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Can we prevent analgesic tolerance to morphine? Study of high-order opioid receptor signal complex and its clinical application.

Research Project

Project/Area Number 17H04323
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Anesthesiology
Research InstitutionJichi Medical University

Principal Investigator

Koshimizu Taka-aki  自治医科大学, 医学部, 教授 (20392491)

Co-Investigator(Kenkyū-buntansha) 土屋 裕義  自治医科大学, 医学部, 講師 (80508755)
東 森生  自治医科大学, 医学部, 講師 (90709643)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
Keywords鎮痛耐性 / 医療用麻薬 / 受容体 / オピオイド / バゾプレッシン / ゲノム編集 / アデニレートサイクラーゼ / アレスチン / バゾプレシン / 高次複合体 / シグナル複合体 / アロステリック効果 / 相互作用 / モルヒネ
Outline of Final Research Achievements

We successfully discovered how V1b vasopressin receptor regulates a process of development of morphine tolerance. V1b receptor complexed with mu-type opioid receptor and enhanced morphine tolerance. Antagonist of V1b receptor was effective to reduce the morphine tolerance. We also found that morphine tolerance was delayed in mice lacking V1b receptors. In the rostral ventromedial medulla, transcripts for V1b and mu opioid receptors are localized. Complex formation among V1b, β-arrestin 2 and mu-receptor resulted in ERK phosphorylation and adenylate cyclase sensitization by morphine and vasopressin. Leucine-rich segment in the V1b carboxyl-terminus was necessary for the association with β-arrestin 2. Our findings indicate that inhibition of V1b receptor, which is complexed with mu receptor, is a molecular target to enhance morphine analgesia without increasing analgesic tolerance.

Academic Significance and Societal Importance of the Research Achievements

持続する痛みに繰り返し医療用麻薬を使用すると、鎮痛効果の減弱(耐性)を来す。臨床では、耐性を避けるために医療用麻薬の投与量を増加させたり、他の麻薬を使用するオピオイドローテーションの対策が取られているが、耐性を減弱させる手段は限られる。安全性を保ったまま非癌性慢性疾患にオピオイド鎮痛薬を使用するプロトコールや、科学的知見に基づく共通認識は十分でなく、過量投与や麻薬への依存症を増加させた。我々は、耐性を減弱させてより効果的な鎮痛治療を可能にする、V1b拮抗薬の働きを世界で初めて見出した。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (40 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (4 results) Journal Article (4 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (26 results) (of which Int'l Joint Research: 6 results,  Invited: 2 results) Remarks (6 results)

  • [Int'l Joint Research] ベルリン大学/キール大学/ドレスデン大学(ドイツ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] University of Portsmouth(英国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of Berlin(ドイツ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Charit Universitatsmedizin Berlin/Christian Albrechts UniversitaKiel(ドイツ)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Vasopressin Increases Urinary Acidification via V1a Receptors in Collecting Duct Intercalated Cells2019

    • Author(s)
      Giesecke Torsten、Himmerkus Nina、Leipziger Jens、Bleich Markus、Koshimizu Taka-aki、F?hling Michael、Smorodchenko Alina、Shpak Julia、Knappe Carolin、Isermann Julian、Ayasse Niklas、Kawahara Katsumasa、Schmoranzer Jan、Gimber Niclas、Paliege Alexander、Bachmann Sebastian、Mutig Kerim
    • Journal Title

      Journal of the American Society of Nephrology

      Volume: 30 Issue: 6 Pages: 946-961

    • DOI

      10.1681/asn.2018080816

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance2018

    • Author(s)
      Koshimizu TA, et al.
    • Journal Title

      Nat Neurosci

      Volume: Epub ahead of print Issue: 6 Pages: 820-833

    • DOI

      10.1038/s41593-018-0144-y

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dynamic Modulation of Mouse Locus Coeruleus Neurons by Vasopressin 1a and 1b Receptors.2018

    • Author(s)
      Campos-Lira E, et al.
    • Journal Title

      Front Neurosci.

      Volume: 12 Pages: 919-919

    • DOI

      10.3389/fnins.2018.00919

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Topical lidocaine inhibits spasm during colonoscopy: a double-blind, randomized controlled trial (with video)2017

    • Author(s)
      Nemoto D, et al.
    • Journal Title

      Endosc Int Open

      Volume: 5(6) Issue: 06 Pages: E402-E407

    • DOI

      10.1055/s-0043-105489

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] オピオイド鎮痛耐性におけるV1bバゾプレッシン受容体複合体の機能解析2020

    • Author(s)
      輿水崇鏡、Chortip S、Fujianti C、Nuttawadee N、藤原葉子、 東森生、土屋裕義、谷口淳一
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] バソプレッシンV1a受容体欠損マウスが示す離乳後の体重減少2020

    • Author(s)
      Hiroyoshi Tsuchiya et. al.
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Analysis of interaction between dimerized receptor and beta-arrestin2020

    • Author(s)
      Ngamlertwong Nuttawadee et. al.
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ラット下垂体前葉の内分泌細胞は基底膜成分ラミニンα3鎖およびα5鎖に反応する2020

    • Author(s)
      東 森生、輿水 崇鏡
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] mu-オピオイド受容体-V1bバゾプレシン受容体複合体と相互作用するbeta-アレスチンの解析2019

