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Molecular-based mechanism underlying oral ulcerative mucositis following anti-cancer drugs

Research Project

Project/Area Number 16K11483
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Functional basic dentistry
Research InstitutionKyushu Dental College

Principal Investigator

Ono Kentaro  九州歯科大学, 歯学部, 教授 (40316154)

Co-Investigator(Kenkyū-buntansha) 人見 涼露  九州歯科大学, 歯学部, 講師 (70548924)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords口内炎 / 疼痛 / 抗癌薬 / 三叉神経節 / プロスタグランジン / TRPV1 / TRPA1 / TRPV4 / 口内炎疼痛 / 5-FU / シスプラチン / TRPチャネル / 細菌浸潤 / 三叉神経節ニューロン / 唾液 / 鎮痛薬 / 細菌感染 / 神経科学 / 麻酔
Outline of Final Research Achievements

The anti-cancer drug 5-fluorouracil-received oral ulcerative mucositis model of rats showed severe mucositis due to massive bacterial infection in the ulcerative region following leucopenia. Bacterial toxins excited pain-related nerves via activation of nociceptive TRP channels. Other oral ulcerative mucositis models by mechanical injury or another anti-cancer drug cisplatin demonstrated different molecular mechanism underlying oral mucositis-induced pain. The Japanese herbal medicine, Hangeshashinto, has been reported to improve oral mucositis in cancer patients. In the 5-fluorouracil-received oral ulcerative mucositis model, the traditional drug elicited anti-nociceptive effect on pain by shogaols at ingredient level.

Academic Significance and Societal Importance of the Research Achievements

癌治療患者における激しい疼痛を伴う口内炎の発症は、臨床上大きな問題となっていたものの、その発症メカニズムは不明であった。本研究成果にて、抗癌剤による全身的な影響が口内炎の症状を増悪させ、特定の侵害受容TRPチャネルを介して痛みを生じていることが明らかとなった。口内炎の発症原因や抗癌剤の種類によって病態やTRPチャネルの種類が異なっていたため、患者によってより効果的な治療法を選択する必要があることが示唆される。また、臨床で使用される漢方薬の西洋科学的エビデンスを提供できたと考えている。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (47 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (1 results) Journal Article (9 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 9 results,  Open Access: 3 results,  Acknowledgement Compliant: 3 results) Presentation (36 results) (of which Int'l Joint Research: 13 results) Book (1 results)

  • [Int'l Joint Research] New York University(米国)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Pain mechanism of oral ulcerative mucositis and the therapeutic traditional herbal medicine hangeshashinto2019

    • Author(s)
      Hitomi Suzuro、Ujihara Izumi、Ono Kentaro
    • Journal Title

      Journal of Oral Biosciences

      Volume: 61 Issue: 1 Pages: 12-15

    • DOI

      10.1016/j.job.2019.01.004

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endothelin-1 Elicits TRP-Mediated Pain in an Acid-Induced Oral Ulcer Model2018

    • 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

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cutaneous pigmentation modulates skin sensitivity via tyrosinase-dependent dopaminergic signalling2017

    • Author(s)
      Ono Kentaro、Viet Chi T.、Ye Yi、Dang Dongmin、Hitomi Suzuro、Toyono Takashi、Inenaga Kiyotoshi、Dolan John C.、Schmidt Brian L.Ono K, Viet CT, Ye Y, Dang D, Hitomi S, Toyono T, Inenaga K, Dolan JC, Schmidt BL
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 9181-9181

    • DOI

      10.1038/s41598-017-09682-4

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Thirst sensation and oral dryness following alcohol intake2017

    • Author(s)
      Inenaga Kiyotoshi、Ono Kentaro、Hitomi Suzuro、Kuroki Ayu、Ujihara Izumi
    • Journal Title

      Japanese Dental Science Review

      Volume: 53 Issue: 3 Pages: 78-85

    • DOI

      10.1016/j.jdsr.2016.12.001

    • NAID

      210000169875

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Alterations in opioid inhibition cause widespread nociception but do not affect anxiety-like behavior in oral cancer mice2017

    • Author(s)
      Ye Yi、Bernab? Daniel G.、Salvo Elizabeth、Viet Chi T.、Ono Kentaro、Dolan John C.、Janal Malvin、Aouizerat Brad E.、Miaskowski Christine、Schmidt Brian L.
    • Journal Title

      Neuroscience

      Volume: 363 Pages: 50-61

    • DOI

      10.1016/j.neuroscience.2017.06.038

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients2017

    • Author(s)
      Viet Chi T.、Dang Dongmin、Aouizerat Bradley E.、Miaskowski Christine、Ye Yi、Viet Dan T.、Ono Kentaro、Schmidt Brian L.
    • Journal Title

