Development of in vivo patch-clamp recording technique from the anterior cingulate cortex

• Project/Area Number: 16K15341
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pain science
• Research Institution: Hyogo Medical University
• Principal Investigator: FURUE Hidemasa 兵庫医科大学, 医学部, 教授 (20304884)
• Research Collaborator: IMOTO Keiji
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 情動 / 鎮痛 / 神経生理的評価 / 生理学 / in vivoパッチクランプ / シナプス / 高次機能 / 青斑核 / 脊髄 / 感情 / パッチクランプ

Outline of Final Research Achievements

Recent studies have shown that anterior cingulate cortex (ACC) is an important brain region in the emotional aspect of pain. However, the neuronal mechanisms for the ACC emotional pain, is not fully understood. In this study, we developed in vivo electrophysiological recordings from ACC neurons, and examined neuronal responses evoked by natural sensory stimulation. Under urethane and isoflurane anesthesia, in vivo extracellular and whole-cell patch-clamp recordings were made from ACC neurons. AAC neurons exhibited up- and down-states and fired spontaneously during up-states. Mechanical stimulation applied to the skin of the hind paw elicited action potentials in ACC neurons. We also developed an in vivo awake recording technique from the ACC. It enabled us to analyze a typical sustained excitation of ACC neurons after cessation of sensory mechanical stimulation applied to the skin. The present in vivo recordings may be useful to develop new analgesic agents and treatments.

Academic Significance and Societal Importance of the Research Achievements

覚醒下前帯状回においてvon Frey刺激に伴う持続性の応答を得ることができるなど、新たな神経生理的記録・評価法の開発に成功した。一方で、麻酔下では、麻酔の影響を受けて感覚応答が減弱したものの、特に、神経障害性モデルを用いた解析から前帯状回ニューロンの閾値は低下し、von Frey刺激の間中持続するモデル特有の応答が記録された。In vivo標本は全身や局所への薬物の投与が可能であることから、本研究で開発した評価・記録法は、基礎医学の発展のみならず、痛みの情動等に対する鎮痛薬の評価に有用であり、難治性疼痛に対する新規治療法開発など今後の応用研究に大いに寄与できる。

