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  • Top
  • Abstract
  • Hurdles for treating chronic pain through targeting of TRPV1
  • TRPV1-targeted, hyperthermia-free inhibition of pathological pain
  • Individuals lacking functional TRPV1
  • Lessons for hyperthermia-free analgesia
  • Conclusion
  • Acknowledgments
  • Footnotes
  • References
  • Version history
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  • Citations to this article

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Commentary Open Access | 10.1172/JCI167338

Striving toward hyperthermia-free analgesia: lessons from loss-of-function mutations of human TRPV1

Tingting Li and Man-Kyo Chung

Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Program in Neuroscience, Center to Advance Chronic Pain Research, Baltimore, Maryland, USA.

Address correspondence to: Man-Kyo Chung, University of Maryland, School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St. 8-South, Baltimore, Maryland 21201, USA. Phone: 410.706.4452; Email: mchung@umaryland.edu.

Find articles by Li, T. in: JCI | PubMed | Google Scholar

Department of Neural and Pain Sciences, School of Dentistry, University of Maryland, Program in Neuroscience, Center to Advance Chronic Pain Research, Baltimore, Maryland, USA.

Address correspondence to: Man-Kyo Chung, University of Maryland, School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St. 8-South, Baltimore, Maryland 21201, USA. Phone: 410.706.4452; Email: mchung@umaryland.edu.

Find articles by Chung, M. in: JCI | PubMed | Google Scholar |

Published February 1, 2023 - More info

Published in Volume 133, Issue 3 on February 1, 2023
J Clin Invest. 2023;133(3):e167338. https://doi.org/10.1172/JCI167338.
© 2023 Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 1, 2023 - Version history
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Nociception and pain in humans lacking a functional TRPV1 channel
Ben Katz, … , Alexander M. Binshtok, Baruch Minke
Ben Katz, … , Alexander M. Binshtok, Baruch Minke
Clinical Medicine Neuroscience

Nociception and pain in humans lacking a functional TRPV1 channel

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Abstract

BACKGROUND Chronic pain is a debilitating illness with currently limited therapy, in part due to difficulties in translating treatments derived from animal models to patients. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with noxious heat detection and inflammatory pain, and reports of adverse effects in human trials have hindered extensive efforts in the clinical development of TRPV1 antagonists as novel pain relievers.METHODS We examined 2 affected individuals (A1 and A2) carrying a homozygous missense mutation in TRPV1, rendering the channel nonfunctional. Biochemical and functional assays were used to analyze the mutant channel. To identify possible phenotypes of the affected individuals, we performed psychophysical and medical examinations.RESULTS We demonstrated that diverse TRPV1 activators, acting at different sites of the channel protein, were unable to open the cloned mutant channel. This finding was not a consequence of impairment in the expression, cellular trafficking, or assembly of protein subunits. The affected individuals were insensitive to application of capsaicin to the mouth and skin and did not demonstrate aversive behavior toward capsaicin. Furthermore, quantitative sensory testing of A1 revealed an elevated heat-pain threshold but also, surprisingly, an elevated cold-pain threshold and extensive neurogenic inflammatory, flare, and pain responses following application of the TRPA1 channel activator mustard oil.CONCLUSION Our study provides direct evidence in humans for pain-related functional changes linked to TRPV1, which is a prime target in the development of pain relievers.FUNDING Supported by the Israel Science Foundation (368/19); Teva’s National Network of Excellence in Neuroscience grant (no. 0394886) and Teva’s National Network of Excellence in Neuroscience postdoctoral fellowship.

Authors

Ben Katz, Rachel Zaguri, Simon Edvardson, Channa Maayan, Orly Elpeleg, Shaya Lev, Elyad Davidson, Maximilian Peters, Shlomit Kfir-Erenfeld, Esther Berger, Shifa Ghazalin, Alexander M. Binshtok, Baruch Minke

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A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents
Shufang He, … , Ye Zhang, Eric R. Gross
Shufang He, … , Ye Zhang, Eric R. Gross
Research Article Neuroscience Vascular biology

A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents

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Abstract

Pain signals are relayed to the brain via a nociceptive system, and in rare cases, this nociceptive system contains genetic variants that can limit the pain response. Here, we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and, further, whether we could target this region with a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N-knockin mouse using CRISPR/Cas9, we discovered that the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral responses to noxious chemical stimuli and less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Furthermore, blocking this K710 region in WT rodents using a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels. These findings identify K710 TRPV1 as a discrete site that is crucial for the control of nociception and provide insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