      The Journal of Pain

      Volume: 18 Issue: 9 Pages: 1046-1059

    • DOI

      10.1016/j.jpain.2017.04.001

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Prostanoid-dependent spontaneous pain and PAR2-dependent mechanical allodynia following oral mucosal trauma: Involvement of TRPV1, TRPA1, and TRPV42017

    • 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

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] [6]-gingerol and [6]-shogaol, active ingredients of the traditional Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced pain via action on Na+ channels.2017

    • Author(s)
      Hitomi, S., Ono, K., Terawaki, K., Matsumoto, C., Mizuno, K., Yamaguchi, K., Imai, R., Omiya, Y., Hattori, T., Kase, Y., Inenaga, K.
    • Journal Title

      Pharmacological Research

      Volume: 117 Pages: 288-302

    • DOI

      10.1016/j.phrs.2016.12.026

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] The traditional Japanese medicine hangeshashinto alleviates oral ulcer-induced pain in a rat model.2016

    • Author(s)
      Hitomi S, Ono K, Yamaguchi K, Terawaki K, Imai R, Kubota K, Omiya Y, Hattori T, Kase Y, Inenaga K.
    • Journal Title

      Arch Oral Biol

      Volume: 66 Pages: 30-37

    • DOI

      10.1016/j.archoralbio.2016.02.002

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] Analgesic effect of isoliquiritigenin on oral ulcer-induced pain by blocking of Nav channels2019

    • Author(s)
      Miyamura,Y.,Hitomi,S.,Ujihara,I.,Terawaki,K.,Omiya,Y.,Morimoto,Y.,Ono,K.
    • Organizer
      FAOPS Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Therapeutic effects of highly-residual ointments on oral ulcerative mucositis2019

    • Author(s)
      Naniwa,M.,Hitomi,S.,Ujihara,I.,Matsuda,K.,Yoshino,K.,Nakamichi,A.,Ono,K.
    • Organizer
      FAOPS Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cisplatin-induced intraoral neuropathy due to TRPA1 sensitization in rats2019

    • Author(s)
      Hitomi,S.,Yamaguchi,K.,Seta,Y.,Ujihara,I.,Ono,K.
    • Organizer
      FAOPS Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 漢方薬半夏瀉心湯の成分イソリクリチゲニンは口内炎性疼痛を緩和する2018

    • Author(s)
      宮村侑一,人見涼露,小野堅太郎
    • Organizer
      日本口腔顔面痛学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 抗がん剤による口腔感覚過敏の発症メカニズム2018

    • Author(s)
      人見涼露,小野堅太郎
    • Organizer
      日本口腔顔面痛学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 口内炎における疼痛発症メカニズム:食に関わる痛覚の生理学的重要性2018

    • Author(s)
      小野堅太郎
    • Organizer
      歯科基礎医学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 半夏瀉心湯含有成分イソリクイリチゲニンは電位依存性イオンチャネルを阻害することで口内炎性疼痛を抑制する2018

    • Author(s)
      宮村侑一,人見涼露,氏原泉,小野堅太郎
    • Organizer
      歯科基礎医学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 甘草成分イソリクイリチゲニンは Navチャネル阻害により口内炎疼痛を抑制する2018

    • Author(s)
      宮村侑一,人見涼露,氏原泉,寺脇潔,大宮雄司,森本泰宏,小野堅太郎
    • Organizer
      西日本生理学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ステロイドおよび抗菌薬を含む高残留性軟膏の口内炎への治癒効果2018

    • Author(s)
      浪花真子,人見涼露,氏原泉,松田一成,小野堅太郎
    • Organizer
      三叉神経領域の感覚ー運動統合機能研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 甘草由来成分イソリクイリチゲニンはNavチャネル抑制により口内炎疼痛を緩和する2018

    • Author(s)
      宮村侑一,人見涼露,氏原泉,寺脇潔,大宮雄司,森本泰宏,小野堅太郎
    • Organizer
      三叉神経領域の感覚ー運動統合機能研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] he Glycyrrhiza ingredient isoliquiritigenin alleviates acute pain by ion channel inhibition2018

    • Author(s)
      Miyamura,Y.,Hitomi,S.,Ujihara,I.,Terawaki,K.,Omiya,Y.,Morimoto,Y.,and Ono,K
    • Organizer
      Asia-Pacific Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 抗がん薬による唾液分泌機能低下は口内炎治癒を妨げる2018