Research Products

• [Int'l Joint Research] ブリストル大学(英国)
• [Int'l Joint Research] キョンヒ大学(韓国)
• [Int'l Joint Research] ソウル大学(韓国)
• [Int'l Joint Research] トロント大学(カナダ)
• [Int'l Joint Research] ブリストル大学(英国)
• [Int'l Joint Research] キョンヒ大学(韓国)
• [Journal Article] Stimulating muscarinic M1 receptors in the anterior cingulate cortex reduces mechanical hypersensitivity via GABAergic transmission in nerve injury rats (2019)
  • Author(s): Koga K, Matsuzaki Y, Migita K, Shimoyama S, Eto F, Nakagawa T, Matsumoto T, Terada K, Mishima K, Furue H, Honda K
  • Journal Title: Brain Research Volume: 1704 Pages: 187-195
  • DOI: 10.1016/j.brainres.2018.10.013
  • Peer Reviewed / Open Access
• [Journal Article] Chronic inflammatory pain induced GABAergic synaptic plasticity in the adult mouse anterior cingulate cortex (2018)
  • Author(s): Koga Kohei、Shimoyama Shuji、Yamada Akihiro、Furukawa Tomonori、Nikaido Yoshikazu、Furue Hidemasa、Nakamura Kazuhiko、Ueno Shinya
  • Journal Title: Molecular Pain Volume: 14 Pages: 1-14
  • DOI: 10.1177/1744806918783478
  • Peer Reviewed / Open Access
• [Journal Article] Ethanol-induced enhancement of inhibitory synaptic transmission in the rat spinal substantia gelatinosa (2018)
  • Author(s): Yamada Akihiro、Koga Kohei、Kume Kazuhiko、Ohsawa Masahiro、Furue Hidemasa
  • Journal Title: Molecular Pain Volume: 14 Pages: 1-13
  • DOI: 10.1177/1744806918817969
  • Peer Reviewed / Open Access
• [Journal Article] 覚醒・意識レベルと疼痛の中枢制御機構 (2018)
  • Author(s): 古江秀昌
  • Journal Title: 兵庫医科大学医学会雑誌 Volume: 43(1)
  • Peer Reviewed
• [Journal Article] Impaired peripheral nerve regeneration in type-2 diabetic mouse model. (2018)
  • Author(s): Pham M. V., Nguyen H. T., Katano, T., Matsumura, S., Aaito, S., Yamada A., Furue, H. and Ito, S.
  • Journal Title: Eur J Neurosci. Volume: 47 Pages: 126-139
  • DOI: 10.1111/ejn.13771
  • Peer Reviewed
• [Journal Article] Medullary raphe nuclei activate the lumbosacral defecation center through the descending serotonergic pathway to regulate colorectal motility in rats. (2018)
  • Author(s): Nakamori H, Naitou K, Horii Y, Shimaoka H, Horii K, Sakai H, Yamada A, Furue H, Shiina T, Shimizu Y.
  • Journal Title: American Journal of Physiology-Gastrointestinal and Liver Physiology Volume: 314
  • DOI: 10.1152/ajpgi.00317.2017
  • Peer Reviewed
• [Journal Article] Optogenetic Activation of Non-Nociceptive Aβ Fibers Induces Neuropathic Pain-LikeSensory and Emotional Behaviors after Nerve Injury in Rats. (2018)
  • Author(s): Tashima R, Koga K, Sekine M, Kanehisa K, Kohro Y, Tominaga K,Matsushita K, Tozaki-Saitoh H, Fukazawa Y, Inoue K, Yawo H, Furue H, Tsuda M
  • Journal Title: eNeuro. Volume: 5(1) Pages: 1-1
  • DOI: 10.1523/eneuro.0450-17.2018
  • NAID: 130007901054
  • Peer Reviewed / Open Access
• [Journal Article] Noradrenergic inhibition of spinal hyperexcitation elicited by cutaneous cold stimuli in rats with oxaliplatin-induced allodynia: electrophysiological and behavioral assessments. (2017)
  • Author(s): Choi S, Yamada A, Kim W, Kim SK, Furue H
  • Journal Title: JPhysiol Sci. Volume: 67(3) Pages: 431-438
  • DOI: 10.1007/s12576-016-0505-9
  • NAID: 40021176454
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 4-isopropylcyclohexanol has potential analgesic effects through the inhibition of anoctamin 1, TRPV1 and TRPA1 channel activities. (2017)
  • Author(s): Takayama Y, Furue H, Tominaga M.
  • Journal Title: Sci Rep. Volume: 7 Pages: 43132-43132
  • DOI: 10.1038/srep43132
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] In vivo electrophysiological analysis of mechanisms ofmonoaminergic pain inhibitory systems (2017)
  • Author(s): Yoshimura M, Furue H
  • Journal Title: Pain Volume: 158
  • DOI: 10.1097/j.pain.0000000000000844
  • Peer Reviewed
• [Journal Article] Acute inflammation reveals GABA(A) receptor-mediated nociception inmouse dorsal root ganglion neurons via PGE(2) receptor 4 signaling (2017)
  • Author(s): Jang IJ, Davies AJ, Akimoto N, Back SK, Lee PR, Na HS, Furue H, Jung SJ, KimYH, Oh SB.
  • Journal Title: Physiol Rep Volume: 5(8)
  • DOI: 10.14814/phy2.13178
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of Nociceptive Behaviors Induced by Formalin in the Glabrous and Hairy Skin of Rats. (2017)
  • Author(s): Erami E, Azhdari-Zarmehri H, Imoto K, Furue H.
