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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
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.
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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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