In recent years neuroscientists have discovered the endocannabinoid system, in fact it was only in 1990 that the cannabinoid receptor was discovered, eventually called the CB1 receptor.
Then a few years later another receptor, now called CB2, was also discovered.
We now know that it is likely that the endocannabinoid system has a number of different receptors mainly on the pre-synaptic neuron.
The strongest candidate for being the CB3 receptor is currently known as the GPR55 but there are other possible candidates.
CB receptors are G protein coupled bio-receptors and they are located throughout the central and peripheral nervous system as well as throughout the rest of the body, particularly the immune system, and this partly explains the widespread medical effects of any phyto-cannabinoids which interact with our own endocannabinoid system.
The next discovery after the receptors was of the ligands. There are two now known for certain to be the main ligands of the endocannabinoid system, that is anandamide and 2-arachidonoylglycerol or 2AG.
Obviously it has been known for many years that during neurotransmission the pre-synaptic neuron releases neurotransmitters into the synaptic cleft, these then bind with neuroreceptors on the post-synaptic neuron.
It seems that the endocannabinoid systems acts as a controller or modulator of that basic system.
Once the post-synaptic neuron has been activated then the anandamide and 2AG are synthesised in the post synaptic neuron, they are released into the synaptic cleft and travel backwards from the post synaptic side to the pre-synaptic side, and bind with the CB receptors, this triggers the reduction in neurotransmitter activity.
In other words, it is a type of feedback loop.
Very simplistically, the endocannabinoid system acts as a fine tuner or controller of the release of other neurotransmitters.
It is likely that this is an oversimplification and that anandamide and 2AG also bind to other receptors. The details are not really known.
We do know that as soon as anandamide and 2AG have interacted with the receptors, they in turn are broken down largely by Fatty Acid Amide Hydrolase (FAAH).
Thus the endocannabinoids seem to be synthesised and then broken down on demand.
So what is the effect of the endocannabinoid system? Well it does seem to have very far-reaching effects and not surprisingly given the distribution of the cannabinoid receptors throughout the body and not just in the central and peripheral nervous systems.
In particular, we know that the endocannabinoid system has a particular role to play in memory, we know, for example that phyto-cannabinoids particularly THC does impair short term memory, thus it is not surprising that the body’s natural endocannabinoid system also has an effect on memory.
In animal models for example, we know that endocannabinoids can result in a neural growth in the hippocampus which of course, is part of the limbic system and has a particular role to play in memory functions.
The exact role of the endocannabinoid system in memory is undoubtedly complicated.
We know also that the endocannabinoid system is intrinsically involved in the modulation of pain, probably by modulating the effects of the other neurotransmitters involved in pain response such as the noradrenaline and GABA Ergic systems.
We also know that increased endocannabinoid signalling within the central nervous system induces sleep and of course, it can cause daytime drowsiness.
It is probable that anandamide also has an effect on the circadian rhythm certain in animals, and probably in man.
We also know that both anandamide and 2AG have an effect on thermoregulation, particularly through the TRPV1 channels.
The endocannabinoid system is also involved in appetite stimulation.
In mice, for example, where they have had the CB1 receptor knocked out, those animals are less hungry and leaner than the mice that continue to have that receptor.
The endocannabinoid system also has an overall homeostatic effect by the controlling of several metabolic functions such as energy storage and nutrient transport.
It may have a role in modulating insulin sensitivity and thus, in turn, a role in such clinical conditions such as obesity or diabetes, or even atherosclerosis.
We know that the endocannabinoid system is also involved in modulating the stress response, particularly anxiety behaviour.
And finally, there are endocannabinoid receptors in the bladder and in the female and male reproductive systems.
In the uterus for example, the system may have a role in regulating the timing of embryonic implantation and if the anandamide levels are either too high or too low this may have an effect on the likelihood of miscarriage.
In embryonic development, it now appears that the endocannabinoid system plays an essential role in development, at both the implantation of the embryo state and after birth in the initiation of suckling in the newborn. It also appears that levels out of range may increase the chance of miscarriage. According to preliminary research, it seems that a reduction of anandamide (one of the main cannabinoids produced in the body) is necessary for implantation to take place. Whereas the initiation of suckling in the newborn seems to require the activation of CB1 receptors, presumably by the presence of high levels of 2AG1.
Just for interest, we know that anandamide levels are increased in aerobic exercise and we also know that anandamide is a euphoriant, and bring those two together it is likely that the endocannabinoid system is involved in the runner’s high.
Cocoa (used to make chocolate) and maca root (used as a popular health ingredient) are two other kinds of food that affect our endocannabinoid system by inhibiting the enzyme FAAH that breaks down cannabinoids, although neither maca or chocolate contain cannabinoids themselves.
Overall it is very clear that the endocannabinoid system has a wide-ranging role in a great variety of bodily functions and thus it is not surprising that using the plant phyto-cannabinoids which interact with our own endocannabinoid system also have far-reaching effects both positive and negative on many aspects of human disease, symptom management, and behaviour.
- Neuroendocrinology Letters Nos.1/2, Feb-Apr Vol.25, 2004
- Trends in Pharmacological Sciences, July 2016, Vol. 37, No. 7
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