• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Complete elucidation of mechanisms of actions of antitussives for developing novel cough-regulating drugs desired by aged peoples

Research Project

Project/Area Number 13557223
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 応用薬理学・医療系薬学
Research InstitutionKumamoto University

Principal Investigator

TAKAHAMA Kazuo  Faculty of Pharmceutical Sciences, Kumamoto University, Department of Hygienic Chemistry, Professor, 薬学部, 教授 (80150548)

Co-Investigator(Kenkyū-buntansha) GOTOH Takeshi  Fundamental Research Laboratories Hisamitsu Pharmaceutical Co., Inc., Chief of Researcher, 中央研究所, 室長
TAKAMUNE Kazufumi  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, Assistant Professor, 理学部, 助教授 (20206882)
SHIRASAKI Tetsuya  Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, Assistant Professor, 薬学部, 助教授 (30264047)
FUKUSHIMA Hidenao  Fundamental Research Laboratories Hisamitsu Pharmaceutical Co., Inc., Researcher, 中央研究所, 研究員
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsantitussive drugs / antitussive action / δ-Antagonists / 5-HT_<1A> receptor / GABA_B receptor / α_2-adrenergic receptor / paratracheal ganglion neurons / G-protein coupled inwardly rectifying K^+ channels / 鎮咳薬 / ブラジキニン / デキストロメトルファン / 内向き整流性K+チャネル / δ受容体アンタゴニスト / 脳単一神経
Research Abstract

