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

镇咳药作用的神经和离子机制研究——面向新一代新型中枢作用药物的开发。

基本信息

批准号：
03671099
负责人：
TAKAHAMA Kazuo
金额：
$ 1.34万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

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.

最近出现了对抗毒剂药理学的关注，因为据报道右旋甲状腺（DM）具有与已知神经递质的高亲和力结合部位不同，并且由于抗毒剂具有多重药理作用，例如抗神经毒性作用，是一种抗神经毒性作用，是一种抗神经毒性作用和抗凝作用。本研究的目的是在哺乳动物大脑的单个神经元中阐明作用及其抗毒剂的机制。从本研究项目中获得的结果如下：1）DL-AP5（一种选择性NMDA受体拮抗剂）直接微注射到咳嗽中心中，在核心的solitarii solitarii及其在豚鼠的附近降低了咳嗽产生的产生。另一方面，将甘氨酸（一种抑制性神经递质注射）选择性地增加了咳嗽的放大器。2）抗毒剂，抗毒剂，施用离子posporter，使豚鼠的皮质和海马中的单个神经元活性抑制了几内亚猪的单个神经元活性。3）低浓度DM但不能有效地抑制NMDA诱导的电流在整个细胞元素模式下的NMDA诱导的电流。有趣的是，所有研究的抗激素均显示出甘氨酸诱导的电流在核Tractus solitarii神经元中的选择性抑制作用。4）使用斑块夹技术进行单个通道分析，表明DM抑制了由甘氨酸诱导的单个通道活性的开放概率。5）5）甘氨酸。在咳嗽生产期间，由微透析技术确定的片核solitarii的水平显着增加。结果可能有助于阐明一种新的方法和策略，以开发新型抗毒剂和中央作用的杜尔格。