Genomics: Insight

The Relationship between TRPV1 and Pain

In 2021, Dr. David Julius and Dr. Ardem Patapoutian won the Nobel Prize in Physiology or Medicine for their discovery of receptors for temperature and touch1. Within this Nobel-prize winning science, the discovery of the TRPV1 receptor has been integral to providing fundamental insights into the mechanisms of pain. TRPV1, an ion channel in the TRP-receptor family, is activated by capsaicin, noxious thermal stimuli, and low pH2. The channel has been observed to have an outsized impact on the pain pathway. In a study conducted by the University of California, San Francisco, Julius et al. built a connection between TRPV1 activation and pain. Pain is the activation of specific sensory neurons by noxious stimuli. The activation of the TRPV1 channel stimulates these sensory neurons, called nociceptors, alerting pain-processing centers in the brain and spinal cord of possible tissue damage. Further studies, also conducted by Julius et al., have confirmed the causal relationship between TRPV1 and pain sensation3. By comparing mice that lacked the TRPV1 receptor with control mice, researchers observed that mice without the TRPV1 receptor were deficient in their response to noxious stimuli, including capsaicin, heat, or protons, all of which produced a response in the pain pathway for the control mice. In the world of pain management, effectively modulating the TRPV1 receptor gene could provide relief to patients. A current application of modulating the TRPV1 receptor is Centrexion Therapeutics STRATI technology, which rapidly inactivates local pain fibers that transmit signals to the brain4. By injecting a synthetic form of capsaicin into patients, the treatment provides temporary pain relief, until the nociceptors regenerate. This paper will examine another TRPV1 channel modulator, splice variant TRPV1b (an alternate version of TRPV1). When the variant is co-expressed with TRPV1, in vitro results show TRPV1b’s potential to negatively regulate TRPV1. 

The channel has been observed to have an outsized impact on the pain pathway. At a time when opioid addiction levels are a serious concern in society, alternative, non-toxic pain management methods need to be deeply researched.

Study Indicating TRPV1b Unresponsiveness to Noxious Stimuli

In a study conducted by Han, et al., researchers used HEK293, human embryonic kidney cells, to first test the responsiveness of TRPV1 and TRPV1b against noxious stimuli5. The researchers, using RT-PCR, first investigated the presence of TRPV1 and TRPV1b mRNA in different human tissues. The highest expression was in the dorsal root ganglia (DRG). Considering this observation, the researchers cloned the TRPV1b from human DRG RNA.

The researchers tested the responses of the two channels to capsaicin, pH, and thermal stimuli. In response to 1µm of capsaicin, the functional activity of TRPV1, measured in terms of pA, is more than 4000pA compared with TRPV1b, which does not respond with any signal. TRPV1b mirrors exactly the behavior of the vector-transfected cell, a cell without either receptor. A similar disparity in responsiveness is observed where the channels are exposed to an acidic pH of 5.0. Although all tested cells show a current (even the vector cell), there is an overwhelming difference in peak current. While TRPV1 produces a signal of over 5000pA, the peak current of TRPV1b is around 1000pA, a fivefold difference in responsiveness. Against 50˚C heat, a stark contrast between TRPV1 and TRPV1b is observed as well. While TRPV1 can generate an electric response of over 600pA, TRPV1b responses are less than 200pA, mirroring the response of the vector cell.

Next, TRPV1 and TRPV1b protein expression was measured in HEK293 cells transfected with TRPV1 plasmid or together with TRPV1b plasmid. In the presence of 50nM capsaicin, percent activity ranged from 100% to less than 10% with the expression of 20x TRPV1b plasmid. In the presence of a pH of 5.0,100% activity dipped to 20% activity when co-expressed with 20x TRPV1b plasmid. In the presence of 50˚C heat, 100% activity decreased to 50% activity under 20x TRPV1b plasmid presence.

TRPV1 Modulation: A Promising Pain Management Alternative Amidst the Opioid Crisis

At a time when opioid addiction levels are a serious concern in society, alternative, non-toxic pain management methods need to be deeply researched. TRPV1b, after initial in vitro tests, has shown promising results as a modulator of TRPV1 mediated responses to noxious stimuli. Considering TRPV1b is found naturally occurring in not only the DRG but also prominently in the fetal brain and cerebellum, the use of TRPV1b as a pain management tool should warrant further research.

References

1. Grunenthal. “The 2021 Nobel Prize for Medicine Was Awarded for the Discovery of the TRPV1 Receptor.” www.grunenthal.com, October 7, 2021. https://www.grunenthal.com/en/press-room/stories/nobel-prize-for-medicine-2021-trpv1.
2. Caterina, Michael J., Mark A. Schumacher, Makoto Tominaga, Tobias A. Rosen, Jon D. Levine, and David Julius. “The Capsaicin Receptor: A Heat-Activated Ion Channel in the Pain Pathway.” Nature 389, no. 6653 (October 1997): 816–24. https://doi.org/10.1038/39807.
3. Caterina, M. J. “Impaired Nociception and Pain Sensation in Mice Lacking the Capsaicin Receptor.” Science 288, no. 5464 (April 14, 2000): 306–13. https://doi.org/10.1126/science.288.5464.306.
4. Centrexion Therapeutics. “Centrexion Therapeutics to Present Data on CNTX-4975 for the Treatment of Chronic Pain Associated with Morton’s Neuroma and Knee Osteoarthritis at American Pain Society 2017 Annual Scientific Meeting,” 2017. https://centrexion.com/wp-content/uploads/2017/05/Centrexion_Therapeutics_to_Present_Data_on_CNTX-4975_for_the_Treatment_of_Chronic_Pain_Associated_with_Mortons_Neuroma_and_Knee_Osteoarthritis_at_American_Pain_Society_2017_Annual_Scientific_Meeting1.pdf.
5. Vos, Melissa H., Torben R. Neelands, Heath A. McDonald, Won Choi, Paul E. Kroeger, Pamela S. Puttfarcken, Connie R. Faltynek, Robert B. Moreland, and Ping Han. “TRPV1b Overexpression Negatively Regulates TRPV1 Responsiveness to Capsaicin, Heat and Low PH in HEK293 Cells.” Journal of Neurochemistry 99, no. 4 (November 2006): 1088–1102. https://doi.org/10.1111/j.1471-4159.2006.04145.x.