Endocannabinoid System

Overview of The TRPV1 Receptor

The TRPV1 receptor is an ion channel that mediates pain perception and transmission in the animal body. It is a member of Transient Receptor Potential subfamily V (vanilloid) cation channels. TRP vanilloid channels, when activated, open to alter intracellular ion concentration and signal to the brain.

In the central nervous system, TRPV1 receptors are in charge of thermoregulation in mammals. In the peripheral nervous system, it responds to noxious heat and acidic conditions, conveying “burning” sensations.

Why is TRPV1 significant

Body temperature and thermoregulation

TRPV1 is the primary control factor of body temperature in mammals. TRPV1 channels are located in the thalamus, the part of the brain that controls body temperature and other basal metrics of homeostasis. In the thalamus, TRPV1 channels register the temperature of blood flowing past them. When the temperature of the blood is warmer than normal, the response of the receptor triggers activity that cools the body down, including induction of sweating.

Likewise, when the blood temperature is colder than usual, the receptor responds by triggering activities that warm the body, including metabolism of brown fat cells and shivering.

Pain perception

Many stimuli are found to act on ion channels present at nociceptor terminals, including TRPV channels. These channels are only found on pain neurons, so when the channels are activated and firing is induced, the signal is interpreted in the brain as pain.

Among all ion channels related to nociception (the perception of pain), the most widely studied receptor is the Transient Receptor Potential Vanilloid 1 receptor of the transient receptor potential (TRP) family.

This receptor is responsible for the “spicy” or “hot” taste of chili peppers, which only act at vanilloid receptors. The molecule responsible for this sought-after sensation is called capsaicin, and it is a potent agonist of TRPV1. Activation of TRPV1 by capsaicin directly causes a flow of ions into the cell, producing an action potential and a sensation of pain. Any molecule that binds to the vanilloid receptor can be classified as a TRPV1 agonist or TRPV1 antagonist depending on the result it produces.

Anandamide and N-Arachidonoyl Dopamine are the body’s two endogenous ligands for this receptor. It is theorized that they both play roles in the pain-relieving and thermoregulatory functions of TRPV1.

TRPV1 receptor structure

The structure of the transient receptor potential vanilloid receptor type 1 has been investigated by scientists and determined to have six transmembrane domains and a pore loop. The pore loop is a short stretch of hydrophobic amino acid residues located between the 5th and the 6th transmembrane domains; this is an essential component for selective ion passage.

Functional TRPV1 receptors are believed to be composed of homomeric or heteromeric complexes resulting in four protein subunits in total. These four subunits assemble in such a way that ions, like calcium and potassium, are able to travel through the pore and through the cell membranes of neurons, epithelial cells, and other cells. The size and characteristics of the pore of an ion channel determine the size and charge of ions that are able to pass through it, as well as the direction (into or out of the cell).

TRPV1 function and location

Research suggests that TRPV1 is a nonselective cation channel which can be stimulated by endogenous and exogenous ligands. TRPV1 is activated by the chemical found in chilis, capsaicin, and also by several endocannabinoids. In addition, acidic conditions and temperatures greater than 109 ℉ (both of which cause a burning sensation) also activate TRPV1 channels. The active flavonoid in mustard & wasabi, allyl isothiocyanate, is a potent agonist of this channel.

Effectively, the function of TRPV1 channels is to protect animals from dangerous acids and temperatures that can cause damage and harm to tissues.

Can TRPV1 be called the CB3 Receptor?

A major reason for the usage of cannabinoids, psychoactive or not, is their ability to elicit a decrease in pain sensitivity. Whether chronic or acute pain, TRPV1 has been implicated in the overall integration of pain signals in the peripheral and central nervous systems. Furthermore, pharmacological elevation of anandamide (AEA) levels have been reported to increase the threshold for pain in rats, meaning they require more of a painful stimulus before pain is perceived.

As previously mentioned, both AEA and N-arachidonoyl dopamine (NADA) are potent agonists of TRPV1. This is posited to be a novel endogenous pain reduction mechanism, as activation of TRPV1 causes subsequent internalization and down-regulation of the receptor, thus reducing total signaling of that receptor type in a given tissue.

Moreover, the role of TRPV1 in thermoregulation coupled with its clear relation to endocannabinoid mechanisms and signaling molecules suggests yet another pathway of the endocannabinoid system in thermoregulation and maintenance of physiological conditions required by other systems of the body.

Taken together, this means TRPV1 is a promising target for pain management therapies moving forward. It also represents an opportunity to expand our understanding of what the endocannabinoid system truly is and how we can use that knowledge to improve health and wellness.