What is the endocannabinoid system? How does the endocannabionide system work?

The endogenous (intracorporeal) cannabinoid system, named after the plant that led to its discovery, is perhaps the most important physiological system involved in creating and maintaining human health.

What is ECS-Endocannabinoid system?

Growing scientific evidence about our physiology was not available to us at school and unfortunately this information is still lacking in most nursing and health schools. The endogenous (intracorporeal) cannabinoid system, named after the plant that led to its discovery, is perhaps the most important physiological system involved in creating and maintaining human health. With the exception of insects, all animals have an Endocannabinoid System (ECS - EKR). It has been discovered that we produce our own cannabinoids, so-called endocannabinoids, which have a similar structure to the compounds found in the cannabis plant; and we have receptors for these molecules. This newly discovered molecular signaling system is essential to life and helps us balance as we face the everyday stress we face. Endocannabinoids and their receptors are found everywhere in the body; in the brain, organs, connective tissues, glands, and immune cells. The endocannabinoid system performs different functions in each tissue, but the goal is always the same: to maintain homeostasis, a stable internal environment despite external environmental fluctuations.

The EKR consists of cannabinoid receptors, associated internally produced molecules (endogenous ligands), and enzymes that synthesize and degrade these molecules.

Cannabioid receptors are G-protein coupled receptors located on cells. The best known cannabinoid receptors are CB1 and CB2, which proved their existence and purpose in the early 1990s. Both types of cannabinoid receptors are found throughout the body, but are distributed differently. CB1 receptors are most abundant in neurons (nerve cells), the brain, the spinal cord, and the peripheral nervous system, as well as other organs in the body. CB2 receptors are found primarily on immune cells, including leukocytes, spleen, and tonsils, but are also present in large numbers in other organs of the body, e.g. in the bed.

We have cannabinoid receptors throughout our body and we have more receptors for cannabinoids than for any other substance. The ECT is the most extensive receptor system in the body. Endocannabinoids bind to cannabinoid receptors in a manner similar to other neurotransmitters and are able to exert various effects through a lock-and-key mechanism-like function. They are able to activate receptors as full or partial agonists (activators), or they can bind to a receptor and act as a neutral antagonist (blocker) that does not activate the receptor; or as an inverse agonist, in which case the receptor is inactivated.

The primary endocannabinoids are anandamide and 2-arachidonoylglycerol (2-AG). Anandamide was discovered in 1992 and found to be an endogenous ligand for the CB1 receptor. Its chemical structure is very similar to that of tetrahydrocannabinol (THC). 2-AG was discovered in 1995 and, unlike anandamide, activates both CB1 and CB2 receptors with high affinity.

Anandamide and 2-AG are synthesized from arachidonic acid, an omega-6 fatty acid. Anandamide is degraded by fatty acid amide hydrolase (FAAH) and 2-AG is degraded by monoacylglyceride lipase. Both endocannabinoids are produced “on demand,” when needed, using precursor molecules on the cell membrane.

The primary function of endocannabinoid activity is to maintain a stable internal environment despite changes in the external environment. This stability is called homeostasis, which endocannabinoids promote at the most basic level. These endocannabinoids regulate homeostasis through a variety of mechanisms, including facilitation of intercellular communication between different cell types.

Endocannabinoids and cannabinoids are also found at the intersection of different systems in the body, thus allowing communication and coordination between different cell types. At the site of injury, for example, cannabinoids can be seen to reduce the release of activators and sensitizers from damaged tissue, stabilize the neuron to prevent excessive firing, and soothe nearby immune cells to prevent the release of inflammatory agents. Three different mechanisms of action, for three different cell types, for a single purpose: to minimize pain and injury.

Cannabinoids promote homeostasis at all levels of biological life, from the subcellular to the organism and presumably to the community and beyond. Here is an example: autophagy is a process in which a cell closes a portion to self-digest and recycle what is mediated by the endocannabinoid system. Although this process keeps normal cells alive, allowing them to maintain a balance between synthesis, degradation, and subsequent recycling of cell products, there is a lethal effect a to malignant tumor cells so that they consume themselves by programmed cell suicide. The death of cancer cells naturally promotes homeostasis and survival at the level of the entire organism.

