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

最近出现了对镇咳药药理学的关注，因为据报道，美沙芬（DM）具有与已知神经递质不同的高亲和力结合位点，并且因为镇咳药具有多重药理作用，如抗惊厥作用、抗神经毒性作用和抗凝作用。本研究旨在阐明止咳药对哺乳动物脑单个神经元的作用及其机制。本研究结果如下：（1）将选择性NMDA受体拮抗剂dl-AP_5直接微量注射到豚鼠孤束核及其附近的咳嗽中枢，可抑制豚鼠的咳嗽产生。另一方面，在咳嗽中枢注射抑制性神经递质甘氨酸，选择性地增加咳嗽幅度; 2）镇咳剂，离子导入，抑制豚鼠皮层和海马单个神经元的活动; 3）低浓度的DM，而不是可待因，有效地抑制NMDA诱导的孤核神经元的电流在全细胞放电模式。有趣的是，4）膜片钳技术的单通道分析表明，DM抑制甘氨酸诱导的孤束核神经元单通道活动的开放概率通过微透析技术测定的孤束核中的甘氨酸水平在咳嗽产生期间显著增加。以上是关于止咳药在哺乳动物脑的单个神经元中的作用的第一份文件。本研究为开发新型镇咳药和中枢作用药物提供了新的思路和策略。

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.