  • Journal Title: Basic Clin Neurosci. Volume: 8(1) Pages: 37-42
  • DOI: 10.15412/j.bcn.03080105
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Corrigendum: Intravenous administration oflidocaine directly acts on spinal dorsal horn and produces analgesic effect: Anin vivo patch-clamp analysis. (2017)
  • Author(s): Kurabe M, Furue H, Kohno T
  • Journal Title: Sci Rep Volume: 7 Pages: 46814-46814
  • DOI: 10.1038/srep46814
  • Peer Reviewed
• [Journal Article] Chemogenetic silencing of GABAergic dorsal horn interneurons induces morphine-resistant spontaneous nocifensive behaviours. (2017)
  • Author(s): Koga K, Kanehisa K, Kohro Y, Shiratori-Hayashi M, Tozaki-Saitoh H, Inoue K, Furue H, Tsuda M
  • Journal Title: Scientific reports Volume: 7(1) Pages: 4739-4739
  • DOI: 10.1038/s41598-017-04972-3
  • Peer Reviewed / Open Access
• [Journal Article] <b>Noradrenergic effects in rat sacral autonomic nucleus using in vitro slice patch-clamp r</b><b>ecordings </b> (2017)
  • Author(s): Kawatani M, Akimoto N, Yamada A, Furue H, Kawatani M
  • Journal Title: Biomed. Res. Volume: 38(6) Issue: 6 Pages: 359-369
  • DOI: 10.2220/biomedres.38.359
  • NAID: 130006248350
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed
• [Journal Article] 脳幹における痛みの抑制と慢性疼痛発現の機構 (2017)
  • Author(s): 御領憲治、古江秀昌
  • Journal Title: 医学のあゆみ Volume: 260(2) Pages: 144-148
• [Journal Article] Stimulation of dopamine D2-like receptors in the lumbosacral defecation centre causes propulsive co lorectal contractions in rats. (2016)
  • Author(s): Kiyotada Naitou, Hiroyuki Nakamori, Takahiko Shiina, Azusa Ikeda, Yuuta Nozue, Yuuki Sano, Takuya Yokoyama, Yoshio Yamamoto, Akihiro Yamada, Nozomi Akimoto, Hidemasa Furue, and Yasutake Shimizu
  • Journal Title: J Physiol Volume: 594 Pages: 4339-4350
  • DOI: 10.1113/jp272073
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intravenous administration of lidocaine directly acts on spinal dorsal horn and produces analgesic effect: An in vivo patch-clamp analysis. (2016)
  • Author(s): Kurabe M, Furue H, Kohno T
  • Journal Title: Scientific Reports Volume: 6 Pages: 0-0
  • DOI: 10.1038/srep26253
  • Peer Reviewed / Open Access
• [Journal Article] Changes in synaptic transmission of substantia gelatinosa neurons after spinal cord hemisection revealed by analysis using in vivo patch-clamp recording. (2016)
  • Author(s): Kozuka Y, Kawamata M, Furue H, Ishida T, Tanaka S, Namiki A, Yamakage M
  • Journal Title: Mol Pain. Volume: 12 Pages: 1-14
  • DOI: 10.1177/1744806916665827
  • NAID: 120007100116
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Involvement of Brain-Enriched Guanylate Kinase-Associated Protein (BEGAIN) in Chronic Pain after Peripheral Nerve Injury. (2016)
  • Author(s): Katano T, Fukuda M, Furue H, Yamazaki M, Abe M, Watanabe M, Nishida K, Yao I, Yamada A, Hata Y, Okumura N, Nakazawa T, Yamamoto T, Sakimura K, Takao T, Ito S
  • Journal Title: eNeuro. Volume: 3(5) Pages: 110-16
• [Presentation] Synaptic responses evoked by optogenetic activation of descending pain modulatory system: Recording from anesthetized animals placed in a stereotaxic apparatus. (2019)
  • Author(s): Furue H
  • Organizer: 9th Federation of the Asian and Oceanian Physiological Societies Congress
  • Int'l Joint Research / Invited
• [Presentation] Alteration of spinal sensory processing from the LUT in rats with streptozotocin-induced diabetes. (2019)
  • Author(s): Tatsuki Nakagawa, Atsushi Hakozaki, Nozomi Akimoto, Noriyuki Ozaki, Masahito Kawatani, Keiji Imoto, Hidemasa Furue
  • Organizer: 9th Federation of the Asian and Oceanian Physiological Societies Congress
  • Int'l Joint Research
• [Presentation] Effects of ethanol on nociceptive synaptic transmission in the rat spinal dorsal horn. (2019)
  • Author(s): Akihiro Yamada, Kohei Koga, Kazuhiko Kume, Masahiro Ohsawa, Keiji Imoto, Hidemasa Furue
  • Organizer: 9th Federation of the Asian and Oceanian Physiological Societies Congress
  • Int'l Joint Research
• [Presentation] Chronic pain model alters GABAergic synaptic transmission in the mice anterior cingulate cortex . (2019)
  • Author(s): Kohei Koga, Shuji Shimoyama, Akihiro Yamada, Hidemasa Furue, Kazuhiko Nakamura, Shinya Ueno
  • Organizer: 9th Federation of the Asian and Oceanian Physiological Societies Congress
