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

Autor: Kamada H; Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan., Emura K; Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan., Yamamoto R; Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan., Kawahara K; Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan., Uto S; Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan., Minami T; Department of Anesthesiology, Osaka Medical and Pharmaceutical University, Takatsuki, 569-8686, Japan., Ito S; Department of Anesthesiology, Osaka Medical and Pharmaceutical University, Takatsuki, 569-8686, Japan., Matsumoto KI; Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, Izumo, 693-8501, Japan., Okuda-Ashitaka E; Department of Biomedical Engineering, Osaka Institute of Technology, Osaka, 535-8585, Japan. emiko.ashitaka@oit.ac.jp.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Oct 28; Vol. 13 (1), pp. 18490. Date of Electronic Publication: 2023 Oct 28.
DOI: 10.1038/s41598-023-45638-7
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje