Endocannabinoid System: An Update

Abstract

The endocannabinoid system (ECS) is nowadays considered as an important neurotransmitter system and, although the chemistry, biochemistry and pharmacology of endocannabinoids (eCBs) have been widely investigated, quite some pieces are still missing to fully understand how this system works. The discovery of anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) dates back to the beginning of 1990 and, since then, their molecular targets, biosynthetic and catabolic enzymes have been identified. In addition, selective pharmacological and genetic tools have been developed both to explore alternative metabolic routes and to produce eCB‐based drugs as therapeutics for the prevention/treatment of a variety of diseases. In this article, we will review the metabolic pathways of eCBs, and the latest advances on their potential receptor targets. Key Concepts The endocannabinoid system is an endogenous network including endocannabinoids, a complex array of receptors, biosynthetic and hydrolytic enzymes, as well as membrane transporters. Endocannabinoids are derivatives of the arachidonic acid. The two most important endocannabinoid transmitters, anandamide and 2‐arachidonoylglycerol, are produced and eliminated through several enzyme pathways. Endocannabinoids play their main roles by targeting both cannabinoid and other membrane and nuclear receptors. The binding of endocannabinoids to cannabinoid, vanilloid and peroxisome proliferator‐activated receptors triggers several signal transduction pathways. The endocannabinoid system is a pleiotropic signalling system that is widely distributed in the central and peripheral nervous systems. Alterations of circulating endocannabinoids levels are involved in the dysregulation of activity of important physiological systems. A deep knowledge of the endocannabinoid system signalling might be translated into the development of pathway‐selective drugs for therapeutic benefit.

2-arachidonyl glycerol modulates astrocytic glutamine synthetase via p38 and ERK1/2 pathways

“…It has been verified that 2-AG could modulate synaptic function, produce neuroprotection, and stimulate MAPK family by bonding to and activating two receptors, CB 1 R and CB 2 R, which are two G-protein-coupled receptors and have been grossly identified in astrocytes [ 23 ]. Previous studies have shown that activation of CB 1 R or CB 2 R results in anti-inflammation, prevention of neurodegeneration, and inhibition of nociceptive signaling pathways [ 24 – 26 ], as well as stimulation of the MAPK cascade [ 27 – 29 ]. Interestingly, activation of CB 1 R or CB 2 R also could inhibit stress-induced activation of the MAPK cascade.…”

Cannabinoid signaling in health and disease

“…The endocannabinoid system is a lipid signaling system that is involved in a wide range of physiological and pathological processes such as energy metabolism and inflammation. Three major components constitute the endocannabinoid system: endocannabinoids, cannabinoid receptors, and endocannabinoid metabolism (Battista et al 2006). Endocannabinoids are endogenously-produced bioactive lipids that activate cannabinoid receptors.…”

Caracterização da hemopressina (agonista inverso de receptores canabinóides do tipo 1) na neuropatia diabética experimental.

“…Adicionalmente, receptores CB1 são ativados por ligantes endógenos derivados de lipídeos de membrana chamados de endocanabinóides (Battista et al, 2006;Boyd, 2006;Di Marzo, Petrosino, 2007). Inúmeros trabalhos têm proposto um papel importante para o sistema endocanabinóide em diferentes condições fisiológicas e fisiopatológicas, dentre elas estão Doença de Parkinson, Alzheimer, depressão, inflamação, obesidade e dor neuropática (Battista et al, 2006;Boyd, 2006;Di Marzo, Petrosino, 2007 (Gilron, Coderre, 2007;Iversen, Chapman, 2002;Pertwee, 2001;Walker, Huang, 2002).…”

“…Inúmeros trabalhos têm proposto um papel importante para o sistema endocanabinóide em diferentes condições fisiológicas e fisiopatológicas, dentre elas estão Doença de Parkinson, Alzheimer, depressão, inflamação, obesidade e dor neuropática (Battista et al, 2006;Boyd, 2006;Di Marzo, Petrosino, 2007 (Gilron, Coderre, 2007;Iversen, Chapman, 2002;Pertwee, 2001;Walker, Huang, 2002). Na nocicepção, foi demonstrado que o Sistema Endocanabinóide atua na regulação da via descendente de dor, em diferentes níveis da via nociceptiva, modulando a inibição da AC, a ativação de canais de potássio e a inibição dos canais de cálcio, exercendo efeito inibitório sobre a liberação de transmissores, agindo de maneira distinta, mas paralela àquela que envolve os opióides (Iversen, Chapman, 2002;Rang et al, 2007).…”