    • Author(s)
      Nuttawadee Ngamlertwong et. al.
    • Organizer
      第140回日本薬理学会関東部会
    • Related Report
      2019 Annual Research Report
  • [Presentation] V1a vasopressin receptor deficient mice as a model for accelerated aging2019

    • Author(s)
      Fujianti Casmad et. al.
    • Organizer
      第34回日本下垂体研究会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Computer vision analysis and deep learning of maternal behavior in mice2019

    • Author(s)
      Sajjaviriya Chortip
    • Organizer
      第34回日本下垂体研究会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Opioid-promoted complex involves mu-opioid and V1b receptors and beta-arrestin 22019

    • Author(s)
      Nuttawadee Ngamlertwong et. al.
    • Organizer
      第63回日本薬学会関東支部大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ラット下垂体前葉の内分泌細胞が接する基底膜を構成するラミニン分子の役割2019

    • Author(s)
      東 森生、輿水崇鏡
    • Organizer
      第141回日本薬理学会関東部会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Deep learning model for analysis of maternal behavior in mice2019

    • Author(s)
      Sajjaviriya Chortip
    • Organizer
      第30回バゾプレシン研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Allosteric effect of Vasopressin on Carboxyl termini of homomeric V1a receptor dimers2019

    • Author(s)
      Ngamlertwong et. al.
    • Organizer
      第29回バソプレシン研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Vasopressin suppress mutual interaction between cytoplasmic tail of V1a receptors2019

    • Author(s)
      Ngamlertwong et. al.
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Analysis of interaction between dimerized receptor and receptor-interacting protein2018

    • Author(s)
      Koshimizu TA et. al.
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] V1a vasopressin receptor involved in the uterus contraction2018

    • Author(s)
      Tsuchiya H et. al.
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] コンピュータービジョンと深層学習を用いたバゾプレッシン受容体遺伝子改変動物の 行動解析2018

    • Author(s)
      Miyazaki M et. al.
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] V1bバゾプレッシン受容体高次複合体によるオピオイド鎮痛の調節2018

    • Author(s)
      Koshimizu TA et. al.
    • Organizer
      第139回日本薬理学会関東部会
    • Related Report
      2018 Annual Research Report
  • [Presentation] バゾプレシン研究最前線:受容体データサイエンスからの期待と展望2018

    • Author(s)
      輿水崇鏡
    • Organizer
      東京腎生理研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] マシンインテリジェンスによるバゾプレシン受容体欠損マウスの表現型解析2018

    • Author(s)
      輿水崇鏡、Chortip S、Fujianti C、Nuttawadee N、藤原葉子、 東森生、土屋裕義、谷口淳一
    • Organizer
      第29回バソプレシン研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 痛みに関わるV1bバゾプレッシン受容体高次複合体の機能解析2018

    • Author(s)
      輿水崇鏡、Nuttawadee Ngamlertwong、藤原葉子、土屋裕義、谷口淳一
    • Organizer
      バゾプレッシン研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Regulation of morphine sensitivity and adenylate cyclase sensitization by carboxyl-terminus of V1b vasopressin receptors2017

    • Author(s)
      Taka-aki Koshimizu, Kenji Honda, and Yukio Takano
    • Organizer
      International Narcotics Research Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] マウス視床下部神経細胞の突起形成へのプロスタグランジンD2 の作用2017

    • Author(s)
      土屋裕義、北條寛典、杉本幸彦、Ngamlertwong Nuttawadee、藤原葉子、輿水崇鏡
    • Organizer
      日本下垂体研究会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 分子系統樹を用いた、オーファンGタンパク質共役型受容体の機能予測2017

    • Author(s)
      笹井隆太郎、宮崎葵、輿水崇鏡
    • Organizer
      自治医大シンポジウム
    • Related Report
      2017 Annual Research Report
  • [Presentation] Comparative analysis of vasopressin V1a receptor distribution in rodent and human kidneys2017

    • Author(s)
      Torsten Giesecke, Taka-aki Koshimizu, et al.
    • Organizer
      2017 Kidney Week
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] バゾプレッシンV1b受容体の痛覚における新知見と応用2017

    • Author(s)
      輿水崇鏡
    • Organizer
      氷川フォーラム
    • Related Report
      2017 Annual Research Report
  • [Presentation] Zwitterionic Polymers for Peptide Hormone Delivery to the Intracellular G-Protein Coupled Receptors2017

    • Author(s)
      Aki Kashiwazaki, Taka-aki Kashimizu, Masaru Tanaka
    • Organizer
      Biomaterials International 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] バゾプレッシン受容体高次複合体の基礎と臨床2017

    • Author(s)
      輿水崇鏡
    • Organizer
      薬師寺人セミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Remarks] 自治医科大学分子薬理学講座

    • URL

      http://www.jichi.ac.jp/molpharm/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 自治医科大学分子薬理学部門

    • URL

      http://www.jichi.ac.jp/molpharm/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 自治医科大学研究情報

    • URL

      http://www.jichi.ac.jp/news/research/2018/20180509.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 福岡大学研究ニュース

    • URL

      https://www.fukuoka-u.ac.jp/research/column/18/05/02090825.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 自治医科大学医学部薬理学講座分子薬理学部門

    • URL

      http://www.jichi.ac.jp/molpharm/

    • Related Report
      2017 Annual Research Report
  • [Remarks] 第32回 日本下垂体研究会学術集会

    • URL

      http://www.jichi.ac.jp/jspr/2017/

    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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