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TRP Channels: The Expanded Endocannabinoid System

Cannabis 101, Cannabis Science / by

Cannabis sprout
Cannabis sprout.

As it currently stands, the endocannabinoid system only consists of CB1 and CB2 receptors. However, there are several cannabinoids with therapeutic properties that hardly bind to these receptors at all. 

For example, non-psychoactive cannabinoids such as CBD and CBG don’t display very much interaction with your CB1 and CB2 receptors. Yet, we know CBD and CBG both have anti-inflammatory effects, among others. 

If multiple major cannabinoids aren’t interacting with CB1 and CB2 receptors, where do they go in the body? What receptors are they communicating with to wield their therapeutic effects?

That’s where transient receptor potential channels come into play.

What Are TRP Channels?

Transient receptor potential channels — better known as “TRP Channels” — are a group of proteins on the surface of cells. TRP channels transduce electrical and chemical signals that communicate temperature, pH levels, smell, taste, and vision to the brain and nerve cells (neurons). 

Certain TRP channels also affect how you perceive pain, which is relevant to how cannabinoids interact with these proteins. 

See, there are three main types of TRP channels: 

  1. TRP Vanilloid (TRPV)
  2. TRP ankyrin (TRPA)
  3. TRP melastatin (TRPM)

Across all three categories, there are 28 different types of TRP channels. But cannabinoids only seem to target six of them thus far.

These six TRP channels are sometimes referred to as “ionotropic cannabinoid receptors,” and they include:

  • TRPV1: This TRP channel is found in the root of spinal cord nerves, which carry sensory information from the nerves throughout your body to your brain. TRPV1 is heavily involved in the sensation of pain and itchiness. There are also several studies currently exploring how substances that affect TRPV1 channels could provide pain relief. 
  • TRPV2: TRPV2 is “ubiquitously expressed in almost all types of cells, but especially high expression levels were found in the brain, lung, and spleen,” says a review in the Cellular Physiology & Biochemistry Journal. TRPV2 is implicated in homeostasis, cardiovascular function, immunity, and inflammation. 
  • TRPV3: TRPV3 is found in the brain, spinal cord, and skin. This TRP channel helps maintain the skin barrier and regulates inflammation, pain, as well as itchiness. 
  • TRPV4: This TRP channel is found in the brain, kidneys, urinary tract, musculoskeletal system, and lungs. It is believed that TRPV4 plays an important role in sensing internal body temperature. TRPV4 also appears to play a vital role in the immune response to lung injury and inflammation. 
  • TRPA1: TRPA1 is found in “pain-sensing neurons.” This TRP channel also appears to react to irritating substances that trigger inflammation. Currently, researchers are investigating TRPA1 as a potential target for therapies that would decrease pain and inflammation. 
  • TRPM8: This TRP channel is found throughout various organs and bodily systems, including the nervous system (brain and spinal cord) as well as the immune system. TRPM8 reacts to cold temperatures. Studies show TRPM8 may also be involved in taste, inflammation, sensing oxidative stress, and regulating homeostasis.

How Are TRP Channels Relevant to Cannabis?

Major cannabinoids such as CBD, THC, CBG, and CBDV all appear to interact with the six TRP channels defined above. While reading through the definitions of those six TRP channels, what’s the one thing they all seem to have in common?

Each of the aforementioned TRP channels affects inflammatory signaling and pain perception. 

To dive into their relation a little further, so far it’s known that each cannabinoid interacts with the following TRP channels:

  • Δ9-THC has the most potent effects on TRPV2. THC also has moderate effects on TRPV3, TRPV4, TRPA1, and TRPM8.
  • Δ9-THCV affects TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8.
  • CBD has the most potent effects on TRPV1 and TRPM8. CBD also affects TRPV2, TRPV3, and TRPA1.
  • CBDV affects TRPV1, TRPV2, TRPV4, TRPA1, and TRPM8.
  • CBG affects TRPV1, TRPV2, TRPV4, TRPA1, and TRPM8.
  • CBN affects TRPV2, TRPV4, TRPA1, and TRPM8.
  • CBC affects TRPA1 and TRPM8.

Many experts theorize the anti-inflammatory and pain-relieving effects of cannabinoids could be — at least in part — due to their interactions with TRP channels. This theory has immense potential to further our understanding of the therapeutic effects of cannabinoids.

