Involvement of spinal gap junction in induction and maintenance of chronic pain

• Project/Area Number: 26460342
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Hiroshima University
• Principal Investigator: Morioka Norimitsu 広島大学, 医歯薬保健学研究院(薬), 教授 (20346505)
• Co-Investigator(Kenkyū-buntansha): 中島 一恵 (久岡一恵 / 中島 一恵(久岡一恵)) 広島大学, 医歯薬保健学研究院(薬), 助教 (20393431) ; 仲田 義啓 広島大学, 医歯薬保健学研究院(薬), 名誉教授 (40133152)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 神経障害性疼痛 / アストロサイト / connexin43 / 脊髄アストロサイト / interleukin-6 / cyclooxygenase-2 / GSK-3β / TNF / グルタミン酸トランスポーター / ユビキチン / プロテアソーム / グルタミン酸 / connexin36

Outline of Final Research Achievements

Spinal dorsal horn astrocytic Cx43 decreased following a peripheral nerve injury. Reduction of Cx43 induced neuropathic pain through downregulation of GLT-1, upregulation of interleukin-6 and cyclooxygenase-2 in spinal dorsal horn. Restoring Cx43 by an adenovirus vector expressing Cx43 or treatment with lycopene ameliorated neuropathic pain. Tumor necrosis factor (TNF) contributed to downregulation of Cx43 expression following peripheral nerve injury. In addition, the ubiquitin-proteasome system was involved in TNF-induced downregulation of Cx43 in cultured spinal astrocytes.

Research Products

• [Journal Article] Stimulation of spinal dorsal horn β2-adrenergic receptor ameliorates neuropathic mechanical hypersensitivity through a reduction of phosphorylation of microglial p38 MAP kinase and astrocytic c-jun N-terminal kinase. (2016)
  • Author(s): Zhang F.F., Morioka N., Abe H., Fujii S., Miyauchi K., Nakamura Y., Hisaoka-Nakashima K., Nakata Y.
  • Journal Title: Neurochemistry International Volume: 101 Pages: 144-155
  • DOI: 10.1016/j.neuint.2016.11.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lycopene ameliorates neuropathic pain by upregulating spinal astrocytic connexin 43 expression. (2016)
  • Author(s): Zhang F.F., Morioka N., Kitamura T., Fujii S., Miyauchi K., Nakamura Y., Hisaoka-Nakashima K., Nakata Y.
  • Journal Title: Life Sciences Volume: 155 Pages: 116-122
  • DOI: 10.1016/j.lfs.2016.05.021
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Tumor necrosis factor-mediated downregulation of spinal astrocytic connexin43 leads to increased glutamatergic neurotransmission and neuropathic pain in mice. (2015)
  • Author(s): Morioka N., Zhang F.F., Nakamura Y., Kitamura T., Hisaoka-Nakashima K., Nakata Y.
  • Journal Title: Ｂｒａｉｎ， Ｂｅｈａｖｉｏｒ， ａｎｄ Ｉｍｍｕｎｉｔｙ Volume: 49 Pages: 293-310
  • DOI: 10.1016/j.bbi.2015.06.015
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Proinflammatory cytokines downregulate connexin 43-gap junction in rat spinal astrocytes via ubiquitin-proteasome system. (2015)
  • Author(s): Zhang F.F., Morioka N., Kitamura T., Hisaoka-Nakashima K., Nakata Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 464 Issue: 4 Pages: 1202-1208
  • DOI: 10.1016/j.bbrc.2015.07.105
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Downregulation of connexin36 in mouse spinal dorsal horn neurons leads to mechanical allodynia (2015)
  • Author(s): Nakamura Y, Morioka N, Zhang FF, Hisaoka-Nakashima K, Nakata Y
  • Journal Title: Journal of Neuroscience Research Volume: 93 Issue: 4 Pages: 584-591
  • DOI: 10.1002/jnr.23515
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] A role of spinal astrocytic connexin43 in maintenance of neuropathic pain. (2016)
  • Author(s): 藤井志織, 森岡徳光, 張 芳芳, 中島一恵, 仲田義啓
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-09
  • Int'l Joint Research
• [Presentation] 神経障害性疼痛発症時における脊髄アストロサイトConnexin43の新たな役割 (2016)
  • Author(s): 藤井志織, 張 芳芳, 中島一恵, 仲田義啓, 森岡徳光
  • Organizer: 第129回日本薬理学会近畿部会
  • Place of Presentation: 広島県医師会館
• [Presentation] 脊髄アストロサイトにおけるconnexin43の発現低下はIL-6及びCOX-2の発現増加を介して痛みを誘発する (2016)
  • Author(s): 藤井志織, 張 芳芳, 中島一恵, 仲田義啓, 森岡徳光
  • Organizer: 第130回日本薬理学会近畿部会
  • Place of Presentation: 京都大学百周年時計台記念館
• [Presentation] The role of spinal astrocytic Cx43 in the maintenance of neuropathic pain (2015)
  • Author(s): Zhang F., Morioka N., Nakamura Y., Fujii S., Hisaoka-Nakashima K., Nakata Y.
  • Organizer: 45th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] 脊髄アストロサイトConnexin43発現低下による神経障害性疼痛発症メカニズムの解析 (2015)
  • Author(s): 藤井志織, 森岡徳光, 張 芳芳, 中島一恵, 仲田義啓
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2015
  • Place of Presentation: 東京大学薬学部
  • Year and Date: 2015-08-29
• [Presentation] 難治性疼痛発症メカニズムに関与する新規制御因子の探索とその治療戦略 (2015)
  • Author(s): 森岡徳光
  • Organizer: 生体機能と創薬シンポジウム2015
  • Place of Presentation: 日本大学薬学部
  • Year and Date: 2015-08-28
  • Invited
• [Presentation] 脊髄アストロサイトConnexin43の神経障害性疼痛発症への関与 (2014)
  • Author(s): 北村智哉、森岡徳光、張 芳芳、藤井志織、中島一恵、仲田義啓
  • Organizer: 第53回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-11-08
• [Presentation] 神経障害性疼痛に対する脊髄後角におけるアストロサイトCx43の関与 (2014)
  • Author(s): 張 芳芳、森岡徳光、北村智哉、藤井志織、中島一恵、仲田義啓
  • Organizer: 第126回日本薬理学会近畿部会
  • Place of Presentation: 和歌山県JAビル
  • Year and Date: 2014-10-24
• [Presentation] 脊髄アストロサイトConnexin43の神経障害性疼痛における機能解明 (2014)
  • Author(s): 北村智哉、森岡徳光、張 芳芳、中島一恵、仲田義啓
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2014
  • Place of Presentation: 近畿大学東大阪キャンパス
  • Year and Date: 2014-08-30
• [Presentation] 脊髄アストロサイトgap junction-Cx43発現低下に対するproteasome系の役割 (2014)
  • Author(s): 張 芳芳、森岡徳光、北村智哉、藤井志織、中島一恵、仲田義啓
  • Organizer: 第125回日本薬理学会近畿部会
  • Place of Presentation: 岡山コンベンションセンター
  • Year and Date: 2014-06-20
• [Remarks] 広島大学大学院医歯薬保健学研究院薬効解析科学ホームページ
  • URL: http://home.hiroshima-u.ac.jp/pha/
• [Remarks] 広島大学大学院医歯薬保健学研究院応用生命科学部門薬効解析科学
  • URL: http://home.hiroshima-u.ac.jp/pha/