Elucidation of the mechanisms of chronic pain by PAC1 receptor and drug discovery.

• Project/Area Number: 26430067
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: University of Toyama
• Principal Investigator: TAKASAKI ICHIRO 富山大学, 大学院理工学研究部(工学), 准教授 (00397176)
• Co-Investigator(Renkei-kenkyūsha): KURIHARA TAKASHI 鹿児島大学, 医歯学総合研究科(医学), 准教授 (60282745) ; TOYOOKA NAOKI 富山大学, 大学院理工学研究部(工学), 教授 (10217565) ; GOUDA HIROAKI 昭和大学, 薬学部, 教授 (60276160)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: PACAP / PAC1受容体 / アロディニア / 脊髄後角 / マイクロアレイ / 創薬 / 慢性疼痛 / 神経障害性疼痛 / ケモカイン / 核内受容体 / アンタゴニスト / Maxadilan

Outline of Final Research Achievements

Activation of spinal PAC1 receptor induces long-lasting mechanical allodynia in mice. In this study, we analyzed the involvement spinal Cyr61 which expression is increased by PAC1 receptor activation on the pain. Intrathecal injection of Cyr61 recombinant protein induced mechanical allodynia. Cyr61 protein increased the expression of chemokine CCL2 and CCL7 mRNA via integrin beta-1 in the astrocyte. The present results suggest that spinal PAC1-Cyr61-chemokine signaling are involved in the chronic pain and that integrin and/or chemokine receptors may be useful target for developing new analgesics.

Research Products

• [Journal Article] Involvement of Cyr61 in PACAP specific receptor-induced long-term allodynia. (2016)
  • Author(s): Maeda T, Nakanishi H, Yokai M, Miyata A, Kurihara T, Takasaki I
  • Journal Title: J Pharmacol Sci Volume: 30
  • Peer Reviewed
• [Journal Article] In silico and pharmacological screening identify novel PAC1 receptor antagonists. (2016)
  • Author(s): Watanabe A, Okada T, Fukuchi M, Gouda H, Kurihara T, Miyata A, Toyooka N, Takasaki I.
  • Journal Title: J Pharmacol Sci Volume: 30
  • Peer Reviewed
• [Journal Article] Convergent effests of Ca2+ and cAMP signals on the expression of immediate early genes in neurons. (2015)
  • Author(s): Fukuchi M, Kanesaki K, Takasaki I, Tabuchi A, Tsuda M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 466 (3) Issue: 3 Pages: 572-577
  • DOI: 10.1016/j.bbrc.2015.09.084
  • Peer Reviewed
• [Journal Article] Neuromodulatory Effect of Gαs- or Gαq-Coupled G-Protein-Coupled Receptor on NMDA Receptor Selectively Activates the NMDA Receptor/Ca2+/Calcineurin/cAMP Response Element-Binding Protein-Regulated Transcriptional Coactivator 1 Pathway to Effectively Induce Brain-Derived Neurotrophic Factor Expression in Neurons. (2015)
  • Author(s): Fukuchi M, Tabuchi A, Kuwana Y, Watanabe S, Inoue M, Takasaki I, Izumi H, Tanaka A, Inoue R, Mori H, Komatsu H, Takemori H, Okuno H, Bito H, Tsuda M.
  • Journal Title: J Neurosci Volume: 35 (14) Pages: 5606-5624
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 新規鎮痛薬の開発を目指した核内受容体Nr4a1アンタゴニストの創製 (2017)
  • Author(s): 磯 芹奈，高原理行，合田浩明，宮田篤郎，栗原 崇，豊岡尚樹，髙﨑一朗
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホールほか
  • Year and Date: 2017-03-15
• [Presentation] PACAP誘導性機械的アロディニアと神経突起伸長におけるBtg2の関与に関する研究 (2017)
  • Author(s): 加藤 翔，宮田篤郎，栗原 崇，髙﨑一朗
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホールほか
  • Year and Date: 2017-03-15
• [Presentation] ニトログリセリン誘発偏頭痛モデルマウスを用いた新規PAC1アンタゴニストの評価 (2017)
  • Author(s): 柴崎知華，渡辺 藍，栗原 崇，宮田篤郎，豊岡尚樹，髙﨑一朗
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホールほか
  • Year and Date: 2017-03-15
• [Presentation] 種々疼痛モデルマウスにおける新規PAC1アンタゴニストの薬理学的評価 (2017)
  • Author(s): 長島涼太，上田隆拡，渡辺 藍，岡田卓哉，栗原 崇，宮田篤郎，豊岡尚樹，髙﨑一朗
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホールほか
  • Year and Date: 2017-03-15
• [Presentation] 難治性疼痛治療を目指したPACAP特異的受容体アンタゴニストの開発 (2017)
  • Author(s): 髙﨑一朗
  • Organizer: 2016年度痛み研究会
  • Place of Presentation: 生理学研究所・岡崎コンファレンスセンター
  • Year and Date: 2017-01-30
• [Presentation] 種々疼痛モデルマウスにおける新規PAC1受容体アンタゴニストの薬理学的評価 (2016)
  • Author(s): 長島涼太，上田隆拡，渡辺 藍，岡田卓哉，栗原 崇，宮田篤郎，豊岡尚樹，髙﨑一朗
  • Organizer: 日本薬学会北陸支部第128例会
  • Place of Presentation: 北陸大学薬学部アネックスホール
  • Year and Date: 2016-11-27
• [Presentation] Involvement of spinal Cyr61 in PAC1 receptor-mediated long-term mechanical allodynia in mice. (2016)
  • Author(s): Takasaki I, Maeda T, Yokai M, Miyata A, Kurihara T.
  • Organizer: 16th World Congress on Pain
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-09-26
  • Int'l Joint Research
• [Presentation] Involvment of Cyr61 in PACAP-specific receptor-induced long-term allodynia. (2016)
  • Author(s): 前田 辰則，中西 秀行，用皆 正文，宮田 篤郎，栗原 崇，髙﨑 一朗.
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2016-03-09
• [Presentation] PACAP および Maxadilan 誘導性の長期アロディニア反応における 脊髄 Cyr61の関与に関する研究. (2015)
  • Author(s): 前田 辰則，中西 秀行，栗原 崇，宮田 篤郎，髙﨑 一朗.
  • Organizer: 第66回日本薬理学会北部会
  • Place of Presentation: 富山（富山国際会議場）
  • Year and Date: 2015-09-18