Ultimately, research in this field provides an opportunity to reshape medicinal cannabis practices. These insights would help product specialists make more informed recommendations when you enter the dispensary.

What is the Expanded Endocannabinoid System?

The “expanded endocannabinoid system” is the idea that the ECS as it stands should be updated to include more than just CB1 and CB2 receptors. Many researchers propose this expanded definition should include TRP channels and the “endocannabinoidome.” 

The endocannabinoidome includes CB1 & CB2 receptors, endocannabinoids, “endocannabinoid-like mediators,” and the enzymes that metabolize endocannabinoids. 

These additions to the current definition of the endocannabinoid system would provide a more holistic and comprehensive way to understand the relationship between cannabinoids and our bodies. 

Furthermore, expanding the endocannabinoid system could help unveil how cannabinoids that don’t target ECS receptors exert their effects on the body. 

Key Takeaway: Redefining the Endocannabinoid System Through TRP Channels

Cannabis bush at sunset
Cannabis bush at sunset.

TRP channels are proteins on the surface of your cells that communicate various sensations, such as temperature, pain, and taste, to your brain. Furthermore, many TRP channels are integral to immune functioning and inflammatory regulation. 

Most importantly, cannabinoids have positive interactions with TRP channels that could explain the pain-relieving effects of CBD, THC, and so forth.  

While the endocannabinoid system regulates a variety of functions regardless of cannabis use, its current definition falls short in some areas. For example, many believe all cannabinoids interact with the ECS. However, that isn’t true — only THC and THCV affect ECS receptors, leaving experts to wonder what other bodily systems the rest of the cannabinoids are interacting with. 

Thus, many researchers have proposed expanding the endocannabinoid system to include other areas of the body, such as TRP channels. Further research on the relationship between cannabinoids and TRP channels present an opportunity for us to better understand how and why medicinal cannabis works. 

References

  1. Think About Cannabis. (2022, February 13). CBG: The Mother of All Cannabinoids. https://thinkaboutcannabis.com/cannabis-science/cbg-the-mother-of-all-cannabinoids 
  2. Think About Cannabis. (2022, February 16). The Science & Mystery Behind CBD. https://thinkaboutcannabis.com/cannabis-science/the-science-mystery-behind-cbd 
  3. Muller, C., Morales, P., & Reggio, P. H. (2019). Cannabinoid Ligands Targeting TRP Channels. Frontiers in Molecular Neuroscience, 11. https://doi.org/10.3389/fnmol.2018.00487 
  4. Li, F., & Wang, F. (2021). TRPV1 in Pain and Itch. Ion Channels in Biophysics and Physiology, 249–273. https://doi.org/10.1007/978-981-16-4254-8_12 
  5. Seebohm, G., & Schreiber, J. A. (2021). Beyond Hot and Spicy: TRPV Channels and their Pharmacological Modulation. Cellular Physiology and Biochemistry, 55(S3), 108–130. https://doi.org/10.33594/000000358 
  6. Scheraga, R. G., Southern, B. D., Grove, L. M., & Olman, M. A. (2020). The Role of TRPV4 in Regulating Innate Immune Cell Function in Lung Inflammation. Frontiers in Immunology, 11. https://doi.org/10.3389/fimmu.2020.01211 
  7. Meents, J. E., Ciotu, C. I., & Fischer, M. J. M. (2019). TRPA1: a molecular view. Journal of Neurophysiology, 121(2), 427–443. https://doi.org/10.1152/jn.00524.2018 
  8. Izquierdo, C., Martín-Martínez, M., Gómez-Monterrey, I., & González-Muñiz, R. (2021). TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation. International Journal of Molecular Sciences, 22(16), 8502. https://doi.org/10.3390/ijms22168502 
  9. Marzo, D. V. (2015, August 14). The Endocannabinoid System and its Modulation by Phytocannabinoids. SpringerLink. https://link.springer.com/article/10.1007/s13311-015-0374-6?error=cookies_not_supported&code=f173545d-9724-4887-9dd3-bc6d1482a0dc 
  10. Think About Cannabis. (2022, March 1). Endocannabinoids vs. Phytocannabinoids. https://thinkaboutcannabis.com/cannabis-science/endocannabinoids-vs-phytocannabinoids