An Introduction to the Endogenous Cannabinoid System

Abstract

The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults. The ECS is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The most abundant cannabinoid receptor is the CB1 cannabinoid receptors, however CB2 cannabinoid receptors, transient receptor potential (TRP) channels, and peroxisome proliferator activated receptors (PPAR’s) are also engaged by some cannabinoids. Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide) are the best-studied endogenous cannabinoids. Despite similarities in chemical structure, 2-AG and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiological and pathophysiological roles to these two endocannabinoids. Because of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiological and pathophysiological roles of the ECS. This review will provide an introduction to the ECS with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia.

Inhibition of monoacylglycerol lipase terminates diazepam‐resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet

“…14,27 These effects were attributed to a reduction of excitatory neurotransmission by 2-AG activation of CB1 receptors. MAGL inhibition may mediate therapeutic effects on SE by 2 main mechanisms: (1) accumulation of 2-AG, which in turn activates the neuronal presynaptic CB1 receptors, thereby reducing glutamate-mediated excitatory over inhibitory neurotransmission 28,29 or acting as allosteric modulator of c-aminobutyric acid A (GABA A ) receptors 30 ;…”

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.…”

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

“…The endocannabinoid system is a complex network of cellular receptors and signaling molecules [7] highly expressed in brain and targeted by cannabis derivatives which, when activated, provides neuroprotection by reducing neuronal damage, neuroinflammation, and oxidative stress, as well as promoting intrinsic repair mechanisms [3]. Thus, chronic stimulation with selective synthetic agonists of CB 1 and CB 2 receptors, the most well-known cannabinoid receptors, reduces cognitive impairment and brain alterations associated with A␤ production, in at least three different animal models of AD [8][9][10][11].…”