Elucidating mechanisms of action of general anesthetics using chemogenetics

• Project/Area Number: 19K22652
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Niigata University
• Principal Investigator: Kamiya Yoshinori 新潟大学, 医歯学系, 准教授 (90381491)
• Co-Investigator(Kenkyū-buntansha): 佐々木 美佳 新潟大学, 医歯学系, 助教 (20774061) ; 倉部 美起 新潟大学, 医歯学系, 助教 (30635579) ; 上野 将紀 新潟大学, 脳研究所, 教授 (40435631)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 麻酔薬 / chemogenetics / 青斑核 / 全身麻酔薬 / 薬理遺伝学 / 電気生理 / DREADD / 薬理遺伝学的手法

Outline of Research at the Start

「麻酔がなぜかかるか？」は現代においても未解明の科学的疑問である。
理由の一つとして、無麻酔下での動物個体からの詳細な生理学的解析が困難であることが挙げられる。本研究では、人為的に外部から青斑核ノルアドレナリン作動性神経のみを制御可能な薬理遺伝学的手法を用い、かつ、無麻酔下での神経活動の解析にチャレンジすることで、近年停滞している麻酔薬による意識消失・覚醒のメカニズムの解明に新たな着眼点から挑む。これらのツールを組み合わせることによって、研究の幅が飛躍的に広がり、従来の知見とは異なる新しい全身麻酔薬の作用機序を見出せる可能性がある。

Outline of Final Research Achievements

The purpose of this study was to use chemogenetics to manipulate noradrenergic (NA) neurons in the locus coeruleus to determine the role of NA neurons in the loss of consciousness and arousal during general anesthesia. To specifically manipulate the NA neurons, an adeno-associated virus (AAV1-PRSx8-hM3Dq-HA) was prepared and injected into the rat locus coeruleus. NA neuron activation only slightly altered the induction and arousal times of volatile anesthetics, but markedly altered the induction and arousal times of intravenous anesthetics. Furthermore, we established a method for electrophysiological analysis under free moving and under the control of the NA neurons

Academic Significance and Societal Importance of the Research Achievements

揮発性麻酔薬（セボフルラン）と静脈麻酔薬（プロポフォール）とで、青斑核NA神経の応答様式が異なることが明らかとなった。セボフルランに比べて、プロポフォール投与時の麻酔導入・覚醒時間はNA神経活性化の影響を強く受けた。このことは、セボフルランに比べてプロポフォールがより特異的に青斑核に作用することを示していると考えられる。また、free moving下での電気生理学的記録に成功したことから、全身麻酔薬投与時の一連の神経活動についてより詳細に解析することが可能となった。今後、この手法を用いて様々な種類の全身麻酔薬の作用機序を調べることができるという点で、非常に意義があることと考えられる。

