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1992 Fiscal Year Final Research Report Summary

Studies on neurnoal and ionic mechanisms of the action of antitussives----oriented for development of novel centrally-acting drugs for coming new generarion.

Research Project

Project/Area Number 03671099
Research Category

Grant-in-Aid for General Scientific Research (C)

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

Principal Investigator

TAKAHAMA Kazuo  Kumamoto University, Dept.of Pharmac.Sci., Associate Professor, 薬学部, 助教授 (80150548)

Co-Investigator(Kenkyū-buntansha) KAI Hirofumi  Kumamoto University, Dept.of Pharmac.Sci., Research Associate, 薬学部, 助手 (30194658)
MIYATA Takeshi  Kumamoto University, Dept.of Pharmac.Sci., Professor, 薬学部, 教授 (90040310)
Project Period (FY) 1991 – 1992
Keywordsantitussive / dextromethorphan / glycine receptor / NMDA receptor / cough center / nucleus tractus solitarii / single brain neuron / patch clamp
Research Abstract

Concern about pharmacology of antitussives has been recently arisen, because dextromethorphan (DM) has been reported to have a high affinity binding site differing from those for known neurotransmitters, and because antitussives have multiplex pharmacological actions such as an anticonvulsant action, an anti-neurotoxic action and an anti-coagulant action. The aim of the present study was to clarfiy the action and its mechanism of antitussives in single neurons of the mammalian brain. The results obtained from the present research project are as follows :
1) Direct microinjection of dl-AP5, a selective NMDA receptor antagonist, into the cough center locarized in the nucleus tractus solitarii of and its vicinity of guinea pigs depressed production of cough. On the other hand, Injection of glycine, an inhibitory neurotransmitter, into the cough center selectively increased the ampltude of cough.
2) Antitussives, iontophoretically applied, depressed the single neuron activities in the cortex and hippocampus of guinea pigs.
3) A low concentration of DM but not codeine effectively depressed NMDA-induced current in nucleus solitarii neurons in a whole-cell configration mode. Interestingly, all antitussives studied showed a selective inhibitory action of glycine-induced current in nucleus tractus solitarii neurons.
4) A single channel analysis using the patch clamp technique showed that DM inhibited the open probability of single channel activities induced by glycine.
5) Glycine levels in the nucleus tractus solitarii determined by a microdialysis technique significantly increased during a period of cough production.
The results presented above are the first documentation of the action of antitussives in single neurons of the mammalina brain. The results might contribute to elucidation of a new approach and strategy for development of novel antitussives and centrally-acting durgs.

  • Research Products

    (16 results)

All Other

All Publications (16 results)

  • [Publications] Kazuo Takahama: "Differences in the mode of cough augmentation by four angiotensin-converting enzyme inhibitors in guinea-pigs." Journal of Pharmacy and Pharmacology. 45・11. 1003-1005 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kazuo Takahama: "Pharmacological properties of airway vagal afferent discharges in guinea-pigs." Canadian Journal of Physiology and Pharmacology. 72. 484 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kazuo Takahama: "Inhalation of phosphoramidon,a neutral endopeptidase inhibitor,induces coughs in awake guinea-pigs." Archives internationales Pharmacodynamie et de Therapie. 330. 241-250 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kazuo Takahama: "Studies on the magnitude and the mechanism of cough potentiation by angiotensin-converting enzyme inhibitorsin guinea-pigs." Journal of Pharmacy and Pharmacology. 48・10. 1027-1033 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kazuo Takahama: "Inhibition of glycine currents by dextromethorphan in neurones dissociated from the guinea-pig nucleus tractus solitarii." British Journal of Pharmacology. 120. 690-694 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hidenao Fukushima: "Inhibition of glycin-induced current by morphine in nucleus tractus solitarii neurones of guinea pigs." Methods and Findings. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shojiro Naomi: "Role of endogenous thromboxane A_2 on dry cough induced by angiotensinconverting enzyme inibitor." Therapeutic Research. 14. 78-83 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo Takahama: "Neurokinin A,but not neurokinin B and substance P,inducescodeine-resistant coughs in awake guinea-pigs." Regulatory Peptides. 46(1-2). 236-237 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo Takahama: "Differences in the mode of cough augmentation by four angiotensn-converting enzyme inhibitors in guinea-pigs." Journal of Pharmacy and Pharmacology. 45(11). 1003-1005 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo Takahama: "Pharmacological properties of airway vagal afferent discharges in guinea-pigs." Canadian Journal of Physiology and Pharmacology. 72. 484 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo Takahama: "Inhalation of phosphoramidon, a neutral endopeptidase inhibitor, induces coughs in awake guinea-pigs." Archives internationales Pharmacodynamie et de Therapie. 330. 241-250 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo Takahama: "Cough-Diversity and the peripheral mechanism of production. (in Japanese, with abstract in English)" Folia Pharmacologica Japon. 105. 41-52 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo Takahama: "Studies on the magnitude and the mechanism of cough potentiation by angiotensin-converting enzyme inhibitors in guinea-pigs : Involvement of bradykinin in the potentiation." Journal of Pharmacy and Pharmacology. 48(10). 1027-1033 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo Takahama: "Inhibition of glycine currents by dextromethorphan in neurones dissociatedfrom the guinea-pig nucleus tractus solitarii." British Journal of Pharmacology. 120. 690-694 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo Takahama: "Physiology and Pharmacology of Cough -New perspective.(in Japanese)" Pharmacia. 33. 365-369 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hidenao Fukushima: "Inhibition of glycine-induced current by morphine in nucleus tractus solitarii neurones of guinea pigs." Methods and Findings. 20 (in press (2). (1998)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-16  

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