    • Author(s)
      人見涼露, 氏原泉, 左合ー伊藤美紗, 鹿山武海, 小野堅太郎
    • Organizer
      日本生理学会大会
    • Related Report
      2017 Research-status Report
  • [Presentation] イソリクリチゲニンは特定の侵害性末梢神経を阻害して口内炎性疼痛に鎮痛効果を示す2018

    • Author(s)
      宮村侑一, 人見涼露, 氏原泉, 寺脇潔, 大宮雄司, 小野堅太郎
    • Organizer
      日本生理学会大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Oral ulcerative mucositis induces pain via endothelin receptor2017

    • Author(s)
      T. Nodai, S. Hitomi, K. Ono, C. Masaki and R. Hosokawa
    • Organizer
      International Association for Dental Research
    • Place of Presentation
      San Francisco
    • Year and Date
      2017-03-22
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Hitomi, S., Ono, K., Ujihara, I., Terawaki, K., Matsumoto, C., Omiya, Y., Inenaga, K.2017

    • Author(s)
      Hitomi, S., Ono, K., Ujihara, I., Terawaki, K., Matsumoto, C., Omiya, Y., Inenaga, K.
    • Organizer
      Oral neuroscience
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Oral ulcerative mucositis induces pain via endothelin receptors.2017

    • Author(s)
      Nodai, T., Hitomi, S., Masaki, C., Ito, M., Hosokawa, R., Ono, K. and Inenaga, K.
    • Organizer
      アジア太平洋国際カンファレンス
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Oral ulcerative mucositis induces pain via endothelin receptor.2017

    • Author(s)
      Nodai, T., Hitomi, S., Ono, K., Masaki, C. and Hosokawa, R.
    • Organizer
      IADR
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 抗がん薬投与後の唾液腺萎縮は口内炎治癒を遅延させる2017

    • Author(s)
      人見涼露、氏原泉、鹿山武海、左合-伊藤 美紗、小野堅太郎
    • Organizer
      三叉神経領域の感覚ー運動統合機能研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 口内炎疼痛に対する半夏瀉心湯の鎮痛メカニズムの解明2017

    • Author(s)
      人見涼露、伊藤美紗、野代知孝、氏原泉、小野堅太郎
    • Organizer
      歯科基礎医学会
    • Related Report
      2017 Research-status Report
  • [Presentation] エンドセリン-1 シグナルを介した口内炎疼痛メカニズム2017

    • Author(s)
      野代知孝,人見涼露,伊藤美紗,氏原泉,正木,細川隆司,小野堅太郎
    • Organizer
      歯科基礎医学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 口内炎疼痛発症にエンドセリン-1が関与する2017

    • Author(s)
      野代知孝, 人見涼露, 伊藤美紗, 正木千尋, 細川隆司, 小野堅太郎, 稲永清敏
    • Organizer
      九州歯科学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] ラット口内炎疼痛に対する半夏瀉心湯の鎮痛メカニズム2017

    • Author(s)
      人見涼露, 小野堅太郎, 山口喜一郎, 寺脇潔, 松本千波, 大宮雄司, 稲永清敏
    • Organizer
      九州歯科学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] RPV1- and TRPA1-mediated spontaneous pain and TRPV4-mediated mechanical pain in orthodontic wire-induced oral mucositis2016

    • Author(s)
      Ito M, Ono K, Hitomi S, Kawamoto T
    • Organizer
      The 29th TAO Annual Meeting
    • Place of Presentation
      Taiwan
    • Year and Date
      2016-12-02
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] A new preclinical pain model of oral ulcer by orthodontic wire appliance2016

    • Author(s)
      M. Ito, K. Ono, S. Hitomi, K. Yamaguchi, T. Nodai, K. Gunjigake, K. Kuroishi, T. Kawamoto, K. Inenaga
    • Organizer
      The 16th International Association for the Study of Pain
    • Place of Presentation
      Yokohama
    • Year and Date
      2016-09-23
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Pain-associated mediators and genes in acetic acid-induced oral ulcerative mucositis2016

    • Author(s)
      T. Nodai, K. Ono, S. Hitomi, M. Ito, R. Hosokawa, K. Inenaga
    • Organizer
      The 16th International Association for the Study of Pain
    • Place of Presentation
      Yokohama
    • Year and Date
      2016-09-23
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 酢酸誘発口内炎モデルラットにおける疼痛関連因子の変化2016

