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Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome

Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers–Danlos syndrome, and TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. We previously reported that TNX-deficient (Tnxb(−/−)) mice exhib...

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Autores principales: Kamada, Hiroki, Emura, Kousuke, Yamamoto, Rikuto, Kawahara, Koichi, Uto, Sadahito, Minami, Toshiaki, Ito, Seiji, Matsumoto, Ken-ichi, Okuda-Ashitaka, Emiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10613304/
https://www.ncbi.nlm.nih.gov/pubmed/37898719
http://dx.doi.org/10.1038/s41598-023-45638-7
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author Kamada, Hiroki
Emura, Kousuke
Yamamoto, Rikuto
Kawahara, Koichi
Uto, Sadahito
Minami, Toshiaki
Ito, Seiji
Matsumoto, Ken-ichi
Okuda-Ashitaka, Emiko
author_facet Kamada, Hiroki
Emura, Kousuke
Yamamoto, Rikuto
Kawahara, Koichi
Uto, Sadahito
Minami, Toshiaki
Ito, Seiji
Matsumoto, Ken-ichi
Okuda-Ashitaka, Emiko
author_sort Kamada, Hiroki
collection PubMed
description Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers–Danlos syndrome, and TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. We previously reported that TNX-deficient (Tnxb(−/−)) mice exhibit mechanical allodynia and hypersensitivity to myelinated A-fibers. Here, we investigated the pain response of Tnxb(−/−) mice using pharmacological silencing of A-fibers with co-injection of N-(2,6-Dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314), a membrane-impermeable lidocaine analog, plus flagellin, a toll-like receptor 5 (TLR5) ligand. Intraplantar co-injection of QX-314 and flagellin significantly increased the paw withdrawal threshold to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not 5 Hz (C fiber responses) in wild-type mice. The QX-314 plus flagellin-induced silencing of Aδ- and Aβ-fibers was also observed in Tnxb(−/−) mice. Co-injection of QX-314 and flagellin significantly inhibited the mechanical allodynia and neuronal activation of the spinal dorsal horn in Tnxb(−/−) mice. Interestingly, QX-314 alone inhibited the mechanical allodynia in Tnxb(−/−) mice, and it increased the paw withdrawal threshold to stimuli at frequencies of 250 Hz and 2000 Hz in Tnxb(−/−) mice, but not in wild-type mice. The inhibition of mechanical allodynia induced by QX-314 alone was blocked by intraplantar injection of a TLR5 antagonist TH1020 in Tnxb(−/−) mice. These results suggest that mechanical allodynia due to TNX deficiency is caused by the hypersensitivity of Aδ- and Aβ-fibers, and it is induced by constitutive activation of TLR5.
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spelling pubmed-106133042023-10-30 Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome Kamada, Hiroki Emura, Kousuke Yamamoto, Rikuto Kawahara, Koichi Uto, Sadahito Minami, Toshiaki Ito, Seiji Matsumoto, Ken-ichi Okuda-Ashitaka, Emiko Sci Rep Article Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers–Danlos syndrome, and TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. We previously reported that TNX-deficient (Tnxb(−/−)) mice exhibit mechanical allodynia and hypersensitivity to myelinated A-fibers. Here, we investigated the pain response of Tnxb(−/−) mice using pharmacological silencing of A-fibers with co-injection of N-(2,6-Dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314), a membrane-impermeable lidocaine analog, plus flagellin, a toll-like receptor 5 (TLR5) ligand. Intraplantar co-injection of QX-314 and flagellin significantly increased the paw withdrawal threshold to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not 5 Hz (C fiber responses) in wild-type mice. The QX-314 plus flagellin-induced silencing of Aδ- and Aβ-fibers was also observed in Tnxb(−/−) mice. Co-injection of QX-314 and flagellin significantly inhibited the mechanical allodynia and neuronal activation of the spinal dorsal horn in Tnxb(−/−) mice. Interestingly, QX-314 alone inhibited the mechanical allodynia in Tnxb(−/−) mice, and it increased the paw withdrawal threshold to stimuli at frequencies of 250 Hz and 2000 Hz in Tnxb(−/−) mice, but not in wild-type mice. The inhibition of mechanical allodynia induced by QX-314 alone was blocked by intraplantar injection of a TLR5 antagonist TH1020 in Tnxb(−/−) mice. These results suggest that mechanical allodynia due to TNX deficiency is caused by the hypersensitivity of Aδ- and Aβ-fibers, and it is induced by constitutive activation of TLR5. Nature Publishing Group UK 2023-10-28 /pmc/articles/PMC10613304/ /pubmed/37898719 http://dx.doi.org/10.1038/s41598-023-45638-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Kamada, Hiroki
Emura, Kousuke
Yamamoto, Rikuto
Kawahara, Koichi
Uto, Sadahito
Minami, Toshiaki
Ito, Seiji
Matsumoto, Ken-ichi
Okuda-Ashitaka, Emiko
Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome
title Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome
title_full Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome
title_fullStr Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome
title_full_unstemmed Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome
title_short Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers–Danlos syndrome
title_sort hypersensitivity of myelinated a-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-x-deficient mice associated with ehlers–danlos syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10613304/
https://www.ncbi.nlm.nih.gov/pubmed/37898719
http://dx.doi.org/10.1038/s41598-023-45638-7
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