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Addendum
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10.1172/JCI205878
Addendum to Nociception and pain in humans lacking a functional TRPV1 channel
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, and Baruch Minke
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Published April 1, 2026 - More info
J Clin Invest. 2026;136(7):e205878. https://doi.org/10.1172/JCI205878.
© 2026 Katz 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/.
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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, marked cold hypersensitivity, with cold pain reported at temperatures that are innocuous to healthy individuals, 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
Original citation: J Clin Invest. 2023;133(3):e153558. https://doi.org/10.1172/JCI153558
Citation for this addendum: J Clin Invest. 2026;136(7):e205878. https://doi.org/10.1172/JCI205878
Following the publication of their article, the authors noted that the description of the cold phenotype in an individual lacking functional TRPV1 due to a homozygous missense mutation in the TRPV1 gene has been misinterpreted in some articles citing this work. For clarity, sentences in the abstract, Results, and Discussion have been updated to better describe the cold phenotype as shown below. The HTML and PDF versions of the paper have been updated.
Abstract
Furthermore, quantitative sensory testing of A1 revealed an elevated heat-pain threshold but also, surprisingly, marked cold hypersensitivity, with cold pain reported at temperatures that are innocuous to healthy individuals, and extensive neurogenic inflammatory, flare, and pain responses following application of the TRPA1 channel activator mustard oil.
Results
The affected individual reveals no sensitivity to capsaicin, an elevated HPT, and marked cold hypersensitivity, with cold pain reported at temperatures that are innocuous to healthy individuals.
Surprisingly, his cold-pain threshold (CPT) and cold tolerance (CT) values were shifted toward warmer temperatures in comparison with those of the control groups (Figure 4, E and F, and Supplemental Figure 4, C and D).
Discussion
Surprisingly, QST measurements of A1 revealed a shift toward warmer temperatures of CPT and CT using a Peltier thermode, whereas normal cold pain tolerance was measured when using the cold pressor test (Figure 4, E–G, Supplemental Figure 4, C and D, and see Methods).
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)