Authors

Shufang He, Vanessa O. Zambelli, Pritam Sinharoy, Laura Brabenec, Yang Bian, Freeborn Rwere, Rafaela C.R. Hell, Beatriz Stein Neto, Barbara Hung, Xuan Yu, Meng Zhao, Zhaofei Luo, Chao Wu, Lijun Xu, Katrin J. Svensson, Stacy L. McAllister, Creed M. Stary, Nana-Maria Wagner, Ye Zhang, Eric R. Gross

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Abstract

Transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin and noxious heat, has been one of the most compelling targets for analgesics. However, systemic inhibition of TRPV1 is an impractical approach as a pain killer, since systemic antagonism induces hyperthermia. Two articles in this issue of the JCI report phenotypes from separate, rare missense mutations of human TRPV1. He, Zambelli, and colleagues investigated TRPV1K710N, which showed reduced functionality, while Katz, Zaguri, and co-authors reported on TRPV1N331K, which led to a complete functional knockout. The findings provide insights that will improve our understanding of the endogenous functions of TRPV1 in humans and may facilitate a rational TRPV1-targeting approach to achieve hyperthermia-free analgesia.

Hurdles for treating chronic pain through targeting of TRPV1

The sensory system detects noxious stimuli and allows us to avoid harmful tissue-damaging injuries (e.g., withdrawing a hand upon touching a hot stove), which is beneficial for survival. However, persistent pain from pathological conditions, such as chronic inflammation of knee joints or peripheral nerve damage, has no such protective value and needs to be treated. Current primary therapeutics for chronic pain are often limited in their analgesic efficacy and may produce adverse side effects. High addiction liability is a problem of opioidergic medications. An ideal treatment for chronic pain needs to selectively alleviate persistent pain conditions without influencing the beneficial pain sensation and without producing adverse side effects.

Capsaicin, the main ingredient of chili pepper, reliably produces acute burning pain in humans and pain-like behaviors in animals. The discovery of transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin (1), opened an era in pain research, which was recognized in 2021 with a Nobel prize to David Julius and Ardem Patapoutian for the discovery of temperature and touch receptors. TRPV1 is a cationic ion channel that can be activated not only by capsaicin, but also by heat, acid, and multiple other exogenous chemicals or endogenous mediators. Now we understand that the burning sensation following the ingestion of capsaicin or exposure to noxious heat is mediated by the activation of TRPV1 expressed in nociceptors, a subset of sensory neurons that respond to noxious stimuli. Functions of TRPV1 are enhanced under inflammatory conditions, and TRPV1 mediates increased pain sensation (hyperalgesia) after tissue injuries. Despite the obvious potential use of TRPV1 inhibitors as pain killers, the systemic pharmacological inhibition of TRPV1 is not practical, since systemic TRPV1 antagonism induces on-target adverse side effects, namely hyperthermia and an increased risk of burn injury by decreasing heat sensation (2). To develop approaches to targeting TRPV1 for alleviation of pathological pain without adverse side effects, highly sophisticated investigations are necessary to reveal the TRPV1 structures associated with in vivo outcomes. A better understanding of the neurobiology and endogenous functions of TRPV1 in humans is critical. The discovery of rare gain-of-function or loss-of-function mutations in SCN9A, a voltage-gated sodium channel gene encoding Nav1.7, revealed its critical role in nociceptors (3). While mild phenotypes associated with common TRPV1 genetic variants are known (4), our understanding of the phenotypic effects of rare TRPV1 mutations is limited. Complete or partial insensitivity to capsaicin, which might be attributable to the reduced expression of TRPV1, has been reported (5, 6). However, genomic mechanisms involving TRPV1 mutations leading to the phenotypes are inconclusive. While such information should increase our understanding of the pathophysiological roles of TRPV1 in humans, developing analgesic strategies through selective targeting of TRPV1 function in humans without adverse side effects is another challenge. Two articles published in this issue of the JCI shed light on overcoming these hurdles.

TRPV1-targeted, hyperthermia-free inhibition of pathological pain

He, Zambelli, and co-authors (7) report on phenotypes of a rare human TRPV1 mutation through reverse translation using a mouse line carrying the ortholog missense mutation. Through a clever in silico approach comparing human TRPV1 rare mutations with avian TRPV1 lacking capsaicin sensitivity, the authors attempted to identify a single residue that eliminates capsaicin sensitivity without altering heat sensitivity or thermoregulation. TRPV1K710N is an extremely rare mutation in humans. The mutation induces structural alteration in the TRP domain that is critical in channel gating and multimerization (8). Cells carrying TRPV1K710N exhibited greatly reduced TRPV1 activation in response to capsaicin in vitro (Figure 1). When the K710-to-N710 mutation of the orthologous TRPV1 residue was created in mice, neurogenic inflammation or capsaicin-induced behavioral responses were reduced by half. Importantly, heat sensitivity in the tail was not affected. Strikingly, Trpv1K710N mice showed a substantial decrease in thermal hyperalgesia and a lack of mechanical hyperalgesia after nerve injury. He, Zambelli, and co-authors further extended the findings and developed a method for targeting the region involving K710 using V1-cal, a membrane-permeable peptide composed of ten amino acids of TRPV1 (R701 to S711) and ten TAT sequences. The V1-cal peptide reduced capsaicin-induced pain-like behaviors and neurogenic inflammation in vivo. Systemic administration of V1-cal peptide via an osmotic pump reversed neuropathy-induced thermal, mechanical, and cold hyperalgesia. In both Trpv1K710N mice and V1-cal–treated naive mice, body temperature was not affected. Although He, Zambelli, and colleagues were unable to validate these TRPV1K710N phenotypes in humans, preclinical data suggest the potential for a hyperthermia-free analgesic approach using a peptide targeting a narrowly defined region of TRPV1.

Phenotypes of two rare loss-of-function missense mutations of human TRPV1.Figure 1

Phenotypes of two rare loss-of-function missense mutations of human TRPV1. Katz, Zaguri, and co-authors (9) reported phenotypes of two individuals carrying TRPV1N331K/N331K, which is located in the ankyrin repeat domain at the N-terminal domain. He, Zambelli, and co-authors (7) reported phenotypes of knockin mice carrying Trpv1K710N/K710N, a loss-of-function missense mutation rarely observed in humans. TRPV1K710N is located in the TRP domain of the C-terminal domain. TRPV1N331K/N331K shows a complete deficit in activation, whereas TRPV1K710N shows a partial loss of function.

Individuals lacking functional TRPV1

In studies of individuals carrying another rare TRPV1 mutation (TRPV1N331K), Katz, Zaguri, and co-authors (9) report on phenotypes resulting from the complete loss of function of TRPV1 (Figure 1). Individuals with the functional knockout commonly carried the rare homozygous missense mutation of TRPV1N331K. The mutation is located in the ankyrin repeat domain, which is critical for channel activation (10). In vitro assays showed that TRPV1N331K was not activated by capsaicin or other agonists. The expression and targeting of TRPV1N331K to the plasma membrane were normal, suggesting that the mutation selectively affects the function of TRPV1, likely through interference with channel gating. Consistently, the homozygous, but not heterozygous, carriers of TRPV1N331K lacked aversion to capsaicin and showed no pain or flare in the skin upon injection of capsaicin. The affected individuals showed a modest reduction in heat pain. Heterozygous TRPV1N331K/+ carriers did not show such phenotypes (9). These findings are consistent with the phenotypes of mice lacking the expression of TRPV1 or humans treated with a TRPV1 antagonist (2). Further genetic analysis of the affected individuals and their family strongly suggested that the phenotypes are primarily derived from the missense mutation of TRPV1. Although another homozygous missense mutation in PROKR1, which is also implicated in pain, was identified in the family, two individuals carrying the homozygous mutation of PROKR1 with heterozygous TRPV1N331K/+ did not show phenotypes comparable to those of the TRPV1N331K/N331K carriers (9). Therefore, the findings convincingly support the contribution of TRPV1 to chemical and thermal pain in humans.

