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The role of morphinone in the tolerance development to morphine

Research Project

Project/Area Number 24659289
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Pain science
Research InstitutionOkayama University

Principal Investigator

NARIMATSU SHIZUO  岡山大学, 医歯(薬)学総合研究科, 教授 (20113037)

Co-Investigator(Kenkyū-buntansha) MATSUOKA Junji  岡山大学, 医学部保健学科, 教授 (30332795)
HANIOKA Nobumitsu  横浜薬科大学, 教授 (70228518)
Co-Investigator(Renkei-kenkyūsha) YAMANO Shigeru  福岡大学, 薬学部, 教授 (80140755)
KITA Hideki  福岡大学, 薬学部, 助教 (60341450)
KUMAMOTO Takuya  武蔵野大学, 薬学部, 教授 (50292678)
FUNAHASHI Tatsuya  松山大学, 薬学部, 教授 (60343646)
TANABE Tomotaka  松山大学, 薬学部, 講師 (60532786)
MASUDA Kazufumi  就実大学, 薬学部, 准教授 (00243486)
KATAOKA Hiroyuki  就実大学, 薬学部, 教授 (80127555)
SAITO Keita  就実大学, 薬学部, 講師 (30454854)
Research Collaborator MATSUNAGA Hisashi  佐賀県医療センター, 好生館薬剤部, 部長 (10569156)
IMAMURA Makio  倉敷成人病センター, 診療支援部, 副部長
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2013: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsモルヒノン / ヒト尿中代謝物 / 17β-ヒドロキシステロイド脱水素酵素 / モルヒネ / エピモルヒネ / μ-受容体-GFP融合タンパク質 / HEK293細胞 / インターナリゼーション / ラット17β-HSD type 2 / ラット17β-HSD type 6 / ドッキングシミュレーション / 耐性発現機構 / μ-受容体 / モルヒネ6位脱水素酵素
Outline of Final Research Achievements

In this project, we characterized morphinone (MON) as an active metabolite of morphine (M), from various view points. Firstly, considerable amounts of MON were detected in urine samples from cancer patients receiving palliative therapy with M in the LC/MS analysis. Secondly, we characterized the enzyme(s) responsible for MON formation using recombinant rat 17β-hydroxysteroid dehydrogenases type 2 and 6, and kinetic analyses revealed that only type 2 catalyzed the conversion of M to MON in the presence of NAD+ or NADP+. Thirdly, HEK293 cells transformed with a vector in which cDNA encodingμ-receptor-green fluorescence protein (GFP)-fusion proteins were introduced. Addition of M as well as DAMGO, a knownμ-receptor agonist, caused internalization of the fusion proteins in the cell membrane. This HEK 293 cell system may be a useful tool to analyze possible interaction between MON and μ-receptor.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (3 results)

All 2015 2012

All Presentation (3 results)

  • [Presentation] ラット 17β-Hydroxysteroid dehydrogenase type 2 及び type 6によるMorphine及び Epimorphine の立体選択的代謝反応の速度論的解析2015

    • Author(s)
      成松鎭雄, 松本考弘,上島将幹,増田和文,加藤久登, 齋藤啓太,片岡洋行,熊本卓哉, 舟橋達也, 田邊知孝, 喜多秀樹, 石田 隆, 山野 茂
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸市
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Annual Research Report
  • [Presentation] ラット 17β-Hydroxysteroid dehydrogenase type 2による Morphine及び Epimorphine の立体選択的代謝反応の機構解明2015

    • Author(s)
      増田和文, 加藤久登, 齋藤啓太, 片岡洋行, 熊本卓哉, 舟橋達也, 田邊知孝, 喜多秀樹, 石田 隆, 山野 茂, 松本考弘, 上島将幹, 成松鎭雄
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸市
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Annual Research Report
  • [Presentation] Species difference in the metabolism of 6-hydroxyl group of morphine and epimorphine: Comparison between guinea pig and human2012

    • Author(s)
      Shizuo Narimatsu
    • Organizer
      International Conference on Biologically Active Substances 'Bioactive Okayama 2012'
    • Place of Presentation
      Okayama, Japan
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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