In this project, at first, we investigated the actions of various centrally-acting antitussives on various currents mediated by 5-HT_<1A>, GABA_B or adrenergic α_2 receptors, in single brain neurons using whole cell and nystatin-perforated patch clamp techniques. Secondarily, we investigated the action of bradykinin (BK) on paratracheal ganglion (PTG) neurons, and further whether BK modified muscarinic and nicotinic responses in PTG neurons using the same techniques. [Results] 1) All non-narcotic centrally-acting antitussives studied inhibited 5-HT_<1A> receptor mediated inward current (I_H<5-HT>) in dorsal raphe (DR) neurons. This action was suggested to be due to inhibition of G-protein coupled inwardly rectifying K^+ channels (GIRK) coupled to 5-HT_<1A> receptor, because these antitussives effectively inhibited GIRK currents irreversibly activated by 5-HT under condition of intracellular perfusion of GTP-γS. 2) δ-Antagonists, naltriben (Nal) and naltrindole, which have an antitussive action, also have the same action on the currents. 3) Badofen, a GABA_B receptor agonist, also activated GIRK currents in DR neurons. 4) DM, cloperastine (Clo) and Nal also inhibited GABA_B receptor mediated currents in a concentration-dependent manner, with IC_<50>s of 8.23 × 10^<-6>M, 1.36 × 10^<-6>M and 4.36 × 10^<-6>M, respectively. 5) DM, do and Nal inhibited not only I_<5-HT> and I_<bac>. But also GIRK currents mediated by α2-adrenoceptor at almost the same concentration. 6) BK strongly activated PTG neurons through inhibition of M-channels. 7) In PTG neurons, BK caused additive effect on muscarinic responses and synergistic effect on nicotinic responses.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Ishibashi H., Mochidome, T., Okai, J., Ichiki, H., Shimada, H., Takahama, K.: "Activation of potassium conductance by ophiopogonin-D in acutely dissociated rat paratracheal neurones"Br.J.Pharmacol.. 132. 461-466 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mochidome, T., Ishibashi, H., Takahama, K.: "Bradykinin activates airway parasympathetic ganglion neurons by inhibiting M-currents"Neuroscience. 105. 785-791 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirasaki, T., Abe, K., Kuwano, K., Soeda, F., Ishibashi, H., Takahama, K.: "Are GIRK channels one of the main targets for non-narcotic antitussives ?"Jpn.J.Pharmacol.. 88. 59 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagano, T., Tamanaha, Y., Shirasaki, T., Soeda, F., Takahama, K.: "Effects of ophiopogonin-D and pinacidil on 4-aminopyridine-or bradykinin-induced vagal afferent discharges from lower airway in guinea pigs"Jpn.J.Pharmacol.. 88. 128 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Abe, K., Shirasaki, T., Soeda, F., Takahama, K.: "δ-Opioid receptor antagonists inhibit inwardly rectifying K^+ currents in acutely dissociated brain neuron"The Pharmacologist. 44. A51 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Abe, K., Shirasaki, T., Soeda, F., Takahama, K.: "Centrally acting antitussives inhibit GIRK currents mediated by various receptors"J.Pharmacol.Sci.. 91. 219 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takahama, K., et al.: "Non-narcotic antitussives inhibit 5HT_<1A> receptor-mediated inwardly rectifying K^+ current in rat dorsal raphe neurones"Br.J.Pharmacol.. (Submitted). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takahama, K.: "Cough : Causes, Mechanisms and Therapy"Blackwell Publishing Ltd.. 200(12) (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishibashi H., T. Mochidome, J. Okai, H. Ichiki, H. Shimada, K. Takahama.: "Activation of potassium conductance by ophiopogonin-D in acutely dissociated rat paratracheal neurones."Br. J. Pharmacol.. 132. 461-466 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mochidome, T., H. Ishibashi, K. Takahama.: "Bradykinin activates airway parasympathetic ganglion neurons by inhibiting M-currents."Neuroscience. 105. 785-791 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirasaki, T., K. Abe, K. Kuwano, F. Soeda, H. Ishibashi, K Takahama: "Are GIRK channels one of the main targets for non-narcotic antitussives ?"Jpn. J. Phormacol.. 88. 59 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagano T., Y. Tamanaha, T. Shirasaki, F. Soeda, K. Takahama.: "Effects of ophiopogonin-D and pinacidil on 4-aminopyridine- or bradykinin- induced vagal afferent discharges from lower airway in guinea pigs."Jpn. J. Phormacol.. 88. 128 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Abe, K., T. Shirasaki, F. Soeda, K. Takahama.: "δ-opioid receptor antagonists inhibit inwardly rectifying K^+ currents in acutely dissociated twain neuron."The Pharmacologist. 44. A51 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Abe, K., T. Shirasaki, F. Soeda, K. Takahama.: "Centrally acting antitussives inhibit GIRK currents mediated by various receptors"J. Pharmacol. Sci.. 91. 219 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takahama, K., K. Kuwano, H. Ishibashi, K. Abe, F. Soeda, T. Shirasaki.: "Non-narcotic antitussives inhibit 5HT_<1A> receptor-mediated inwardly rectifying K^+ cunent in rat dorsal raphe neurones."Br. J. Pharmacol.. Submitted. (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirasaki T., K. Abe, F. Soeda, K. Takahama.: "δ-Opioid receptor antagonists inhibit GIRK currents in acutely dissociated brainstem neurons of rat"Brain Research. submitted. (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takahama K.: "Mechanisms of actions of centrally-acting antitussives. -Electrophysiological and neurochemical analysis-, "Cough: Causes, Mechanisms and Therapy", eds. H. Boushey, KF. Chung and J. Widdcombe."Blackwell Publishing Ltd, Oxford. 225-236 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Keisuke Abe: "Centrally acting antitussive inhibit GIRK currents mediated by various receptors"Journal of Pharmacological Sciences. 91(Sulli.I). 219 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kazuo Takahama (Eds.H.Boushey, K.F.Chung, J.Widdicombe): "Cough : Causes, Mechanisms and Therapy"Blackwell Publishing Ltd., London(印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Motidome, H.Ishibashi, K.Takahama: "Bradykinin activates airway parasympathetic ganglion neurons by inhibiting M-currents"Neuroscience. 105・No.3. 785-791 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Shirasaki, K.Abe, K.Kuwano, F.Soeda, H.Ishibashi, K.Takahama: "Are GIRK channels one of the main targets for non-narcotic antitussives ?"Jpn. J. Pharmcol.. 88・Suppl.. 59 (2002)

    • Related Report
      2001 Annual Research Report

URL: 

Published: 2002-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi