Mechanisms of gilal cell-dependent synapse remodeling in primary somatosensory cortex underlying development of chronic pain

• Project/Area Number: 26860380
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pain science
• Research Institution: University of Yamanashi
• Principal Investigator: SHIBATA Keisuke 山梨大学, 総合研究部, 助教 (50580411)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: アストロサイト / 神経障害性疼痛 / 一次体性感覚野 / ATP / シナプス再編 / 神経回路組み替え / グリア性神経回路組み替え / グリア性シナプス再編 / 慢性疼痛 / アロディニア / グリア細胞機能変調 / 異常神経回路

Outline of Final Research Achievements

We showed that an increase in extracellular ATP concentration ([ATP]e) in S1 by PNI is an initial event that triggers the astrocyte-mediated mechanical allodynia. Using microdialysis screening in vivo, we found that 1) [ATP]e was increased within contralateral S1 by PNI, which was preceded by synapse-remodeling, 2) a single brief ATP-treatment into S1 was enough to induce excess Ca2+ excitation and up-regulation of thrombospondin-1 (TSP-1), one of synaptogenic factors, in astrocytes, synapse-remodeling in S1 and subsequent mechanical allodynia, and 3) the ATP-induced mechanical allodynia was dependent on astrocytic Ca2+ excitation. These results suggested that the increase in [ATP]e within S1 is a key event that initiates the astrocyte-dependent synapse-remodeling and subsequent mechanical allodynia.

