ANESTHETICS & ANALGESICS--CELLULAR & MOLECULAR ACTIONS

全身麻醉药和镇痛药的作用机制 临床上所需的效果尚不清楚。 在此提出的工作 该计划旨在确定这些药物的分子靶点，并 阐明在这些靶点采取行动导致麻醉的方式，或 analgesia. 基本的想法是，这些药物作用于蛋白质， 特别是涉及信息传递的膜通道， 神经元在突触处。 现有数据表明，麻醉剂和 镇痛剂可以影响许多膜通道（电压和 配体门控），并且其中一些变化可能是减少 神经细胞的兴奋性 不幸的是， 能够确定效应特异性或评估的数据 特定影响可能与生产有关的可能性 临床预期结果。 该计划的一个目标是确定可能的 麻醉剂和镇痛剂的神经元靶点，通过定量检测 药物对细胞膜电流作用的量效关系 神经元 其中一个项目将研究对电压门控钙的影响- 选择性渠道（林格尔博士），这是中央 在活动依赖性递质释放和神经元 兴奋性 两个项目将研究药物对突触后神经元的作用。 传输门控通道（Covey和施泰因巴赫博士），这是必不可少的 突触后细胞的反应。 比较和对比 这些研究的结果将指出功能改变的通道 通过临床相关的药物浓度，并将确定 作用是麻醉剂或止痛剂的特征。 最终目标是 该计划旨在阐明麻醉剂和 通过药理学分析，镇痛剂对蛋白质有影响， 和动力学数据。 获得的结果将提供必要的信息，以确定可能的 细胞和分子的作用，这些作用是临床所需的 这些药物的影响。 此外，还将深入了解 麻醉剂和止痛剂发挥作用的机制。

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.