The Endocannabinoid System and its Modulation by Phytocannabinoids.
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 (CB1R) and cannabinoid receptor type-2 (CB2R); 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 CB1R and CB2R. 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 CB1R and CB2R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, 80078, Pozzuoli, NA, Italy. vdimarzo@icb.cnr.it.
Vincenzo
V
Di Marzo
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, 80078, Pozzuoli, NA, Italy.
Fabiana
F
Piscitelli
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D063388:Endocannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D043882:Receptors, Cannabinoid / Q000378:metabolism*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010936:Plant Extracts; D043882:Receptors, Cannabinoid
Endocannabinoidome; Endocannabinoids; Phytocannabinoids; TRP channels