A Detailed Review Of Cannabinoid Receptors

What are cannabinoid receptors?

Cannabinoid receptors are one of the three major components of the endocannabinoid system, alongside endocannabinoids and their enzymes. These structures serve as binding sites for both endocannabinoids and external phytocannabinoids. When activated, cannabinoid receptors trigger cellular signalling pathways that catalyse physiological changes.

Cells, such as neurons, feature many different receptor types on their surfaces. However, a molecule needs to be the right fit in order to bind to a certain receptor—much like a lock and key. Molecules that “fit” just right are referred to as a ligand of that receptor.

As their name suggests, only cannabinoids can latch onto cannabinoid receptor sites. When they do, they cause local changes within the cell, as well as more widespread changes by altering chemicals that a particular cell releases.

More specifically, cannabinoid receptors are known as G protein-coupled receptors (GPCRs). These receptors exist in the cell membrane in an inactive state. During this time, a so-called G protein remains attached to the side of the receptor inside the cell. When a ligand makes contact, the G protein associated with the receptor initiates the first changes to occur inside the target cell.

A deeper look at cannabinoid receptors

There are two primary cannabinoid receptor types: CB1 and CB2. However, research also posits the existence of a third, “orphan” cannabinoid receptor. Known as GPR55, endocannabinoids have been shown to bind to this novel site.

The endocannabinoid system plays a very important role in maintaining homeostasis—biological balance—within the human body, and cannabinoid receptors play a large role in this function.

The comprehensive network helps to regulate other bodily systems, including the nervous system, endocrine system, and immune system. Cannabinoid receptors in these locations play a large role in the “master regulator” status of the endocannabinoid system.

Let’s explore the two primary cannabinoid receptors, their role in the body, and how CBD affects them both.

The CB1 receptor

CB1 receptors are found largely within the brain. They appear in regions such as the hippocampus, hypothalamus, and amygdala. These receptor sites also occur in the following areas:

• Central nervous system
• Peripheral nervous system
• Immune system
• Gastrointestinal tract
• Skeletal muscles
• Liver
• Reproductive system
• Cardiovascular system

CB1 receptors are mainly concentrated at presynaptic nerve terminals and are activated as endocannabinoids travel “backwards”—in retrograde fashion—across the synaptic cleft.

This unique modus operandi contributes to the regulatory role of this system, allowing endocannabinoids and cannabinoid receptors to change incoming signals from neurons downstream.

Several phytocannabinoids, endocannabinoids, and synthetic cannabinoids bind to CB1 receptors as agonists, meaning they activate it and cause some sort of action.

Endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) bind to CB1 receptors, but with different levels of potency. AEA binds as a partial agonist with high affinity, whereas 2-AG binds as a full agonist with moderate-to-low affinity.

As the primary psychoactive constituent of cannabis, THC binds to the CB1 receptor to produce psychotropic effects. Upon binding, THC exerts its effects on emotion, reward, and memory processing.

A whole host of synthetic cannabinoids also have the ability to bind to the CB1 site.

Once a ligand binds to CB1 receptors, a wide range of physiological changes can occur. Overall—governed by ligand release—the CB1 receptor is involved in a wide range of important functions, such as:

• Learning, memory, and cognition
• Reward and addiction
• Sleep
• Neuroprotection
• Energy metabolism
• Vasodilation
• Cardiac function
• Pain signalling
• Bone remodelling
• Intraocular pressure

CB2 receptor

CB2 receptors are much less widespread than their CB1 counterparts. These receptors exist mainly on immune cells such as microglia, osteoclasts, and osteoblasts. They also appear on neurons throughout the nervous system.

CB2’s presence within the immune system suggests that the site plays a regulatory role herein. Thus far, activation of the receptor has shown promise in the treatment of inflammatory diseases in animal models.

Various endocannabinoids and phytocannabinoids act as ligands of the CB2 receptor. These include:

• 2-AG
• Caryophyllene (a terpene produced in cannabis flowers)

As with the CB1 receptor, an array of synthetic cannabinoids also activate this receptor site.

The activation of CB2 receptors also clearly plays an important role in maintaining homeostasis in the human body. Research suggests the site could be targeted in the future treatment of:

• Acute pain
• Chronic inflammatory pain
• Neuropathic pain
• Neuroinflammation
• Neurodegeneration
• Multiple sclerosis
• Huntington’s disease
• Inflammatory bowel diseases
• Liver cirrhosis

How are cannabinoid receptors influenced by CBD?

CBD influences both CB1 and CB2 receptors. Although research has yet to conclusively pinpoint its mechanism of action, CBD has been shown to act as an allosteric modulator, weak antagonist, and inverse agonist of cannabinoid receptors.

Essentially, this means the cannabinoid might block or interfere with these receptors to some degree, and also change the way they respond to other ligands.

CBD might indirectly activate the CB1 receptor by ramping up levels of the ligand AEA. The cannabinoid stops enzymes from breaking down AEA and also stops the reuptake of the endocannabinoid.

CBD works as an inverse agonist of the CB2 receptor, meaning it lowers receptor activity. This mechanism may enable CBD to influence immune cells in a beneficial way.

CBD may also antagonise the novel third cannabinoid receptor. However, this hypothesis requires further clarification.

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