Lessons for hyperthermia-free analgesia

The results from Katz, Zaguri, and colleagues (9) suggest species differences in the roles of TRPV1 and help us to anticipate the potential effects of TRPV1 antagonism in humans. The homozygous carrier of TRPV1N331K/N331K showed a reduction in cold pain (9), which is consistent with the necessity of TRPV1 for cold nociception and cold hyperalgesia in rodents (11). Therefore, TRPV1 antagonism possibly influences the protection from both noxious heat and cold. In the carrier homozygous for TRPV1N331K/N331K, pain and flare induced by allyl isothiocyanate (mustard oil), an agonist of transient receptor potential ankyrin subtype 1 (TRPA1), was increased (9). This finding is reminiscent of a report of an individual carrying mutations in the introns of TRPV1 who is completely insensitive to capsaicin and exhibits increased sensitivity to a garlic extract, another TRPA1 activator (5). This phenomenon may be attributable to the interactions of TRPA1 and TRPV1 in sensory neurons (12). However, there is no evidence that in vivo responses to the activation of TRPA1 are greater in TRPV1-knockout mice, suggesting that species-specific mechanisms regulate TRPV1-TRPA1 interactions. Since TRPA1 is a sensor of multiple environmental irritants (13), TRPV1 antagonism potentially increases sensitivity to chemical irritation in humans. In contrast, histamine-mediated itch and skin flare were not altered in the affected individual (9), which is consistent with the lack of effect of a TRPV1 antagonist on histamine-induced itch in healthy volunteers (14). Considering the profound involvement of TRPV1 with itch in rodents (15), there is an apparent gap in pruriceptive mechanisms between mice and humans.

Although TRPV1N331K/N331K carriers had a normal core body temperature, they showed excessive sweating, which might be a compensatory response to their lifelong deficiency in TRPV1-mediated body temperature regulation (9). This finding might suggest that the disturbance of thermoregulation by TRPV1 antagonism is physiologically adaptable, which is consistent with the observation that repeated administration of TRPV1 antagonists attenuates hyperthermia (16, 17).

Unlike with conventional TRPV1 antagonists, He, Zambelli, and co-authors reported that systemic administration of V1-cal did not produce hyperthermia in mice, suggesting that the region-specific targeting of TRPV1 can lead to potential hyperthermia-free analgesia (7). Further determination of mechanisms through which partial antagonism by V1-cal produces robust analgesia without altering body temperature would strengthen the study’s translational value. It would be critical to determine the efficacy of V1-cal in inhibiting TRPV1 upon polymodal activation, since hyperthermia mediated by a TRPV1 antagonist depends on its inhibition of the activation by acid but not by heat or capsaicin (18). The outcomes may guide the design of small molecules relating to TRPV1K710. It will also be important to determine the effects of V1-cal on baseline pain-like responses to noxious heat, cold, and mechanical stimuli in vivo. Mechanisms of TRPV1 inhibition by V1-cal are puzzling. A previous study shows that a membrane-tethered peptide targeting different residues within the TRP domain interferes with TRPV1 subunit association and decreases inflammatory pain (19). Any off-target effects of V1-cal also need to be carefully assessed (e.g., studying V1-cal effects in TRPV1-KO mice).

Conclusion

TRPV1 has been one of the most compelling targets for the development of analgesics. Topical capsaicin, a TRPV1 agonist, is approved for treating chronic neuropathic pain (20), and it is fascinating to navigate the potential strategies for the treatment of chronic pain conditions using both TRPV1 agonists and antagonists. A better understanding of modality-specific TRPV1 functions and antagonism should expedite the development of a class of TRPV1 antagonists and achieve hyperthermia-free analgesia.

Acknowledgments

This work was supported by NIH grants R01 DE027731, R01 DE031477, and R35 DE030045.

Address correspondence to: Man-Kyo Chung, University of Maryland, School of Dentistry, Department of Neural and Pain Sciences, 650 W. Baltimore St. 8-South, Baltimore, Maryland 21201, USA. Phone: 410.706.4452; Email: mchung@umaryland.edu.

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2023, Li et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2023;133(3):e167338. https://doi.org/10.1172/JCI167338.

See the related article at A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents.

See the related article at Nociception and pain in humans lacking functional TRPV1 channel.

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Version history
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  • Top
  • Abstract
  • Hurdles for treating chronic pain through targeting of TRPV1
  • TRPV1-targeted, hyperthermia-free inhibition of pathological pain
  • Individuals lacking functional TRPV1
  • Lessons for hyperthermia-free analgesia
  • Conclusion
  • Acknowledgments
  • Footnotes
  • References
  • Version history
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