Research Products

• [Journal Article] Distance of catheter tip dislocation in continuous interscalene brachial plexus block (2022)
  • Author(s): Abe Tatsuya、Fujiwara Takashi、Kamiya Yoshinori
  • Journal Title: Korean Journal of Anesthesiology Volume: 75 Issue: 1 Pages: 97-99
  • DOI: 10.4097/kja.21227
  • Peer Reviewed
• [Journal Article] Subanesthetic Dose of Propofol Activates the Reward System in Rats (2021)
  • Author(s): Nagata Isao、Sasaki Mika、Miyazaki Tomoyuki、Saeki Kensuke、Ogawa Ken-ichi、Kamiya Yoshinori
  • Journal Title: Anesthesia & Analgesia Volume: Publish Ahead of Print Issue: 2 Pages: 414-426
  • DOI: 10.1213/ane.0000000000005847
  • Peer Reviewed
• [Journal Article] Sex differences in pain-induced modulation of corticotropin-releasing hormone neurons in the dorsolateral part of the stria terminalis in mice (2021)
  • Author(s): Hagiwara Hiroko、Sakimura Kenji、Abe Manabu、Itoi Keiichi、Kamiya Yoshinori、Akema Tatsuo、Funabashi Toshiya
  • Journal Title: Brain Research Volume: 1773 Pages: 147688-147688
  • DOI: 10.1016/j.brainres.2021.147688
  • Peer Reviewed
• [Journal Article] Effects of the Kampo medicine Yokukansan for perioperative anxiety and postoperative pain in women undergoing breast surgery: A randomized, controlled trial (2021)
  • Author(s): Tanaka Moegi、Tanaka Tsunehiko、Takamatsu Misako、Shibue Chieko、Imao Yuriko、Ando Takako、Baba Hiroshi、Kamiya Yoshinori
  • Journal Title: PLOS ONE Volume: 16 Issue: 11 Pages: e0260524-e0260524
  • DOI: 10.1371/journal.pone.0260524
  • Peer Reviewed / Open Access
• [Journal Article] Low-dose Droperidol Reduces the Amplitude of Transcranial Electrical Motor-evoked Potential (2021)
  • Author(s): Mitsuma Yusuke、Furutani Kenta、Deguchi Hiroyuki、Kamiya Yoshinori、Tanaka Takahiro、Kitamura Nobutaka、Baba Hiroshi
  • Journal Title: Journal of Neurosurgical Anesthesiology Volume: Publish Ahead of Print Issue: 4 Pages: 424-428
  • DOI: 10.1097/ana.0000000000000784
  • Peer Reviewed
• [Journal Article] Serotonin Plays a Key Role in the Development of Opioid-Induced Hyperalgesia in Mice (2021)
  • Author(s): Sasaki Mika、Kamiya Yoshinori、Bamba Keiko、Onishi Takeshi、Matsuda Keiichiro、Kohno Tatsuro、Kurabe Miyuki、Furutani Kenta、Yanagimura Harue
  • Journal Title: The Journal of Pain Volume: - Issue: 6 Pages: 715-729
  • DOI: 10.1016/j.jpain.2020.12.008
  • Peer Reviewed / Open Access
• [Journal Article] Low-dose droperidol suppresses transcranial electrical motor-evoked potential amplitude: a retrospective study (2020)
  • Author(s): Deguchi Hiroyuki、Furutani Kenta、Mitsuma Yusuke、Kamiya Yoshinori、Baba Hiroshi
  • Journal Title: Journal of Clinical Monitoring and Computing Volume: Publish Ahead of Print Issue: 1 Pages: 1-1
  • DOI: 10.1007/s10877-020-00464-4
  • Peer Reviewed
• [Journal Article] Neurosteroid dehydroepiandrosterone sulphate enhances pain transmission in rat spinal dorsal horn (2019)
  • Author(s): Yamamoto Goh、Kamiya Yoshinori、Sasaki Mika、Ikoma Miho、Baba Hiroshi、Kohno Tatsuro
  • Journal Title: British Journal of Anaesthesia Volume: 印刷中 Issue: 2 Pages: e215-e225
  • DOI: 10.1016/j.bja.2019.03.026
  • Peer Reviewed / Open Access
• [Journal Article] A Bolus Dose of Ketamine Reduces the Amplitude of the Transcranial Electrical Motor-evoked Potential: A Randomized, Double-blinded, Placebo-controlled Study (2019)
  • Author(s): Furutani K, Degichi H, Matsuhashi M, Mitsuma Y, Kamiya Y, Baba H
  • Journal Title: J Neurosurg Anesthesiol Volume: Oct, 16 Issue: 3 Pages: 1-1
  • DOI: 10.1097/ana.0000000000000653
  • Peer Reviewed
• [Journal Article] Acute spatial spread of NO-mediated potentiation during hindpaw ischaemia in mice. (2019)
  • Author(s): Onishi T, Watanabe T, Sasaki M, Kamiya Y, Horie M, Tsukano H, Hishida R, Kohno T, Takebayashi H, Baba H, Shibuki K
  • Journal Title: J Physiol. Volume: 597 Issue: 13 Pages: 3441-3455
  • DOI: 10.1113/jp277615
  • Peer Reviewed / Open Access
• [Presentation] Opioid-induced hyperalgesia induced by chronic administration of morphine is caused by serotonin in spinal dorsal horn and, in part, through the 5-HT3 receptor. (2019)
  • Author(s): Mika Sasaki, Yoshinori Kamiya, Keiko Bamba, Moegi Tanaka, Takeshi Ohnishi
  • Organizer: Neuroscience 2019