Role of the endothelin in oral cancer related pain

• Project/Area Number: 15K11320
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Kyushu Dental College
• Principal Investigator: HARANO NOZOMU 九州歯科大学, 歯学部, 講師 (50423976)
• Co-Investigator(Kenkyū-buntansha): 小野 堅太郎 九州歯科大学, 歯学部, 教授 (40316154) ; 人見 涼露 九州歯科大学, 歯学部, 助教 (70548924)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Orofacial pain / Oral Pathology / Inflammation / Neuropharmacology / Neuroscience / Infectious disease / ET-1 / TRPA1 / TRPV1 / 口内炎 / ガン性疼痛 / ボセンタン / BQ-123 / BQ-788 / ５－ＦＵ

Outline of Final Research Achievements

ET-1 is upregulated in oral mucosal inflammation, although it has not been shown to induce pain in oral ulcers. In the present study, we investigated the involvement of ET-1 signaling with oral ulcer-induced pain using our proprietary assay system in conscious rats.
ET-1 upregulation following oral bacterial invasion via the ulcerative region elicits TRPA1-mediated spontaneous pain due to ETB receptor-accelerated prostanoid production, and TRPA1- and TRPV1-mediated mechanical allodynia via both ETA and ETB receptors, while ET-1-indepedent pathways also induce pain
in the model. The findings highlight the potential of endothelin signaling blockers as effective analgesics for oral ulcer patients, together with the significant analgesic effects of the clinically available drug bosentan.

Research Products

• [Journal Article] Endothelin-1 Elicits TRP-Mediated Pain in an Acid-Induced Oral Ulcer Model (2018)
  • Author(s): Nodai T.、Hitomi S.、Ono K.、Masaki C.、Harano N.、Morii A.、Sago-Ito M.、Ujihara I.、Hibino T.、Terawaki K.、Omiya Y.、Hosokawa R.、Inenaga K.
  • Journal Title: Journal of Dental Research Volume: 印刷中 Issue: 8 Pages: 901-908
  • DOI: 10.1177/0022034518762381
  • Peer Reviewed / Open Access
• [Journal Article] Prostanoid-dependent spontaneous pain and PAR2-dependent mechanical allodynia following oral mucosal trauma: Involvement of TRPV1, TRPA1, and TRPV4 (2017)
  • Author(s): Misa Ito, Kentaro Ono, Suzuro Hitomi, Tomotaka Nodai, Teppei Sago, Kiichiro Yamaguchi, Nozomu Harano, Kaori Gunjigake, Ryuji Hosokawa, Tatsuo Kawamoto and Kiyotoshi Inenaga
  • Journal Title: Molecular Pain Volume: 13 Pages: 1-17
  • DOI: 10.1177/1744806917704138
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Distinct TRPV1- and TRPA1-based mechanisms underlying enhancement of oral ulcerative mucositis-induced pain by 5-fluorouracil. (2016)
  • Author(s): Yamaguchi, K., Ono, K., Hitomi, S., Ito, M., Nodai, T., Goto, T., Harano, N., Watanabe, S., Inoue, H., Miyano, K., Uezono, Y., Matoba, M., Inenaga, K.
  • Journal Title: Pain Volume: 157 Issue: 5 Pages: 1004-1020
  • DOI: 10.1097/j.pain.0000000000000498
  • Peer Reviewed / Open Access
• [Journal Article] Novel methods of applying direct chemical and mechanical stimulation to the oral mucosa for traditional behavioral pain assays in conscious rats (2015)
  • Author(s): Hitomi S, Ono K, Miyano K, Ota Y, Uezono Y, Matoba M, Kuramitsu S, Yamaguchi K, Matsuo K, Seta Y, Harano N, Inenaga K.
  • Journal Title: J Neurosci Methods Volume: 239 Pages: 162-169
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 抗癌薬5-フルオロウラシル投与後の口内炎誘発疼痛にTRPV1とTRPA1が関与す る (2015)
  • Author(s): 山口喜一郎, 小野堅太郎, 人見涼露, 野代知孝, 伊藤美紗, 左合徹平, 原野望, 稲永清敏
  • Organizer: 三叉神経領域の感覚－運動統合機能研究会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-28
• [Presentation] Mechanism 116 | underlying oral ulcerative mucositis-induced pain in chemotherapy-received rat model (2015)
  • Author(s): Yamaguchi K, Ono K, Hitomi S, Harano N, Sago T, Watanabe S, Inenaga K.
  • Organizer: Neuroscience
  • Place of Presentation: Chicago
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] 5-フ ルオロウラシル投与ラットにおける口内炎誘発疼痛のメカニズム (2015)
  • Author(s): 山口喜一郎, 小野堅太郎, 人見涼露, 原野望, 左合徹平, 渡辺誠之, 稲永清敏
  • Organizer: 歯科基礎医学会
  • Place of Presentation: 新潟
  • Year and Date: 2015-09-11