Evidence suggests that the earliest components of the EQF evolved 600 million years ago in marine sack animals. Furthermore, diseases often develop when there is an endocannabinoid deficiency or disorder. These facts alone demonstrate the importance of proper EQF functioning for the healthy existence of higher level organizations.

The endocannabinoid system, with its intricate activity in our immune system, nervous system, and all organs of the body, is literally a bridge between body and soul. Once we understand this system, we begin to see a mechanism that explains how states of consciousness promote health or disease.

In addition to regulating our internal and cellular homeostasis, cannabinoids influence an individual’s relationship with the external environment. Socially, cannabinoid administration clearly alters human behavior, often supporting sharing, humor, and creativity. Through neurogenesis (the formation of new brain cells), neuronal plasticity, and learning, cannabinoids directly affect an individual’s openness and ability to transcend patterns of thinking and behavior that limit previous situations. Erasing these old patterns is an essential part of health in our rapidly changing environment.

At the time this article was born (February 2015), a search of articles in scientific journals published on PubMed for the past 20 years returned 8,637 hits for the word cannabis. Add the word “cannabinoid” and the number of articles found increases to 20,991. That’s an average of more than two scientific publications a day for the past 20 years! These figures not only show the scientific interest in understanding cannabis and its ingredients and the magnitude of the financial investment, but also emphasize the need for good quality assessments and summaries like this document.

CANNABIONID RECEPTORS

Most have heard of the two cannabinoid receptors, CB1 and CB2. In fact, endocannabinoids can bind to at least 8 additional receptors. The simple view is that there are two receptors in the endocannabinoid system, but some also gossip about a third.

This view of the endocannabinoid system is obsolete in many respects, i.e., incomplete, as the knowledge is already much more advanced. If only the psychotropic effects of cannabis are examined, there is probably no need for a receptor other than the CB1 receptor. However, if we want to address the health effects of cannabis, we need to learn much more.

A brief history of the endocannabinoid system

In the mid-1980s, THC was thought to exert its effects through perturbation of cell membranes. This proved to be wrong in 1988 when it was discovered that cannabinoids could bind to specific receptors in the brains of rats. In 1990, the human CB1 receptor was identified as the primary receptor that mediated the effects of THC.

Of course, we would not have such a receptor without an endogenous ligand. Anandamide (AEA) was the first endocannabinoid to be discovered to activate the CB1 receptor. Unlike many other signaling molecules that are pre-prepared and stored in vesicles awaiting release, anandamide is a lipid molecule that is produced by specific enzymes on demand.

This pioneering research was quickly followed by the discovery of a second cannabinoid receptor, which is most expressed in immune cells, and a second endocannabinoid, named 2-arachidonylglycerol (2-AG).

There is no doubt that the decade from the mid-1980s to the mid-1990s remains one of the most important in the history of cannabinoid research. However, research from the next decade is largely ignored by most cannabis sites.

From the mid-1990s to the mid-2000s, important information was revealed that we rarely hear. For example, the list of endocannabinoids has been expanded to include noladin ether, palmitoylethanolamine (PEA), virodhamine, and oleoylethanolamide (OEA) internal compounds.

More importantly, research on endocannabinoid receptors has been extensive. It is now known that many of the effects of endocannabinoids are not mediated by either the CB1 or CB2 receptors. These include health-related effects such as blood pressure, inflammation, pain, and cancer cell growth. In fact, endocannabinoids can bind directly to at least eight different receptors in addition to CB1 and CB2.

The following is an overview of the different receptors that are either part of the endocannabinoid system or part of another signaling system, but are modulated by endocannabinoids.

Cannabinoid CB1 receptor

The CB1 receptor is the most famous in the endocannabinoid system. This receptor, like the following 4, is part of a group of receptors called G-protein coupled receptors (GPCRs). These receptors are located within the cell membrane and, upon activation, initiate a signaling cascade within the cell that leads to specific effects. The two most common endocannabinoids for CB1 activation are anandamide and 2-AG.

