Endocannabinoid system


The endocannabinoid system (ECS) in mammals is highly conserved among species and classically formed by endogenous cannabinoids (endocannabinoids), such as anandamide (AEA) and 2-araquidonoilglycerol (2-AG), by the cannabinoid receptors (CB1 and CB2), as well as by enzymes responsible for the synthesis and degradation of endocannabinoids. The ECS plays an important modulating role in physiological functions, not only in the central nervous system (CNS), where it was first found, but also in the autonomic nervous system, endocrine, immune, gastrointestinal, reproductive, and other systems.

The ECS was first described after the identification and isolation of constituent cannabinoids from the Cannabis sativa plant, where the main psychotropic component is Δ9-tetrahydrocannabinol (THC). The several studies on the structure and activity of natural cannabinoids extracted from Cannabis sativa, in addition to the development of synthetic cannabinoids, have led to the identification of the main physiological functions that are modulated by this class of compounds. However, almost two decades separate the discoveries about the action of cannabinoids3 from the characterization and cloning of the first cannabinoid receptor, the CB1 receptor as a specific target of cannabinoids.

The main cannabinoid receptors are called CB1 and CB2 and belong to and are involved with remarkably similar cellular signaling systems. CB1 is mostly found in the cells of the brain and other elements of the CNS, while CB2 is present in the cells of the immune system, but it is possible to find both receptors in almost every cell of the body. Besides cannabinoid receptors, several pharmacological studies have shown the capacity of cannabinoids to interact directly with other cell receptors, such as the transient receptor potential vanilloid, type 1 (TRPV1)12. This interaction of the ECS elements with other physiological systems is described as expanded Endocannabinoid system and reflects the huge importance of the ECS to regulate important functions in our organism.

Since its discovery to the present day, the ECS is also considered a therapeutic target in a variety of pathophysiological processes, such as neurological syndromes, obesity, metabolic syndrome, chronic pain, complications of diabetes, and neurodegenerative, inflammatory, cardiovascular, liver, gastrointestinal, cancer and many other diseases. In some cases, the change in the ECS activity is transient, being a response of the organism to a certain insult, thus seeking to reduce pathophysiological symptoms or the progression of a disease. In other cases, the activation of the ECS may be part of the etiology of some disorders, being the increase or decrease of the ECS activity the result of the change in the expression of its receptors or in the metabolism of endocannabinoids


1) HOWLETT, A. C. The cannabinoid receptors. P rostaglandins and Other Lipid Mediators, v . 6 8-69, p. 619-631, 2002.

2) DI MARZO, Vincenzo et al. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. T rends in neurosciences, v. 21, n. 12, p. 5 21-528, 1998.

3) MECHOULAM, Raphael et al. Chemical basis of hashish activity. S cience, v. 169, n. 3 945, p. 611-612, 1 970.

4) HOWLETT, Allyn C. et al. The cannabinoid receptor: biochemical, anatomical and behavioral characterization. T rends in neurosciences, v. 13, n. 10, p. 420-423, 1 990.

5) DEVANE WA et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 34(5): 605-613.

6) MATSUDA LA et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 346: 561-564.

7) FELDER CC et al. LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J Pharmacol Exp Ther. 284(1): 291-297.

8) LAUCKNER JE et al. The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci U S A. 102(52):19144-19149.

9) BRANDES RP et al. The extracellular regulated kinases (ERK) 1/2 mediate cannabinoid-induced inhibition of gap junctional communication in endothelial cells. Br J Pharmacol. 136(5):709-716.

10) RUEDA D et al. The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/B-Raf/ERK pathway. J Biol Chem. 277(48):46645-46650.

11) RODRÍGUEZ DE FONSECA F et al. The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol. 40: 2-14.

12) ZYGMUNT PM  et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 400: 452-457.

13) DE PETROCELLIS L et al. An introduction to the endocannabinoid system: from the early to the latest concepts. Best Pract Res Clin Endocrinol Metab. 23: 1-15.

14) DEVANE WA et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 258: 1946-1949.

15) MECHOULAM R et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 50(1): 83-90.

16) SUGIURA T et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 215(1): 89-97.

17) UEDA N et al. Metabolism of endocannabinoids and related N-acylethanolamines: canonical and alternative pathways. FEBS J. 280(9): 1874-1894.

18) PACHER P et al. Modulating the endocannabinoid system in human health and disease–successes and failures. T he FEBS journal, v. 280, n. 9, p. 1918-1943, 2013.

Whatsapp Chat