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

彻底阐明镇咳药作用机制，开发老年人所需的新型止咳药物

基本信息

批准号：
13557223
负责人：
TAKAHAMA Kazuo
金额：
$ 1.41万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

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.

在这个项目中，首先，我们使用全细胞和NYSTATATATATATATIT蛋白孔孔孔的斑块夹在单个脑神经元中研究了由5-HT_ <1A>，GABA_B或肾上腺素α_2受体介导的各种电流对各种电流的作用。其次，我们研究了缓激肽（BK）对副神经节神经元（PTG）神经元的作用，并进一步使用相同技术在PTG神经元中修改了毒蕈碱和烟碱反应。 [结果] 1）在背raphe（DR）神经元中，所有非麻醉性中心作用的抗毒剂都抑制了5-HT_ <1A>受体介导的内向电流（I_H <5-HT>）。 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）具有抗议作用的Δ抗抗烷，Naltriben（NAL）和Naltrindole在电流上也具有相同的作用。 3）GABA_B受体激动剂Badofen也激活了神经元中的少女电流。 4）DM，Cloperastine（CLO）和NAL还以浓度依赖性方式抑制GABA_B受体介导的电流，IC_ <50> s的8.23×10^<-6> M，1.36×10^<-6> M，和4.36×M和4.36×10^<-6> m，分别抑制。 5）DM，DO和NAL不仅抑制I_ <5-ht>和I_ <baC>。而且还以几乎相同的浓度介导的α2-肾上腺素受体介导的girk电流。 6）BK通过抑制M通道强烈激活PTG神经元。 7）在PTG神经元中，BK对毒蕈碱反应和对烟碱反应的协同作用产生了额外的影响。