The highest levels of CB1 expression are in the central nervous system. In fact, there are more CB1 receptors in the brain than any other type of GPCR. However, despite being characterized as a “brain receptor,” it is also found in many different tissues in the body: the cardiovascular system, the reproductive, immune system, the gastrointestinal tract, and the peripheral nerves, just to name a few.

In 1999, the first mouse was created with a genetically deleted CB1 receptor (i.e., “CB1 knockout”). An excellent review summarizes the many functions of the CB1 receptor that have been discovered through this approach.

Given the wide distribution of the CB1 receptor, it is not surprising that it appears to be involved in almost everything.

In summary:

• regulates learning and memory,
• neuronal development and synaptic plasticity,
  
• regulates rewards and addictions,
  
• reduces pain
• reduces neuroinflammation and degeneration,
• regulates metabolism and food intake,
  
• regulates bone mass,
  
• cardiovascular effects.

Cannabinoid CB2 receptor

The CB2 receptor is located primarily in the periphery, rather than the central nervous system. It is mainly expressed in immune cells, which plays an important role in inflammation. However, it is now known that CB2 is expressed in a number of cells, including the central nervous system, liver, and bones. CB1 is no longer the only cannabinoid receptor that affects memory and cognition.

The amino acid sequence of the CB2 receptor is relatively similar to the CB1 receptor. Thus, it is not surprising that the CB2 receptor is activated by similar cannabinoids as the CB1 receptor, including anandamide and 2-AG.

Using mice with a genetically deleted receptor, several functions of CB2 have been explored. CB2-deficient mice suffered from severe problems in various disease models:

•  allergic and autoimmune inflammatory diseases
•  osteoporosis (loss of bone mass)
  
•  neurodegenerative diseases
  
•  ischemic injury due to stroke or heart attack
  
•  chronic pain
  
•  liver damage and disease
  
•  alcohol and nicotine addiction
  
•  weight gain
  
•  stress responses
  

Based on these animal data, there is no guarantee that activation of CB2 receptors will help these problems in humans. There is additional non-clinical and clinical evidence for many of these problems.

“Atypical” cannabinoid receptors

We have known for some time that CB1 and CB2 receptors do not mediate all the effects of cannabinoids. How do we know that? Mice with genetically deleted CB1 and CB2 receptors were crossed to create mice that did not have any of these receptors. If cannabinoids did not activate another receptor, there could be no effect of THC or anandamide in these mice.

However, since the first report in 1999, a variety of effects of cannabinoids have been observed in these double knockout mice. For example, cannabinoids are still able to affect blood pressure, pain, inflammation, and gastric motility in the absence of CB1 and CB2 receptors.

At this point, the hunt for new cannabinoid receptors has begun! Since then, we have discovered that endocannabinoids bind to a number of receptors that are not considered part of the endocannabinoid system.

GPR18

This receptor was discovered in 1997, but it has been an “orphan receptor” for years, which means they don’t know what its ligand is. A surprising discovery was made in 2006 - this receptor can be activated with endocannabinoids!

GPR18 can be activated with anandamide, but this major endocannabinoid ligand is N-arachidonylglycine (NAG), a metabolite of anandamide.

The GPR18 receptor is highly expressed in the spinal cord, small intestine, immune cells, spleen, bone marrow, thymus, lung, testes, and cerebellum.

Activation of GPR18 can lower blood pressure and also has significant function in immune cells. It acts as an effective chemoattractant - which means it causes the migration of immune cells.

GPR55

This receptor is similar to GPR18. It was an orphan recipe for years until its ligands were discovered. GPR55 is activated by 2-AG and anandam endocannabinoids, but its major ligand appears to be a more recently putative endocannabinoid called lysophosphatidylinositol (LPI).

This receptor is highly expressed in the central nervous system as well as in the adrenal glands, gastrointestinal tract, lungs, liver, uterus, bladder, and kidneys. Its wide tissue distribution plays a role in many body systems.

