PAR2-dependent phosphorylation of TRPV4 at the trigeminal nerve terminals contributes to tongue cancer pain

Ryuta Akasaka, Akihiko Furukawa, Yoshinori Hayashi, Suzuro Hitomi, Ryo Koyama, Eri Oshima, Miki Tamura, Mamiko Yonemoto, Yasushi Hojo, Ryosuke Takahashi, Ikuko Shibuta, Koichi Iwata, Yoshiyuki Yonehara, Masamichi Shinoda

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Objective: This study aimed to clarify the interactions between the tongue and primary afferent fibers in tongue cancer pain. Methods: A pharmacological analysis was conducted to evaluate mechanical hypersensitivity of the tongues of rats with squamous cell carcinoma (SCC). Changes in trigeminal ganglion (TG) neurons projecting to the tongue were analyzed using immunohistochemistry and western blotting. Results: SCC inoculation of the tongue caused persistent mechanical sensitization and tumor formation. Trypsin expression was significantly upregulated in cancer lesions. Continuous trypsin inhibition or protease-activated receptor 2 (PAR2) antagonism in the tongue significantly inhibited SCC-induced mechanical sensitization. No changes were observed in PAR2 and transient receptor potential vanilloid 4 (TRPV4) levels in the TG or the number of PAR2-and TRPV4-expressing TG neurons after SCC inoculation. In contrast, the relative amount of phosphorylated TRPV4 in the TG was significantly increased after SCC inoculation and abrogated by PAR2 antagonism in the tongue. TRPV4 antagonism in the tongue significantly ameliorated the mechanical sensitization caused by SCC inoculation. Conclusions: Our findings indicate that tumor-derived trypsin sensitizes primary afferent fibers by PAR2 stimulation and subsequent TRPV4 phosphorylation, resulting in severe tongue pain.

Original languageEnglish
Pages (from-to)356-364
Number of pages9
JournalJournal of Oral Biosciences
Volume65
Issue number4
DOIs
Publication statusPublished - Dec 2023

Keywords

  • Phosphorylation
  • Protease-activated receptor 2
  • Squamous cell carcinoma
  • Trigeminal ganglion
  • Trypsin

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