What is the Endocannabinoid System?

Updated: May 21, 2019

The endocannabinoid system (ECS) is thought to be 600-million-years-old. It is present in every animal species, except insects, and is one of the most evolutionarily preserved biological systems known.1 The ECS consists of four primary components: 1. Cannabinoid receptors (i.e. CB1, CB2); 2. Endocannabinoids (i.e. Internally produced compounds which interact with cannabinoid receptors); and 3-4. Enzymes that both synthesize and degrade endocannabinoids.

It is fun to think that our bodies produce the same psychotropic compounds we seek from the Cannabis plant when we use it for “recreational” purposes. This is not technically correct however. We don’t produce THC or CBD – which are phytocannabinoids - but we do produce compounds that are structurally similar. The compounds that we produce are called endocannabinoids. Endocannabinoids interact with cannabinoid receptors in a similar fashion as THC and other phtyocannabinoids.

The ECS is an internal regulatory system which functions to restore homeostasis, or equilibrium, following a cellular stressor. The ECS communicates with all other systems in the body, perhaps most importantly, with the central and peripheral nervous systems (i.e. CNS, PNS respectively).

There are two types of cannabinoid receptorsCB1 and CB2. Both are G protein-coupled receptors (GPCRs). The CB1 receptor is THE most densely populated receptor in the human central nervous system.2

It is important to note that CB1 receptors are noticeably absent in the brain stem, which is why cannabis does not suppress respiration. The most common cause of opioid overdose mortality is respiratory suppression mediated by opioid receptors in the respiratory center in the brainstem. This is not a risk with cannabis.

To simplify, the geographical distribution of the two types of cannabinoid receptors in the human body is described as follows (See Figure 1):

CB1 receptors are mostly located in the CNS and PNS

CB2 receptors are mostly located in the periphery, on organs and on immune cells

In truth, their distribution is more complex.

Figure 1

It is important to note that CB1 receptors are noticeably absent in the brain stem, which is why cannabis does not suppress respiration. The most common cause of opioid overdose mortality is respiratory suppression mediated by opioid receptors in the respiratory center in the brainstem. This is not a risk with cannabis.

To a large degree, the effects of cannabinoids – both endogenous and exogenous (i.e. Phyto and pharmaceutical cannabinoids) - are determined by the location and density of these cannabinoid receptors (See Figure 2).

Figure 2

Cannabinoid receptors in the amygdala, for example, mediate mood and emotional responses. Cannabinoid receptors in the cerebral cortex mediate cognition, motor and sensory function, and learning/memory. Cannabinoid receptors in the hypothalamus mediate appetite. There are many other examples.

While the ECS is often described as a “neuroregulatory system”, it is much more than that. Neuroregulation, however, is a useful starting point for describing how this system works.

Neuroregulation

Neurons communicate with one another via chemical messengers called neurotransmitters. Dopamine, serotonin, glutamate and norepinephrine are all examples of neurotransmitters. These chemicals are mostly peptides – small proteins – and are stored in vesicles (i.e. Small fluid-filled sacs) at the distal end of neurons. When a signal is propagated to the end of a neuron (i.e. Presynaptic neuron), neurotransmitters are released and travel across the synapse to awaiting receptors on the next neuron (i.e. Postsynaptic neuron) (See Figure 3).

Figure 3

Once bound to a receptor, an electrochemical cascade is often initiated inside that neuron. This then induces some physiological effect in the neuron itself and beyond. Unlike most neurotransmitters, endocannabinoids are fatty acids, not peptides, and they are synthesized on demand, as opposed to being synthesized ahead of time and stored in vesicles. Another important difference is the direction they travel. Endocannabinoids diffuse in a “retrograde” fashion, meaning they travel from the post-synaptic neuron to the pre-synaptic neuron.3 The opposite direction of traditional neurotransmitters. This retrograde transmission is key in understanding the neuroregulatory effect (See Figure 4).

Figure 4

Endocannabinoids bind to cannabinoid receptors on the pre-synaptic neuron and basically tell that nerve to stop secreting other neurotransmitters, like glutamate for example. Glutamate is an excitatory neurotransmitter. This means that it leads to excitation, or firing, of subsequent neurons. When endocannabinoids bind to cannabinoid receptors on the pre-synaptic neuron, vesicles stop spilling their glutamate into the synapse. This is the way that endocannabinoids regulate transmission of other neurotransmitters. This mechanism is often referred to as Depolarization-Induced Suppression of Excitation (or Suppression of Inhibition when referring to inhibitory neurotransmitters).

Depolarization-Induced Suppression of Excitation is one of the ways that the ECS protects the nervous system from hyperactivity during seizures. In fact, excessive secretion of glutamate (i.e. Excitotoxicity) is a common feature of many neurodegenerative diseases (e.g. Parkinson's, Alzheimers).

Endocannabinoids are produced on-demand during periods of inflammation, or whenever there is a chemical, mechanical or thermal insult that disrupts the normal function of a cell. In this way, the endocannabinoid system is thought to return a stressed cell to homeostasis, a more balanced state.

Autocrine and paracrine regulation A lesser known function of the endocannabinoid system is autocrine and paracrine regulation. Autocrine regulators are substances produced by a cell that regulate the cell itself. Paracrine regulators are substances produced by a cell that regulate nearby cells. Examples of autocrine and paracrine regulation often occur in the immune system (See Figure 5).

Figure 5

In an inflammatory state, as depicted in Figure 4, white blood cells (i.e. Immune cells), like mast cells and macrophages, infiltrate surrounding tissues and secrete inflammatory substances (e.g. Cytokines, like TNF-alpha). Endocannabinoids are produced on-demand during periods of inflammation, or whenever there is a chemical, mechanical or thermal insult that disrupts the normal function of a cell. In this way, the endocannabinoid system is thought to return a stressed cell to homeostasis, a more balanced state.

Figure 5 depicts a macrophage secreting anandamide, one of the principal endocannabinoids. Anandamide interacts with cannabinoid receptors on two different targets – the macrophage itself (Autocrine) and a nearby mast cell (Paracrine). This causes a decrease in the production and secretion of TNF-alpha and other inflammatory chemicals. Ultimately, this leads to decreased inflammation and reduced infiltration of other inflammation-producing white bloods cells.

A third target is also depicted in Figure 5, a nerve cell (i.e. Neuron) from the myenteric plexus. The myenteric plexus is largely responsible for mediating motility - or movement - in the gastrointestinal tract. Here, anandamide binds to CB1 receptors on neurons of the myenteric plexus. This leads to a decrease in the production and secretion of acetylcholine and tachykinin (i.e. Other neurotransmitters). Acetylcholine mediates smooth muscle contraction in the gut. When its production and secretion is inhibited, motility in the gut in slowed. This is the mechanism by which cannabinoids reduce gut motility. This can be either therapeutic, like in the presence of diarrhea, or counterproductive, like in the presence of constipation.

The Bottom Line The ECS is an internal regulatory system which functions to restore homeostasis following a cellular stressor. The ECS communicates with all other systems in the body, perhaps most importantly, the central and peripheral nervous systems. We are learning more and more about the critical role the ECS plays in both physiological and pathological states. Stay tuned!

References:

1. McPartland JM, Matias I, Di Marzo V, Glass M. Evolutionary origins of the endocannabinoid system. Gene. 2006;370:64-74. 2. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77(2):299-318. 3. Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain injury: therapeutic implications. Trends Mol Med. 2002;8(2):58-61.

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