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

点击翻译按钮获取中文摘要

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.