In the mid 1980s, researchers at St. Louis University made two groundbreaking discoveries that transmogrified our paradigm of human biology. The first finding was that cannabinoids inhibit adenylate cyclase (a cellular enzyme) through Gi/o proteins. This is signal transduction, and it requires cellular receptors. The second finding was that radiolabelled synthetic cannabinoids demonstrated high affinity for cerebral binding sites .
The implication was clear: the brain has its own endogenous receptors for cannabinoids. G-protein coupled CB1 and CB2 receptors were confirmed shortly thereafter, and a new biological system was announced: the endocannabinoid system (ECS) .
CB1 receptors are located predominantly at nerve terminals (central and peripheral) and moderate neurotransmitter release. Their distribution correlates to effects related to hypokinesia, catalepsy, and analgesia .
CB2 receptors are positioned prevailingly on immune cells; they regulate cytokine release and cell migration and are associated with inflammation [1-2].
Cannabinoid receptors are among the most abundant receptors in the human brain. They are connected to neurodegeneration, epilepsy, and cognitive deficiencies. These receptors are present in other locations in the body, such as the liver, bones, muscles, and heart, where they exert a plethora of physiological effects [2-4].
Cannabinoids also influence TRPV1 receptors on sensory neuron fibers that help regulate body temperature [4-5]. The ECS additionally likely involves novel G protein-coupled receptors and CB1 allosteric sites .
Figure 1: Sites and Actions of the ECS. Source: Zou S and Kumar U. (2018)
Of course, if there are endocannabinoid receptors, there must be endocannabinoids. The human body synthesizes the lipid neurotransmitters anandamide (named after the Sanskrit ananda for ‘bliss’) and 2-arachidonoyl glycerol (2-AG) as required, but they are rapidly cleared via enzymatic activity. At CB1 sites, these endocannabinoids modulate neurotransmission. At CB2 sites, they moderate immune cell activity .
Anandamide activates the TRPV1 receptor . Given that TRPV1 receptors detect pain stimuli, their inhibition or desensitization reduces pain [5,7].
The Endocannabinoid System: Big Picture
The endocannabinoid system plays a major role in pain signaling pathways. We can interpret the ECS as a modulatory system for pain and stress. It is also pivotal in brain and endocrine function . We might think of the ECS as a biological stabilizer when the human organism encounters imbalance.
If the body suffers a lack of endocannabinoids for whatever reason, the result is clinical endocannabinoid deficiency. This condition has been connected to chronic migraine, irritable bowel syndrome, fybromalgia, and other illnesses . Stimulating and upregulating the ECS has significant therapeutic promise.
In this primer, we covered only the surface of this complex and fascinating system. Our understanding of the ECS has amplified in subsequent decades, but much elucidation remains.