How was the endocannabinoid system discovered?

Research on the psychoactive molecule of the plant Cannabis Sativa , delta-9-tetrahydrocannabinol (THC), allowed the discovery of membrane receptors for this molecule on the surface of cells. A receiver is like a lock, where one or more keys can be used to open a door. In biology, this key is called a ligand, and in the same way that a key is able to open a specific gate, a ligand will be able through its receiver to cause a specific signal that may eventually lead to a biological effect.

The first cannabinoid receptor , which was named CB1 ( type-1 cannabinoid receptor ) later, was discovered in 1988 [1] and is responsible for the well-known euphoric effects of THC.
The discovery of a receptor on which a cannabinoid could be attached from the plant Cannabis Sativa (an exogenous cannabinoid therefore) led scientists to search for the existence of endogenous ligands (produced by our body). The term “endocannabinoid” was thus used for the first time in the mid-1990s to designate these endogenous ligands.
Since the identification of the first endocannabinoid, anandamide , in the pig brain [2], numerous studies have contributed to the discovery of a communication system expressed in humans and all mammals, called the “endocannabinoid system” or SEC.

Recent research at the SEC level, in addition to demonstrating that this system acts in the regulation of many fundamental physiological processes of our body, report its involvement in many pathological situations.

The endocannabinoid system, a major player in cellular homeostasis

The functions of the endocannabinoid system are very long to enumerate, because a priori all the physiological processes of our body can involve its intervention. If one were to summarize very simply this relatively complex system, one could say that it is a “pro-homeostatic” system , that is to say, it will act in such a way as to maintain the balance (homeostasis) of our body. When talking about cellular homeostasis, we refer to the body’s ability to maintain its inner balance. At the level of the human body, it is for example the management of weight, body temperature, blood sugar, heart rate …

Endocannabinoid system, endocannabinoids and endocannabinoidoma: the differences

The endocannabinoid system (SEC) is a communication system composed of CB1 and CB2 cannabinoid membrane receptors, endogenous ligands called endocannabinoids and enzymes (proteins that activate or accelerate a chemical reaction) responsible for the synthesis and degradation of these molecules. [3].

Endocannabinoids are more specifically fatty acid derivatives formed from the lipids contained in cell membranes. These molecules are esters, ethers or amides of fatty acids, capable of activating the CB1 and CB2 receptors. The two main endocannabinoids are derivatives of arachidonic acid (an omega-6): anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Anandamide binds preferentially to the CB1 receptor and 2-AG to the CB2 receptor.
Endocannabinoids are produced “on demand” as a result of a stimulus (eg stress) and there is in principle no formal proof of a form of storage of these molecules. Endocannabinoids will mainly act locally and transiently because they are rapidly degraded after their synthesis.

Advances in SEC research have led to the discovery of new mediators called endocannabinoids-like , belonging to the same families of compounds as endocannabinoids, but acting on other receptors. This “extension” of the endocannabinoid system is called ” endocannabinoidoma ” [4].

To summarize , we therefore have a main system, the SEC, which is part of a much larger communication system called the “endocannabinoidoma”. The signaling molecules of this system are on the one hand the endocannabinoids and on the other hand the endocannabinoid-like compounds. Endocannabinoids are derived from omega-6 or omega-3 long chain unsaturated fatty acids: arachidonic acid or EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). Endocannabinoid-like compounds are formed from other types of acids such as linoleic, oleic, palmitic and stearic acids (the latter two are saturated fatty acids).

Where are the CB1 and CB2 endocannabinoid receptors in the body?

SEC is mainly represented in the central nervous system but it has also been detected in peripheral tissues such as the digestive system, liver and pancreas, cardiovascular system, lungs, adipose tissue, adrenal glands, the system. reproductive, skin, bones and muscles [5]. Thus CB1 and CB2 receptors are globally detected in almost all cells of the body.
However, we can observe a distribution that varies according to the nature of the receiver. Indeed, CB1 is mainly located in the central nervous system and peripheral nerve endings, while CB2 is mainly found in the cells of the immune system and the spleen.

