Mechanical allodynia in mice with tenascin-X deficiency associated with Ehlers-Danlos syndrome

• Published in: Scientific reports 2020-04, Vol.10 (1), p.6569-6569, Article 6569
• Main Authors: Okuda-Ashitaka, Emiko, Kakuchi, Yuka, Kakumoto, Hiroaki, Yamanishi, Shota, Kamada, Hiroki, Yoshidu, Takafumi, Matsukawa, Satoshi, Ogura, Naoya, Uto, Sadahito, Minami, Toshiaki, Ito, Seiji, Matsumoto, Ken-ichi
• Format: Article
• Language: English
• Subjects: 631/378; 692/4017; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Chemical stimuli; Dorsal horn; Ehlers-Danlos syndrome; Ehlers-Danlos Syndrome - complications; Extracellular matrix; Extracellular signal-regulated kinase; Fibers; Formaldehyde; Humanities and Social Sciences; Hyperalgesia - complications; Hyperalgesia - drug therapy; Hyperalgesia - physiopathology; Hypersensitivity; Inflammation; Male; Mice, Inbred C57BL; Molecular modelling; multidisciplinary; Myalgia; NADP; NADPH-diaphorase; Nitric oxide; Pain; Pain - complications; Pain - pathology; Pain - physiopathology; Pain perception; Paresthesia; Phosphorylation; Polyneuropathy; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Science; Science (multidisciplinary); Spinal Cord Dorsal Horn - drug effects; Spinal Cord Dorsal Horn - pathology; Spinal Cord Dorsal Horn - physiopathology; Tenascin; Tenascin - deficiency; Tenascin - genetics; Tenascin - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-63499-2

Tenascin-X (TNX) is a member of the extracellular matrix glycoprotein tenascin family, and TNX deficiency leads to Ehlers-Danlos syndrome, a heritable human disorder characterized mostly by skin hyperextensibility, joint hypermobility, and easy bruising. TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. However, the molecular mechanisms by which TNX deficiency complicates pain are unknown. Here, we examined the nociceptive behavioral responses of TNX-deficient mice. Compared with wild-type mice, TNX-deficient mice exhibited mechanical allodynia but not thermal hyperalgesia. TNX deficiency also increased pain sensitivity to chemical stimuli and aggravated early inflammatory pain elicited by formalin. TNX-deficient mice were significantly hypersensitive to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not to stimuli at frequency of 5 Hz (C fiber responses). In addition, the phosphorylation levels of extracellular signal-related kinase, an active neuronal marker, and the activity of NADPH-diaphorase, a neuronal nitric oxide activation marker, were enhanced in the spinal dorsal horns of TNX-deficient mice. These results suggest that TNX deficiency contributes to the development of mechanical allodynia and hypersensitivity to chemical stimuli, and it induces hypersensitization of myelinated A fibers and activation of the spinal dorsal horn.