Research Products

• [Journal Article] P2Y6-deficiency increases micturition frequency and attenuates sustained contractility of the urinary bladder in mice (2017)
  • Author(s): Kira S,Yoshiyama M,Tsuchiya S,Shigetomi E,Miyamoto T,Nakagomi H,Shibata K,Mochizuki T,Takeda M,Koizumi S
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 771-771
  • DOI: 10.1038/s41598-017-00824-2
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Clock Genes Regulate the Circadian Expression of Piezo1, TRPV4, Connexin26, and VNUT in an Ex Vivo Mouse Bladder Mucosa. (2017)
  • Author(s): 5.Ihara T, Mitsui T, Nakamura Y, Kira S, Nakagomi H, Sawada N, Hirayama Y, Shibata K, Shigetomi E, Shinozaki Y, Yoshiyama M, Andersson KE, Nakao A, Takeda M, Koizumi S
  • Journal Title: PLoS One Volume: 12 Issue: 1 Pages: e0168234-e0168234
  • DOI: 10.1371/journal.pone.0168234
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Urothelial ATP exocytosis: regulation of bladder compliance in the urine storage phase (2016)
  • Author(s): Nakagomi H,Yoshiyama M,Mochizuki T,Miyamoto T,Komatsu R,Imura Y,Morizawa Y,Hiasa M,Kira S,Fujishita K,Shibata K,Shigetomi E,Shinozaki Y,Takeda M,Koizumi S
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 29761-29761
  • DOI: 10.1038/srep29761
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] An effective therapeutic approach for oxaliplatin-induced peripheral neuropathy using a combination therapy with goshajinkigan and bushi. (2016)
  • Author(s): Mizuno K, Shibata K, Komatsu R, Omiya Y, Kase Y, Koizumi S.
  • Journal Title: Cancer Biology & Therapy Volume: 17(11) Pages: 1206-1212
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Clock mutant mouse is a novel experimental model for nocturia and nocturnal polyuria. (2016)
  • Author(s): Ihara, T., Mitsui, T., Nakamura, Y., Kira, S., Miyamoto, T., Nakagomi, H., Sawada, N., Hirayama, Y., Shibata, K., Shigetomi, E., Shinozaki, Y., Yoshiyama, M., Nakao, A., *Takeda, M. *Koizumi, S.
  • Journal Title: Neurourology and Urodynamics Volume: 36 Issue: 4 Pages: 1034-1038
  • DOI: 10.1002/nau.23062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain. (2016)
  • Author(s): Kim SK, Hayashi H, Ishikawa T, Shibata K, Shigetomi E, Shinozaki Y, Inada H, Roh SE, Kim SJ, Lee G, Bae H, Moorhouse AJ, Mikoshiba K, Fukazawa Y, Koizumi S, Nabekura J.
  • Journal Title: J Clin Invest Volume: 126(5) Issue: 5 Pages: 1983-1997
  • DOI: 10.1172/jci82859
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 一次体性感覚野におけるATPを介したアストロサイト性シナプス再編の分子メカニズム (2017)
  • Author(s): 久保田啓太、柴田圭輔、江藤圭、稲田浩之、篠崎陽一、繁冨英治、御子柴克彦、鍋倉淳一、小泉修一
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎パブリックホール、長崎新聞文化ホール アストピア（長崎、長崎市）
  • Year and Date: 2017-03-15
• [Presentation] 一次体性感覚野のATP増加がアストロサイト性シナプス再編及び機械的アロディニアを引き起こす (2017)
  • Author(s): 柴田圭輔、久保田啓太、石川達也、篠崎陽一、繁冨英治、御子柴克彦、鍋倉淳一、小泉修一
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎パブリックホール、長崎新聞文化ホール アストピア（長崎、長崎市）
  • Year and Date: 2017-03-15
• [Presentation] 大脳皮質体性感覚野のグリア性神経回路組み替えによる末梢感覚情報の変化-プリンシグナリングの関与- (2017)
  • Author(s): 柴田圭輔、久保田啓太、小泉修一
  • Organizer: CREST合同ミーティング
  • Place of Presentation: 勝沼ぶどうの丘センター（山梨、甲州市）
  • Year and Date: 2017-02-07
• [Presentation] 慢性疼痛形成時の一次体性感覚野におけるATPの役割 (2016)
  • Author(s): 柴田圭輔、久保田啓太、石川達也、鍋倉淳一、小泉修一
  • Organizer: 第20回Japan Purine Club Meeting
  • Place of Presentation: 東京慈恵会医科大学 (東京、港区)
  • Year and Date: 2016-10-26
• [Presentation] ブシ末による慢性疼痛のグリア性制御 (2016)
  • Author(s): 小泉修一、柴田圭輔
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: 韓国、ソウル
  • Year and Date: 2016-07-21
  • Int'l Joint Research
• [Presentation] アストロサイトのプリン作動性シグナルによる一次体性感覚野における神経ネットワーク制御 (2016)
  • Author(s): 久保田啓太、柴田圭輔、江藤圭、稲田浩之、石川達也、高梨健太、繁冨英治、篠崎陽一、鍋倉淳一、小泉修一
  • Organizer: 第89回 日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-09
• [Presentation] グリア細胞とシナプInhibition by Goshajinkigan, a traditional Japanese medicine, of paclitaxel-induced peripheral neuropathy via astrocytesスの近接場光学顕微鏡観察 (2016)
  • Author(s): Kenta Takanashi, Keisuke Shibata, Keita Kubota, Keita Mizuno, Yuji Omiya, Yoshio Kase, Schuichi Koizumi
  • Organizer: 第89回 日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-09
• [Presentation] グリア細胞とシナプスの近接場光学顕微鏡観察 (2016)
  • Author(s): 酒井優、岡部菜央、櫻井杏梨、篠崎陽一、柴田圭輔、繁冨英治、小泉修一、内山和治、堀裕和、小林潔
  • Organizer: 日本光学会ナノオプティクス研究グループ第22回研究討論会
  • Place of Presentation: 東京農工大学 科学博物館 本館（東京都小金井市）
  • Year and Date: 2016-03-01
• [Presentation] 牛車腎気丸の抗癌剤誘発ニューロパチー抑制作用 (2016)
  • Author(s): 高梨健太、柴田圭輔、水野景太、大宮雄司、小泉修一
  • Organizer: 第18回応用薬理シンポジウム
  • Place of Presentation: 名古屋大学 医学部 医系研究棟1号館 地下会議室（愛知、名古屋市）
• [Remarks] 山梨大学大学院総合研究部薬理学教室
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/pharmaco/1-Japanese/home.html
• [Remarks] 山梨大学大学院医学工学総合研究部薬理学教室
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/pharmaco/1-Japanese/home.html