GPR55 activation causes hypotension (lowers blood pressure), is anti-inflammatory, and in some cases anti-nociceptive (analgesic). GPR55 regulates energy intake and consumption, which can have an impact on diseases such as obesity and diabetes. It is also expressed in bone cells and may therefore play a role in osteoporosis. GPR55 is neuroprotective and reduces neurodegeneration in multiple sclerosis.

GPR119

GPR119 is expressed in a limited number of tissues. It is found primarily in the pancreas and gastrointestinal tract - suggesting that it may play a role in regulating energy and metabolism.

GPR119 is activated primarily by the OEA endocannabinoid, while others, such as anandamide and 2-AG, are only minimally activated.

Activation reduces food intake, improves blood sugar levels and reduces body weight. These effects appear to be mediated by the regulation of hormones such as insulin and GLP-1.

Vanilloid receptors

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel that is also expressed on sensory neurons and in the brain. In sensory nerves, TRPV1 acts as a sensor for things that could potentially cause tissue damage. It is activated by heat and inflammatory substances, sending a feeling of pain to the brain. The most famous activator of TRPV1 is capsaicin, a component of chili peppers that cause burning pain. TRPV1 dysregulation also plays a role in chronic pain.

Interestingly, anandamide is a TRPV1 channel activator. Sensory neurons often co-express both the CB1 receptor and the TRPV1 receptor, making clear the role of anandamide in the generation of pain signals.

Serotonin receptors

There are several serotonin (5-HT) receptor subtypes that mediate the various effects of serotonin. The 5-HT3 subtype is unique among 5-HT receptors in that it is a ligand-gated ion channel instead of a GPCR.

The 5-HT3 receptor is best known for mediating nausea and vomiting, especially after chemotherapy. Many anti-nausea drugs work by blocking this ion channel. It also plays a role in neuropathic pain.

Anandamide binds directly to the 5-HT3 receptor and inhibits its activation. However, it does not work by blocking the main serotonin binding site of the receptor. Instead, it binds to another site on the receptor and acts as a negative allosteric modulator. In other words, it alters the conformation of the receptor to minimize 5-HT activation.

Inhibition of 5-HT3 is at least partly responsible for the analgesic effects of cannabinoids that are not mediated through conventional CB1 or CB2 receptors.

Glycine receptors

Glycine receptors (GlyRs) are ligand-gated ion channels that inhibit nerve activation. GlyRs are expressed in the spinal cord, where they regulate the transmission of pain to the brain.

Anandamide is able to bind directly to GlyRs and increase channel activation. Anandamide does not bind to the major agonist site and is unable to activate GlyRs alone. Like the 5-HT3 receptor, anandamide acts as an allosteric modulator. It binds at another site on GlyR and enhances glycine activation

This is another mechanism by which endocannabinoids can reduce spinal cord pain in a manner independent of CB1 and CB2 receptors.

Peroxisome proliferator-activated receptors

Peroxisome proliferator-activated receptors (PPARs) are fundamentally different from the receptors described above. Instead of being located within the cell membrane, PPARs are located within the cell, can bind directly to DNA sequences, and alter the transcription of targeted genes. PPARs have three isoforms: α, β, and γ.

Anandamide and 2-AG have the potential to activate PPARα, but the activating effect of OEA and PEA endocannabinodes is much stronger. Anandamide and 2-AG are also able to activate PPARγ.

PPARs regulate cellular functions in almost all tissues. Some of the effects of endocannabinoids attributable, at least in part, to PPARα or PPARγ activation include neuroprotective effects against ischemia and neurodegeneration, decreased nicotine dependence, analgesia, antitumor effects, vasorelaxation, weight loss, and reduced inflammation.

Interestingly, there are already approved drugs that act through PPARα activation (to treat cholesterol disorders and triglyceride metabolism) and through PPARγ activation (to treat insulin resistance and lower blood sugar).

Other possible endocannabinoid targets

Other potential targets for endocannabinoids have also been identified. However, it is not clear whether these play a significant role in the effects of endocannabinoids. These include voltage-gated ion channels, NMDA receptors, acetylcholine receptors, and glycine transporters.