  • Int'l Joint Research
• [Presentation] Activation of spinal parasympathetic neuronal circuit by noxious afferent fibers. (2018)
  • Author(s): Furue H
  • Organizer: Spring meeting of Korean Pain Research Society (IASP, Korean Chapter)
  • Int'l Joint Research / Invited
• [Presentation] Activation of spinal parasympathetic neuronal circuit by noxious afferent fibers (2018)
  • Author(s): Furue H
  • Organizer: Spring Meeting of Korean Pain Research Society (IASP, Korean Chapter)
  • Int'l Joint Research / Invited
• [Presentation] TRP チャネルと ANO1 を標的とした 4-イソプロピルシクロヘキサノールによる疼痛お よび掻痒の緩和. (2018)
  • Author(s): 高山靖規、古江秀昌、富永真琴
  • Organizer: 第95回日本生理学会大会
• [Presentation] ユビキチンプロテアソームシステムを介した前帯状回シナプス前長期増強の調節機構 (2018)
  • Author(s): 古賀浩平、矢尾育子、瀬藤光利、古江秀昌、ずお みん
  • Organizer: 第95回日本生理学会大会
• [Presentation] 下部尿路から脊髄への知覚伝達機構 (2018)
  • Author(s): 中川達貴、箱崎敦志、秋元 望、 尾崎紀之、 井本敬二、 古江秀昌
  • Organizer: 第95回日本生理学会大会.
• [Presentation] in vivo 前帯状回皮質感覚応答の解析 (2018)
  • Author(s): 山田彬博、古賀浩平、井本敬二、粂 和彦、大澤匡弘、古江秀昌
  • Organizer: 第95回日本生理学会大会
• [Presentation] ４－イソプロピルシクロヘキサノールのイオンチャネル阻害作用 (2018)
  • Author(s): 高山靖規、古江秀昌、富永真琴
  • Organizer: 第39回日本疼痛学会
• [Presentation] 覚醒下前帯状回皮質感覚応答のIn vivo解析. (2017)
  • Author(s): 山田彬博, 大澤匡弘, 粂和彦, 井本敬二, 古江秀昌
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松（静岡県浜松市）
  • Year and Date: 2017-03-28
• [Presentation] ノルアドレナリン神経による上行性および下行性の痛覚調整機構 (2017)
  • Author(s): 古江秀昌
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長﨑ブリックホール（長崎県長崎市）
  • Year and Date: 2017-03-15
  • Invited
• [Presentation] ノルアドレナリン神経による上行性および下行性の痛覚調節機 (2017)
  • Author(s): 古江秀昌
  • Organizer: 第90回日本薬理学会年会
  • Invited
• [Presentation] In vivo analysis of sensory neuronal activities in the anterior cingulate cortex (2017)
  • Author(s): Akihiro Yamada, Kohei Koga, Kazuhiko Kume, Masahiro Ohsawa and Hidemasa Furue
  • Organizer: 第44回日本脳科学会
• [Presentation] Cingulate presynaptic long-term potentiation contributes to chronic pain induced anxiety (2017)
  • Author(s): Kohei Koga, Akihiro Yamada, Hidemasa Furue and Min Zhuo
  • Organizer: 第44回日本脳科学会
  • Invited
• [Presentation] 下部尿路からの脊髄への感覚伝達機構の解析 (2017)
  • Author(s): 中川達貴、秋元 望、箱崎敦志、古江秀昌
  • Organizer: 第110 回近畿生理学談話会プログラム
• [Presentation] Spinal Nociceptive Transmission from the Lower Urinary Tract (2016)
  • Author(s): N. Akimoto, A. Hakozaki, M. Kawatani, K. Imoto, M. Kawatani, H. Furue
  • Organizer: International Association for the Study of Pain(IASP)
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-09-26
  • Int'l Joint Research
• [Presentation] Effects of ethanol on GABAergic synaptic transmission in the rat spinal dorsal horn. (2016)
  • Author(s): A.Yamada, M. Ohsawa, K. Kume, K. Imoto, H. Furue
  • Organizer: International Association for the Study of Pain(IASP)
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-09-26
  • Int'l Joint Research
• [Presentation] Noradrenergic inhibition of spinal hyperexcitation elicited by cutaneous cold stimuli in rats with oxaliplatin-induced allodynia: Electrophysiological and behavioral assessments (2016)
  • Author(s): S. Choi, S. Kim, S. Oh, H. Furue
  • Organizer: International Association for the Study of Pain(IASP)
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-09-26
  • Int'l Joint Research
• [Presentation] Electrophysiological analysis of local anesthetic actions on nociceptive synaptic transmission in the adult rat spinal cord. (2016)
  • Author(s): D. Uta, M. Yoshimura, R. Kawatsu, K. Imoto, H. Furue
  • Organizer: International Association for the Study of Pain(IASP)
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-09-26
  • Int'l Joint Research
• [Presentation] Spinal GABAergic Synaptic Responses Elicited by Optogenetic Activation of Descending Noradrenergic System (2016)
  • Author(s): H. Furue, L. Hickey, Y. Li, A. Pickering, K. Imoto
  • Organizer: International Association for the Study of Pain(IASP)
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-09-26
  • Int'l Joint Research
• [Remarks] 兵庫医科大学 生理学 神経生理部門ホームページ
  • URL: https://www.hyo-med.ac.jp/department/neurophysiol/index.html
• [Remarks] 兵庫医科大学生理学神経生理部門ホームページ
  • URL: http://www.hyo-med.ac.jp/department/neurophysiol/index.html
• [Remarks] 生理学研究所神経シグナルホームページ
  • URL: http://www.nips.ac.jp/~furue/index.html