Can we prevent analgesic tolerance to morphine? Study of high-order opioid receptor signal complex and its clinical application.
| Project/Area Number |
17H04323
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Anesthesiology
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| Research Institution | Jichi Medical University |
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Principal Investigator |
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| 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)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| 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)
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| 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 |
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| 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.
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| 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。
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Report
(4 results)
Research Products
(40 results)
