Investigation of the mechanism of opioid tolerance formation by visualization real-time analysis and development of new analgesic methods

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K11754
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Nagasaki University
• Principal Investigator: KURATA Shinji 長崎大学, 病院(歯学系), 助教 (20325666)
• Co-Investigator(Kenkyū-buntansha): 上園 保仁 国立研究開発法人国立がん研究センター, 研究所, 分野長 (20213340)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: オピオイド / オピオイド受容体 / 耐性

Outline of Final Research Achievements

To develop optimal perioperative analgesia, we investigated the effects of opioid receptor (OR) activity on opioid drugs and analgesics effect on the intracellular localization of μOR by visualization real-time analysis and Analysis of G-protein activity by the CellKey system.
(1) Remifentanil (RF) activates the G protein pathway of μORs, which is involved in analgesia, in a concentration-dependent manner. It also promotes the activity of the β-arrestin pathway, which is involved in side effects. (2) The combination of RF and S(+)ketamine have no effect on the G-protein activity of RF-activated μORs, but inhibits the activation of the β-arrestin pathway.
These results suggest that S(+) ketamine may be useful in preventing the development of RF-induced side effects such as acute tolerance formation.

Free Research Field

歯科麻酔学

Academic Significance and Societal Importance of the Research Achievements

歯科・口腔外科領域では，持続的な鎮痛を行うことが難しく，手術の痛みや慢性痛で苦しむ患者も多い。鎮痛には医療用麻薬（オピオイド）が使用されているが，時に呼吸抑制や耐性形成（効きづらくなる）を発症しその対応に難しくなることがある。そこで副作用が少ないかつ効果的な鎮痛作用を併せ持つ，鎮痛方法の確立は重要である。本研究で得られた結果は，オピオイド製剤の特性を一部解明するとともに，呼吸抑制・耐性形成の副作用の問題を解決し，また適切な鎮痛方法の確立・新規鎮痛薬の開発に貢献できると考える。