    • Author(s)
      人見涼露, 小野堅太郎, 野代知孝, 伊藤美紗, 正木 千尋、細川 隆司、稲永清敏
    • Organizer
      第58回歯科基礎医学会
    • Place of Presentation
      北海道
    • Year and Date
      2016-08-24
    • Related Report
      2016 Research-status Report
  • [Presentation] 矯正ワイヤー誘発新規口内炎モデルにおける疼痛発症メカニズム2016

    • Author(s)
      伊藤美紗、小野堅太郎、人見 涼露、野代 知孝、郡司掛香織、黒石加代子、川元 龍夫、稲永 清敏
    • Organizer
      第58回歯科基礎医学会
    • Place of Presentation
      北海道
    • Year and Date
      2016-08-24
    • Related Report
      2016 Research-status Report
  • [Presentation] 酢酸誘発口内炎モデルラットにおける病態と遺伝子変化2016

    • Author(s)
      野代知孝、小野堅太郎、人見涼露、伊藤美紗、正木千尋、細川隆司、稲永清敏
    • Organizer
      第76回九州歯科学会総会
    • Place of Presentation
      北九州
    • Year and Date
      2016-05-28
    • Related Report
      2016 Research-status Report
  • [Presentation] 矯正ワイヤーによる新規口内炎モデルラットの開発2016

    • Author(s)
      伊藤美紗、小野堅太郎、人見涼露、山口喜一郎、野代知孝、郡司掛香織、黒石加代子、川元龍夫、稲永清敏
    • Organizer
      第76回九州歯科学会総会
    • Place of Presentation
      北九州
    • Year and Date
      2016-05-28
    • Related Report
      2016 Research-status Report
  • [Presentation] 口内炎疼痛に対する抗ガン薬シスプラチンの影響2016

    • Author(s)
      小野堅太郎、山口喜一郎、人見涼露、野代知孝、自見英治郎、稲永清敏
    • Organizer
      第76回九州歯科学会総会
    • Place of Presentation
      北九州
    • Year and Date
      2016-05-28
    • Related Report
      2016 Research-status Report
  • [Presentation] A new preclinical pain model of orthodontic wire appliance-induced oral ulcer2016

    • Author(s)
      Ito M, Ono Kentaro, Hitomi S, Yamaguchi K, Nodai T, Gunjigake K, Kuroishi K, Kawwamoto T, Inenaga K
    • Organizer
      Asia-Pacific Conference
    • Place of Presentation
      Kitaksyushu
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] The change of pain-associatedediators and genes in acetic acid-induced oral ulcerative mucositis model2016

    • Author(s)
      Nodai T, Ono K, Hitomi S, Ito M,Masaki C, Hosokawa R, Inenaga K
    • Organizer
      Asia-Pacific Conference
    • Place of Presentation
      Kitaksyushu
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 機械的外傷後の口腔粘膜疼痛メカニズム2016

    • Author(s)
      伊藤美紗、小野堅太郎、人見涼露、野代知孝、川元龍夫、稲永清敏
    • Organizer
      第10回三叉神経領域の感覚ー運動統合機能研究会
    • Place of Presentation
      長野県佐久市
    • Related Report
      2016 Research-status Report
  • [Presentation] 酢酸誘発口内炎モデルラットの疼痛発症メカニズムに対するエンドセリン1の関与2016

    • Author(s)
      野代知孝、人見涼露、小野堅太郎、伊藤美紗、正木千尋、細川隆司、稲永清敏
    • Organizer
      第10回三叉神経領域の感覚ー運動統合機能研究会
    • Place of Presentation
      長野県佐久市
    • Related Report
      2016 Research-status Report
  • [Presentation] 矯正ワイヤー誘発口内炎における疼痛発症メカニズム2016

    • Author(s)
      伊藤美紗、小野堅太郎、人見涼露、郡司掛香織、黒石加代子、川元龍夫
    • Organizer
      第75回日本矯正歯科学会大会
    • Place of Presentation
      徳島
    • Related Report
      2016 Research-status Report
  • [Presentation] 酢酸誘発口内炎モデルラットに発症する口腔内疼痛に対するエンドセリン1の関与2016

    • Author(s)
      野代知孝、人見涼露、小野堅太郎、伊藤美紗、正木千尋、細川隆司、稲永清敏
    • Organizer
      第58回歯科基礎医学会
    • Place of Presentation
      北海道
    • Related Report
      2016 Research-status Report
  • [Book] 口腔顔面痛の診断と治療ガイドブック第2版2016

    • Author(s)
      日本口腔顔面痛学会
    • Total Pages
      248
    • Publisher
      医歯薬出版
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2022-02-21  

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