and new potential leads for drug development
Comprehensive reviews of the most widely used pharmacological tools for the study of the endocannabinoid system have been published very recently.114, 115 These tools include: (1) inhibitors of endocannabinoid cellular uptake, such as AM404, LY-2183240, VDM11, UCM707, OMDM-1, OMDM-2 and AM1172, in increasing order of selectivity; (2) inhibitors of FAAH, such as URB-597, OL-135, BMS-1, SA-47, PF-750 and N-arachidonoyl-serotonin (which also antagonizes TRPV1 receptors); (3) inhibitors of MAGL,
Anatomy of the endocannabinoid system, its general strategy of action and its pathological disruption
Studies carried out immediately after the molecular characterization of CB1 and CB2 receptors established the distribution of their mRNAs in several mammalian tissues, with a very high abundance of CB1 in the brain and of CB2 in immunocompetent cells and tissues.129 We now know, however, that both receptors, and CB1 in particular, are much more widely distributed than originally believed. For example, the liver, initially used as a ‘negative control’ to validate probes and antibodies designed
Summary
The endocannabinoid system is a complex and pleiotropic endogenous signalling system discovered in the late 1990s from studies on the mechanism of action of Δ9-tetrahydrocannabinol. It includes: (1) at least two G-protein-coupled receptors, known as the cannabinoid CB1 and CB2 receptors; (2) the endogenous ligands of these receptors, known as endocannabinoids, of which anandamide and 2-arachidonoylglycerol are the best studied; and (3) proteins and enzymes for the regulation of endocannabinoid
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