Anytime that someone begins talking about the therapeutic values of cannabis they at some point are very likely to start talking about the endocannabinoid system and it’s natural place in your body, but what is it? What does it do? Does that mean we have a biological system just for cannabis and cannabinoids? While it is easy to talk about cannabinoids interacting with the endocannabinoid system, this system itself is quite complex and contains many different parts. Here we will look at what all is encompassed when discussing the endocannabinoid system, and the various roles that it has in the physiological processes of your body.
The Endocannabinoid System
There are a few different pieces making up the endocannabinoid system. There are receptors known as cannabinoid receptors throughout the central and peripheral nervous system. These receptors are on the surface of these neural cells and bind to compounds made within the body referred to as endocannabinoid ligands, endocannabinoids, or sometimes endogenous ligands. When the endocannabinoids bind to the cannabinoid receptors on the surface of the cells, the interaction causes important changes within the cell that can lead to a wide range of different outcomes in the body. The broad range of outcomes is due to the fact that cannabinoid receptors are one of the most highly expressed receptor types in the nervous system and are present in nearly every part of the brain.
The Receptors
The receptors that interact with both endocannabinoids, and cannabinoids derived from cannabis such as THC and CBD, were discovered by researchers trying to determine how the psychoactive properties of THC took effect. The discovery of these receptors, of which there are two (CB1 and CB2), led to the discovery of the entire endocannabinoid system. While both CB1 and CB2 are spread throughout the central and the peripheral nervous system, CB1 receptors are more heavily expressed in the central nervous system (the brain and spinal column), and CB2 receptors are more heavily expressed in the peripheral nervous system (the nerves running through your body). The cannabinoid receptors are the most highly expressed receptor type in the brain, despite not being discovered until after many of the other receptors found in the brain.
Cannabinoid receptors are of the family of receptors that are called G-coupled protein receptors. This family of receptors are known for passing through the membrane of the cell seven times. When the endocannabinoids bind to these receptors on the outside of the cell, it causes the portion of the protein that is on the inside of the cell to change shape. When this happens it results in a cascade of activities within the cell, where different enzymes within the cell get turned on or off depending on their role in cellular functions.
The Bodies Own Endocannabinoids
So if the body has cannabinoid receptors, did the body evolve these receptors just to interact with the cannabinoids made by cannabis? This was the question that researchers had to consider after the discovery of the cannabinoid receptors. They were quick to recognize however that this was not the case. This realization is what led researchers to seek out and identify the natural ligands for these receptors.
The body doesn’t make the cannabinoids that a cannabis plant does, instead the body makes endocannabinoids. The endocannabinoids might look quite different in their structure when compared to cannabinoids like THC or CBD, however, the bonds connecting many of the atoms in the endocannabinoids are able to move around which allows them to fit into the binding pocket on their receptors. The first endocannabinoid to be discovered was anandamide. The name anandamide comes from the words ananda which in sanskrit means bliss, and amide which is an important functional group found in the structure of the molecule. The next endocannabinoid to be discovered was 2-arachidonoylglycerol or 2-AG. 2-AG and anandamide are both very similar in structure and both are eicosanoids that break down into arachidonic acid. While other compounds have also shown to have endocannabinoid like effects, they have yet to be classified as full endocannabinoids.
The Binding of Anandamide and 2-AG
The endocannabinoids are very lipophilic and do not dissolve well in the water based environments of intra and extracellular fluids. As such they do not travel well in these fluids and are made only a short distance from where the receptors that will receive their signal are. In fact, endocannabinoids are not fully made in the cell at all. Instead the eicosanoid precursors are made in the cell and the final steps in the synthesis of the endocannabinoids are taken on the outside surface of the cell. As soon as they are made, the natural cannabinoid ligands are released into the space between the neurons. At the other side of the neural terminal lie the receptors to which the endocannabinoids will bind. When the binding of the ligands to the receptors occurs, the receptors change shape.
The change in shape of the receptor can cause a number of downstream effects to occur. The cannabinoid receptors are associated with phosphorylation activities in the cell which means that binding at the receptors leads to a number of proteins either being turned on to carry out their biological activities, or being turned off such that they stop performing their tasks in the cell. Whether a specific protein gets turned on or off, depends on the role that protein plays in a particular pathway. Cells have evolved to limit what is known as futile cycling. This occurs when pathways that lead to opposite results run at the same time, such as if the body were to be making sugars while also breaking them down at the same time. There would be no benefit of this to the cell, so many cellular processes are linked to each other such that when one turns on, the pathway that would otherwise lead to futile cycling will be turned off.
The Down Cascade Effects of Endocannabinoid Binding
There is a well understood set of effects that endocannabinoid binding at receptors lead to. Before this was understood however it was evident by the effects of THC that stimulation of the cannabinoid receptors was linked to mood regulation. Indeed, the binding of endocannabinoids has an effect on the release of neurotransmitters in the brain. When endocannabinoids bind, the result is an effect in K+ and Ca2+ ion channels. The net effect is that presynaptic K+ ion channels are activated while presynaptic Ca2+ ion channels are deactivated. By controlling these ion channels, the binding of endocannabinoids regulates the release of neurotransmitters such as glutamate and gamma aminobutyric acid (GABA). These neurotransmitters as you probably guessed are crucial to the regulation of your mood. Other down cascade effects of the binding of endocannabinoids include the inhibition of adenylyl cyclase and the activation of mitogen activated protein kinases. Both of which are crucial to many cellular functions and are carried out in nearly all types of cells.
The Oddballs and Stragglers
While this is a good summary of the endocannabinoid system and the components of that system, it does not tell the whole story. In fact the story is quite complicated and still being discovered. As mentioned before, in addition to the endocannabinoids discussed, there are other compounds found in the body that display endocannabinoid-like properties. Compounds such as 2-arachidonoylglycerol ether (2-AGE) and N-arachidonoyldopamine (NADA) have similar structures, and have shown similar properties to the known endocannabinoids. However, their roles in physiological processes are not fully understood therefore they have not been classified as endocannabinoids.
Similar to the fact that there are other compounds that display endocannabinoid-like properties, there are also receptors beyond just the cannabinoid receptors which can be acted upon by endocannabinoids. For example, TRPV1 also known as the vanilloid receptor, is typically acted upon by capsaicin. However, it has been shown that AEA has roughly the same binding affinity to this receptor as does capsaicin. Another receptor that is often referred to as an orphan receptor due to lack of belonging to other receptor class types, called GPR55 has also been shown to have an affinity for endocannabinoids. This receptor, while being different from the CB1 and CB2 receptors, shares the similarities of also being a G-coupled protein receptor, being involved in Ca2+ ion channel regulation, and is expressed in the brain. These similarities have caused some to suggest that this orphan receptor should in fact be classified as a cannabinoid receptor, however the science is still not clear enough yet to make that classification.
A System of Fun
As we have seen the endocannabinoid is a complicated system with many different parts, which probably comes as no surprise given the wide array of biological processes that are affected by the endocannabinoid system. With a few key players, the cannabinoid receptors, and the endocannabinoid ligands, the body has created a system that is capable of playing a role in a wide variety of cellular processes and functions. Aside from just mood regulation, the endocannabinoid system is important in digestion and inflammation pathways. In the future we’ll look at some of these pathways in greater detail!
Reference:
Scherma, M., Masia, P., Satta, V. et al. Brain activity of anandamide: a rewarding bliss?. Acta Pharmacol Sin 40, 309–323 (2019). https://doi.org/10.1038/s41401-018-0075-x