| Project/Area Number |
17K11114
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Anesthesiology
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| Research Institution | Teikyo University |
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Principal Investigator |
Tomohiko Aoe 帝京大学, 医学部, 教授 (90311612)
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| Co-Investigator(Kenkyū-buntansha) |
國分 宙 千葉大学, 医学部附属病院, 助教 (50782695)
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| Project Period (FY) |
2017-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | オピオイド / 慢性疼痛 / 下行性疼痛抑制系 / 痛覚過敏 / 耐性 / トランスレーショナルリサーチ / ストレス / 神経科学 |
|---|
| Outline of Final Research Achievements |
We previously reported that signaling from the endoplasmic reticulum (ER) stress contributed to the development of morphine tolerance. We examined the effects of pharmacological chaperones that alleviate ER stress on opioid tolerance development by assessing thermal nociception in mice. Pharmacological chaperones such as tauroursodeoxycholic acid and 4-phenylbutyrate suppressed the development of morphine tolerance and restored analgesia. Chaperones alone did not cause analgesia. Although morphine administration induced analgesia when glycogen synthase kinase 3β (GSK3β) was in an inactive state due to serine 9 phosphorylation, repeated morphine administration suppressed this phosphorylation event. Co-administration of chaperones maintained the inactive state of GSK3β. These results suggest that ER stress may facilitate morphine tolerance due to intracellular crosstalk between the UPR and MOR signaling. Pharmacological chaperones may be useful in the management of opioid misuse.
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| Academic Significance and Societal Importance of the Research Achievements |
モルヒネを始めとするオピオイドは優れた鎮痛薬であるが、慢性疼痛疾患への連用では耐性や痛覚過敏性の形成が問題となり得る。本研究でオピオイド耐性形成に小胞体ストレスが関与することが示唆され、また、小胞体ストレスを緩和する薬理学的シャペロンの併用使用により、鎮痛作用が保たれることが明らかになった。癌性疼痛などに対するオピピオイド製剤の使用に際し薬理学的シャペロンの併用が有用であることが示唆された。
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