ANESTHETICS & ANALGESICS--CELLULAR & MOLECULAR ACTIONS

全身麻醉药和镇痛剂的作用机制 临床上想要的效果还不清楚。在本报告中提出的工作 该计划旨在定义这些药物的分子靶点(S)，并 阐明在这些靶点上的行动会导致麻醉或 止痛药。潜在的想法是这些药物作用于蛋白质，并且在 尤其是参与信息传递的膜通道 突触上的神经元。现有数据表明，麻醉剂和 止痛药可影响多个膜通道(电压和 配基门控)，其中一些变化可能是导致 神经细胞的兴奋性。不幸的是，很少有量化的 能够确定影响或评估的特异性的数据 一种给定的效应可能与 临床期望的结果。该计划的一个目标是确定可能的 通过定量检测麻醉剂和镇痛剂的神经元靶点 药物作用于心肌细胞膜电流的量效关系 神经元。其中一个项目将研究电压门控钙离子的影响。 选择性通道(林格尔博士)，这是中央 活性依赖性递质释放与神经元的重要性 兴奋性。两个项目将研究药物对突触后的作用 发射机选通通道(柯维博士和施泰因巴赫博士)，这是必不可少的 对突触后细胞的反应。比较和对比 这些研究的结果将表明通道的功能发生了变化 通过临床上相关的药物浓度，并将确定哪些 作用是麻醉剂或镇痛剂的特征。的最终目标是 该计划旨在阐明麻醉剂和药物的作用机制 通过药理学分析，止痛剂对蛋白质有影响 以及在项目中获得的动力学数据。 所获得的结果将提供所需的信息来确定 临床所需的细胞和分子作用 这些药物的效果。此外，还将深入了解 麻醉剂和镇痛剂起作用的机制。

The mechanisms by which general anesthetics and analgesics have their clinically desired effects are not understood. The work proposed in this Program seeks to define the molecular target(s) for these drugs, and to clarify the way in which action at these targets results in anesthesia or analgesia. The underlying idea is that these drugs act on proteins, and in particular on membrane channels involved in information transfer between neurons at synapses. The available data indicate that anesthetics and analgesics can affect a number of membrane channels (both voltage- and ligand-gated), and that some of the changes could underlie a decrease in excitability of nerve cells. Unfortunately, there are few quantitative data which allow determination of the specificity of effects, or assessment of the likelihood that a given effect might be related to production of the clinically desired results. One goal of the Program is to determine likely neuronal targets of anesthetics and analgesics, by quantitatively examining the dose-effect relationship of drug action on membrane currents in neurons. One project will study effects on voltage-gated calcium- selective channels (Drs. Lingle ), which are of central importance in activity-dependent transmitter release and neuronal excitability. Two projects will study drug actions on postsynaptic transmitter-gated channels (Drs. Covey and Steinbach), which are essential to the response of the postsynaptic cell. Comparing and contrasting the results of these studies will indicate channels whose function is altered by clinically relevant concentrations of drug, and will determine which actions are characteristic of anesthetics or analgesics. A final goal of the Program is to elucidate the mechanism by which anesthetics and analgesics have their effects on proteins, by analyses of pharmacological and kinetic data obtained in the projects. The results obtained will provide information required to determine likely cellular and molecular actions which underlie the clinically desired effects of these drugs. Furthermore, insights will be gained into the mechanisms by which anesthetics and analgesics have their actions.