TRPV1: The Paradoxical Pain Receptors of The Endocannabinoid System

One of the less-discussed parts of the endocannabinoid system is the point at which it dovetails with the subsystems that sense pain and burning and activate inflammation response — the TRP or “transient receptor potential” system of neuroreceptors. TRPV1 stands for “transient receptor potential cation channel vanilloid 1.” That’s a big string of nonsense until you understand what “transient receptor potential cation channel” means.

It’s the name applied to 28 different TRP cation channel receptors throughout your body, skin, and limbs that sense pain from heat, chemicals or trauma, and various forms of benign sensory input. They’re all related in that they have a particular type of positive charge (a “cation”) that helps them handle many different kinds of stimuli and chemical ligands (that is, molecules that enter and activate the TRP receptors like keys in locks).

Researchers added “vanilloid 1” as an additional identifier because one of the first chemicals discovered to activate it was similar to vanillin, the stuff that makes vanilla beans taste good. Other TRP channel types are also activated by vanilloids, hence the number designation. 

TRPV1 plays a particular role in heat sensation and pain caused by burns. The spicy compound in chili peppers — capsaicin — activates TRPV1 as well, chemically fooling it into sending a burning sensation to your brain. Mustard and menthol also activate TRPV1.

If your nervous system were an army, your CB1 and CB2 receptors (the two main endocannabinoid receptors) would be high-ranking generals, interacting with government officials and overseeing different combat and reconnaissance operations to make sure they’re running smoothly. TRP receptors, including TRPV1, are the soldiers on the front lines, sustaining casualties from the handle of the hot skillet you just accidentally grabbed, or the Lego you just stepped on in your bare feet, or the hot mustard at the Chinese restaurant, etc.

TRPV1 receptors are also in joints; a 2015 study in Arthritis Research & Therapy looked at the potential for cannabinoids to treat arthritis inflammation.  Furthermore, inflammation initiated by overactive signaling from TRPV1 seems to play a major role in irritable bowel diseases (IBD) like Crohn’s and others. Researchers have traced the effectiveness of cannabis or its distilled cannabinoids in treating IBD, in part, to cannabinoid modulation of TRPV1.

TRPs are responsible for the immediate pain of a burn or other stimulus, as well as telling your body to send backup in the form of chemicals that promote inflammation. One example would be opening blood vessels to increase blood flow to tissue damaged by a burn, making the skin around the injury red and puffy.

“TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides,” states the Arthritis article.

How does cannabis affect TRPV1 receptors?

Phytocannabinoids in cannabis work to reduce inflammation, counterintuitively, by ACTIVATING the TRPV1 receptors. You would think this would lead to more pain and inflammation, right? Well, the opposite is true. The inflammation and pain reduction works because the TRPV1 receptors get flooded with chemicals that plug them up and overwhelm them.

“One feature sought for exploitation from these TRP channels, especially TRPV1, is desensitization,” explains a Frontiers in Molecular Neuroscience study. “TRPV1 becomes rapidly desensitized upon activation, rendering the channel (immune) to further stimulation. This mechanism is thought to underlie the paradoxical (painkilling) effect of TRPV1 and may explain the reduced neuronal activity upon activation of other TRP channels”

Just like any other part of your body heals, your cells have ways to rest and repair the receptors on the cell membranes. Once a TRPV1 receptor is temporarily worn out, the cell internalizes it, or sucks it inside and removes it from operation to recondition it. When this happens to billions of receptors as a result of flooding the system with cannabinoids, there are significantly fewer TRPV1 receptors in operation, meaning significantly less inflammation and pain.

Interestingly, arthritis researchers have been pursuing a parallel approach with capsaicin creams distilled from chili peppers. These work on the same principle to force your cells to internalize TRPV1 receptors, thus reducing inflammation. They aren’t ideal, though, because concentrated capsaicin is dangerous to breathe around or spill on yourself.

But recent research has shown TRPV1 isn’t the only TRP that interacts with cannabinoids. As of 2019, six TRPs from three sub groups of the 28 TRPs studied showed some interaction with cannabinoids, whether plant-based or endogenous.

“The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids,” states the 2019 study published in Frontiers in Molecular Neuroscience. “To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity”

The TRPV1 protein that forms the receptor is coded by the gene of the same name, according to GeneCards.org. This gene is associated with the gene that codes for TRPV4; both came from a single gene in our evolutionary past. Mutations of the TRPV1 gene are associated with bladder disease and somatoform disorders. Somatoform disorders are symptoms that fail to lead clinicians to an underlying physical or neurological cause and are grouped as psychiatric disorders.