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Nociception and pain in humans lacking a functional TRPV1 channel
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 pai...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9888381/ https://www.ncbi.nlm.nih.gov/pubmed/36454632 http://dx.doi.org/10.1172/JCI153558 |
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author | Katz, Ben Zaguri, Rachel Edvardson, Simon Maayan, Channa Elpeleg, Orly Lev, Shaya Davidson, Elyad Peters, Maximilian Kfir-Erenfeld, Shlomit Berger, Esther Ghazalin, Shifa Binshtok, Alexander M. Minke, Baruch |
author_facet | Katz, Ben Zaguri, Rachel Edvardson, Simon Maayan, Channa Elpeleg, Orly Lev, Shaya Davidson, Elyad Peters, Maximilian Kfir-Erenfeld, Shlomit Berger, Esther Ghazalin, Shifa Binshtok, Alexander M. Minke, Baruch |
author_sort | Katz, Ben |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9888381 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-98883812023-02-06 Nociception and pain in humans lacking a functional TRPV1 channel Katz, Ben Zaguri, Rachel Edvardson, Simon Maayan, Channa Elpeleg, Orly Lev, Shaya Davidson, Elyad Peters, Maximilian Kfir-Erenfeld, Shlomit Berger, Esther Ghazalin, Shifa Binshtok, Alexander M. Minke, Baruch J Clin Invest Clinical Medicine 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. American Society for Clinical Investigation 2023-02-01 /pmc/articles/PMC9888381/ /pubmed/36454632 http://dx.doi.org/10.1172/JCI153558 Text en © 2023 Katz et al. https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Clinical Medicine Katz, Ben Zaguri, Rachel Edvardson, Simon Maayan, Channa Elpeleg, Orly Lev, Shaya Davidson, Elyad Peters, Maximilian Kfir-Erenfeld, Shlomit Berger, Esther Ghazalin, Shifa Binshtok, Alexander M. Minke, Baruch Nociception and pain in humans lacking a functional TRPV1 channel |
title | Nociception and pain in humans lacking a functional TRPV1 channel |
title_full | Nociception and pain in humans lacking a functional TRPV1 channel |
title_fullStr | Nociception and pain in humans lacking a functional TRPV1 channel |
title_full_unstemmed | Nociception and pain in humans lacking a functional TRPV1 channel |
title_short | Nociception and pain in humans lacking a functional TRPV1 channel |
title_sort | nociception and pain in humans lacking a functional trpv1 channel |
topic | Clinical Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9888381/ https://www.ncbi.nlm.nih.gov/pubmed/36454632 http://dx.doi.org/10.1172/JCI153558 |
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