| 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
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| 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.
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