The physiological roles of the endocannabinoid system

The SEC plays so many and different roles that it is difficult to list them all. As an example, we can cite its role in neuronal plasticity , control of emotions and learning abilities .
The endocannabinoid system is also involved in the control of appetite and lipogenesis (formation of fat cells). He takes part in the management of hormonal stress responses (secretion of adrenaline and corticosterone) and in the functioning of the cardiovascular system (vasodilatation and blood pressure).
SEC also plays a major role in the digestive system (control of motility and intestinal secretions) as well as in the control of inflammation and activity of immune cells [6].
It should be known that the two cannabinoid receptors can act on the same physiological parameter, very often in the same way but in some cases in an opposite way.

Endocannabinoid system and diseases

During pathological situations, changes in the tissue levels of the endocannabinoid and endocannabinoid-like mediators occur. As it is recognized that these mediators are not stored but only produced on demand, changes in tissue concentrates ions therefore correspond to their release from cells, and therefore to the activation of cannabinoid receptors.

The two most studied endocannabinoids, 2-AG and anandamide, have different concentrates ions in the following pathologies: inflammatory and immunological diseases (autoimmune diseases and allergies), neurological and neuropsychological diseases , osteoporosis , cardiovascular pathologies and cancers [7]. Endocannabinoid damage can also be related to obesity and metabolic diseases.

Surprisingly, for a given pathology, either an increase or a decrease in the levels of endocannabinoids may be demonstrated, and either a deleterious effect or a positive effect of receptor activation in the tissues and organs concerned. by pathology. Online Dispensary Canada No Card  Concentrates Canada In addition, it has been observed that the levels of both endocannabinoids 2-AG and anandamide may vary in the same direction or in a totally opposite manner [7].

It would seem, therefore, very difficult to predict the effects of a decrease or increase in the activity of the endocannabinoid system in a given pathology. However, it is clear that at the tissue level, the SEC can be affected in many different ways by a stimulus and this will depend not only on the nature but also on the duration of the stimulus.
The great diversity of action and the omnipresence of the SEC at the level of the organism thus brings a significant difficulty in the development of molecules capable of targeting only certain tissues.

In conclusion

The endocannabinoid system is one of the most important and complex body communication systems . Its main function is to react to stress in order to allow the internal environment to keep its balance . The alteration of its functioning and the levels of its lipid mediators (endocannabinoids) in certain tissues can contribute to the installation as well as the progression of various pathologies .

The latest research points out that the functioning of the endocannabinoid system can be impacted by many environmental factors such as lifestyle and nutrition, as well as the existence of a strong link between this system and the gut microbiota.

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References

[1] Devane, WA, Dysarz, FA, Johnson, MR, Melvin, LS, and Howlett, AC (1988). Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605-613.

[2] Devane, WA, Hanus, L., Breuer, A., Pertwee, RG, Stevenson, LA, Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A., and Mechoulam, R. (1992). Isolation and structure of a brain constitute that binds to the cannabinoid receptor. Science 258, 1946-1949.

[3] Fezza, F., Bari, M., Florio, R., Talamonti, E., Feole, M., and Maccarrone, M. (2014). Endocannabinoids, related compounds and their metabolic routes. Molecules 19, 17078-17106.

[4] Marzo, VD, and Wang, J. (2014). The Endocannabinoidome: The World of Endocannabinoids and Related Mediators (Academic Press). 13-19.

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[5] Sberna, A.-L., Degrace, P., and Vergès, B. (2016). Endocannabinoid system: effects on carbohydrate metabolism, but also lipid metabolism. Metabolic Disease Medicine 10, 407-414.

[6] Ligresti, A., Petrosino, S., and Di Marzo, V. (2009). From endocannabinoid profiling to ‘endocannabinoid therapeutics.’ Current Opinion in Chemical Biology 13, 321-331.

[7] Di Marzo, V. (2008). Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 7, 438-455.