Roles of locus coeruleus astrocytes for mechanisms and treatments of chronic pain

• Project/Area Number: 16K08985
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pain science
• Research Institution: Akita University
• Principal Investigator: Hayashida Kenichiro 秋田大学, 医学系研究科, 准教授 (40769634)
• Co-Investigator(Kenkyū-buntansha): 河谷 正仁 秋田大学, 医学系研究科, 教授 (00177700) ; 木口 倫一 和歌山県立医科大学, 医学部, 講師 (90433341)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 慢性痛 / 下行性抑制 / 神経障害性疼痛 / 疼痛 / 青斑核 / アストロサイト / 下行性抑制系 / 内因性鎮痛 / グルタミン酸 / ノルアドレナリン / 前頭葉

Outline of Final Research Achievements

This research project focused on the roles of locus coeruleus (LC) for endogenous analgesic system and brain functions to understand mechanisms and treatments of chronic pain. We observed that down regulation of glutamate transporters in the LC during chronification of neuropathic pain results in abnormal LC neuronal activities to cause impaired endogenous analgesia and cognitive functions.

Academic Significance and Societal Importance of the Research Achievements

本研究は、痛みの慢性化に伴う青斑核の病態を明らかにし、青斑核の異常が慢性痛だけでなく認知機能異常の一因になることを示した。また、この青斑核の異常は、既存薬であるバルプロ酸や抗うつ剤で予防・治療できる可能性を示した。これらの結果は、これまでの慢性痛の病態理解に新しい知見を加えるだけでなく、治療ターゲットとしての青斑核の重要性を示唆しており、新しい慢性痛治療法開発につながることが期待できる。

Research Products

• [Journal Article] Blockade of α2-adrenergic or metabotropic glutamate receptors induces glutamate release in the locus coeruleus to activate descending inhibition in rats with chronic neuropathic hypersensitivity (2019)
  • Author(s): Hayashida Ken-ichiro、Kimuram Masafumi、Eisenach James C.
  • Journal Title: Neuroscience Letters Volume: 676 Pages: 41-45
  • DOI: 10.1016/j.neulet.2018.04.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Psychosocial Stress Delays Recovery of Postoperative Pain Following Incisional Surgery in the Rat (2019)
  • Author(s): Arora Vipin、Martin Thomas J.、Aschenbrenner Carol A.、Hayashida Kenichiro、Kim Susy A.、Parker Renee A.、Eisenach James C.、Peters Christopher M.
  • Journal Title: Neuroscience Volume: 382 Pages: 35-47
  • DOI: 10.1016/j.neuroscience.2018.04.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel agonist of α₄β₂* neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain (2019)
  • Author(s): Sudo Roberto T、Hayashida Kenichiro、Santos Alu?zio N、Kawatani Masahito、Monteiro Carlos ES、Moreira Roberto D、Trachez Margarete M、Montes Guilherme C、Zapata-Sudo Gisele
  • Journal Title: Journal of Pain Research Volume: Volume 11 Pages: 2453-2462
  • DOI: 10.2147/jpr.s169637
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Psychosocial stress delays recovery of postoperative pain following incisional surgery in the rat (2018)
  • Author(s): Arora V, Ph, Martin T.J., Aschenbrenner C.A., Hayashida KI, Kim S, Parker R.A., Eisenach J.C., Christopher M. Peters C.M.
  • Journal Title: Neuroscience Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antinociception induced by a novel α 2A adrenergic receptor agonist in rodents acute and chronic pain models (2017)
  • Author(s): Sudo Roberto Takashi、do Amaral Rachel Vieiralves、Monteiro Carlos Eduardo da Silva、Pitta Ivan da Rocha、Lima Maria do Carmo、Montes Guilherme Carneiro、Ririe Douglas Gordon、Hayashida Kenichiro、Zapata-Sudo Gisele
  • Journal Title: Eur J Pharmacol Volume: 815 Pages: 210-218
  • DOI: 10.1016/j.ejphar.2017.09.018
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Antinociceptive profile of a new agonist of alpha4beta2 nicotinic receptor in rodent models of acute and chronic pain (2017)
  • Author(s): Sudo RT, Santos AN, Debom RC, Hayashida KI, Trachez MM, Zapata-Sudo G
  • Organizer: 2017 Anesthesiology Annual Meeting
  • Int'l Joint Research
• [Presentation] Alpha4beta2型ニコチン受容体を介する脊髄における鎮痛メカニズム (2017)
  • Author(s): 林田健一郎、河谷正仁、Sudo RT.
  • Organizer: 160回日本獣医学会学術集会
• [Patent(Industrial Property Rights)] 動物実験装置 (2017)
  • Inventor(s): 林田健一郎
  • Industrial Property Rights Holder: 秋田大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Acquisition Date: 2018
• [Patent(Industrial Property Rights)] 動物実験装置 (2017)
  • Inventor(s): 林田健一郎
  • Industrial Property Rights Holder: 秋田大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017-03-28