The Endocannabinoid System and its Modulation by Phytocannabinoids

Abstract

The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ 9 -tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)-cannabinoid receptor type-1 (CB 1 R) and cannabinoid receptor type-2 (CB 2 R); their two most studied endogenous ligands, the "endocannabinoids" N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism. However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB 1 R and CB 2 R. Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with "endocannabinoid-like" mediators that may or may not interact with the same proteins as Δ 9 -tetrahydrocannabinol and other phytocannabinoids. In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors. Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets. Here, we review the whole world of ligands, receptors, and enzymes, a true "endocannabinoidome", discovered after the cloning of CB 1 R and CB 2 R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Other endogenous lipids that bind cannabinoid receptors were identified, i.e., 2-arachidonyl-glyceryl-ether (noladin ether) (326), N-arachidonoyl-dopamine (NADA) (76), and O-arachidonoyl-ethanolamine (virodhamine) (691). However, despite some efforts by the scientific community to characterize the metabolism of these molecules, their role as endocannabinoids is still controversial, and yet, the picture of the ECS has become more and more complicated over the years (222,371,432,494). Additional key players (i.e., endocannabinoid-like molecules, putative orphan receptors, and alternative metabolic pathways) are being proposed to be part of this evolutionarily conserved and finely regulated lipid signaling system, whose number of additional potential components is predicted to raise even further in the future.…”

Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation

“…For example, in the BAT, cold elevated the levels of these two NAEs, possibly due to its stimulatory action on the mRNA levels of Abhd4 and Gde1 (which, therefore, might contribute to the biosynthesis of PEA and OEA, but not AEA, in this tissue). It is important to remember that OEA and PEA do not directly activate CB1 and CB2 receptors, and were reported to act on other targets of potential importance for the regulation of adipose tissue metabolism, i.e., PPAR ␣ , TRPV1 ( 33 ), and GPR55 (in the case of PEA) or GPR119 (in the case of OEA) ( 34,35 ). Therefore, the role of these two mediators in the control of BAT activation in the two tissues, measured here by quantifying the levels of the mRNAs encoding for the corresponding proteins ( Fig.…”

Developing Robust Standardised Analytical Procedures for Cannabinoid Quantification: Laying the Foundations for an Emerging Cannabis-Based Pharmaceutical Industry

“…The current understanding of the bioactivity of cannabinoids is based on their interaction with the human endocannabinoid system, a complex network comprising of 2 G protein-coupled receptors, a number of thermosensitive transient receptor potential cation channels, at least 2 endocannabinoids (anandamide and 2-arachidonoyl-glycerol), as well as associated biosynthetic pathways [9]. The human endocannabinoid system acts as a versatile broad-spectrum modulator of numerous biological systems and is involved in neurological and immunological pathologies [10, 11].…”