Development of novel analgesic strategy based on the intracellular localization analysis of opioid receptors using real time visualization assay

Research Project

Project/Area Number	18K08858
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 55050:Anesthesiology-related
Research Institution	Nagasaki University
Principal Investigator	MURATA Hiroaki 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (90437856)
Co-Investigator(Kenkyū-buntansha)	上園保仁東京慈恵会医科大学, 医学部, 教授 (20213340) 宮野加奈子東京慈恵会医科大学, 医学部, 准教授 (50597888)
Project Period (FY)	2018-04-01 – 2023-03-31
Project Status	Completed (Fiscal Year 2022)
Budget Amount *help	¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000) Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000) Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000) Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords	オピオイド鎮痛薬 / オピオイド受容体 / 脱感作 / 細胞内陥入 / βアレスチン / オピオイド / 受容体 / 細胞内局在 / 二量体
Outline of Final Research Achievements	Remifentanil and fentanyl are two major opioid analgesics often used for perioperative analgesia. We investigated the desensitization profiles of remifentanil and fentanyl to the μ-opioid receptor using human embryonic kidney 293 cells stably expressing HaloTag-tagged μ-opioid receptor. The efficacy and potency during the first administration of remifentanil or fentanyl in activating the μ-opioid receptor were almost equal. Similarly, in β arrestin recruitment, which determines desensitization processes, they showed no significant difference. Repetitive administration of fentanyl resulted in a stronger μ-opioid receptor desensitization potency than that of remifentanil. Subsequently, we demonstrated that remifentanil possessed a higher internalization potency of the μ-opioid receptor than fentanyl by the real-time visualization assay.
Academic Significance and Societal Importance of the Research Achievements	レミフェンタニルとフェンタニルは効果発現時間や作用持続時間など臨床的な特徴はやや異なるものの鎮痛力価は同等といわれ、周術期疼痛管理に用いられる標準的なオピオイド鎮痛薬である。オピオイド鎮痛薬の使用においては耐性形成や痛覚過敏誘発などの問題が指摘されているが、本研究成果はこれらの発生メカニズムに関与する分子機序を示唆するものであり学術的意義がある。また、これらの現象を踏まえた最適な周術期のオピオイド鎮痛薬使用プロトコルを提唱する基盤となる成果が得られたと考えられ、より優れた周術期疼痛管理に貢献できる点で社会的意義もあると言える。