| First Author | Kamada H | Year | 2023 |
| Journal | Sci Rep | Volume | 13 |
| Issue | 1 | Pages | 18490 |
| PubMed ID | 37898719 | Mgi Jnum | J:342900 |
| Mgi Id | MGI:7546522 | Doi | 10.1038/s41598-023-45638-7 |
| Citation | Kamada H, et al. (2023) Hypersensitivity of myelinated A-fibers via toll-like receptor 5 promotes mechanical allodynia in tenascin-X-deficient mice associated with Ehlers-Danlos syndrome. Sci Rep 13(1):18490 |
| abstractText | 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 (Adelta fiber responses) and 2000 Hz (Abeta fiber responses), but not 5 Hz (C fiber responses) in wild-type mice. The QX-314 plus flagellin-induced silencing of Adelta- and Abeta-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 Adelta- and Abeta-fibers, and it is induced by constitutive activation of TLR5. |
