MOLECULAR MECHANISM OF LOCAL ANESTHETIC ACTION

我研究的长期目标是了解当地如何 麻醉剂阻断了神经传导。拟议中的项目已将 强调区分局部和局部的具体效果 麻醉药对神经膜的非特异性作用。这个 具体作用将通过检测药物-钠通道来研究 交互作用和非特定影响将通过使用 作为一般膜性能的探针的疏水离子。这两种类型的 实验将在电压钳制的鱿鱼轴突中进行 具体目标：(1)确定钠失活机制在 药物通道阻断作用相对于静息和 通过使用不同的试剂来消除钠灭活的使用依赖阻断。 (2)确定激活门在调控中的作用 使用依赖块(A)通过比较电压依赖于 依赖使用的阻断剂对钠通道的激活作用，以及(B) 通过比较从使用依赖块中恢复的电压依赖关系 以激活钠离子通道。(三)确定 局麻药阻断作用的效度和电压依赖性 不同种类的永久离子在不同浓度下的存在 在用链霉蛋白酶处理过的轴突中。这些结果将使用 具有多离子占位功能的势垒模型。(4)界定 外加或内加氢离子在调节回收中的作用 依赖于使用的块。(5)确定局麻药的作用和 其他膜干扰剂对人工门控电流的影响 并将这些影响与它们对钠离子的影响进行比较 选通电流。 我们对产生局部麻醉作用的机制的理解将 也提供了对抗心律失常和抗惊厥的理解 行动是由那些表现出局部麻醉作用的药剂引起的。

The long-term objective of my research is to understand how do local anesthetics block the nerve conduction. The proposed project has placed the emphasis on discriminating between the specific effect of local anesthetics from their non-specific effects on nerve membranes. The specific effect will be studied by examining the drug-Na channel interactions and the non-specific effects will be investigated by using hydrophobic ions as probes of general membrane properties. Both types of experiments will be performed in voltage-clamped squid axons with the specific aims: (1) to determine the role of Na inactivation machinery in the drug channel blocking action with respect to the resting and use-dependent blocks by using different agents to remove Na inactivation. (2) To determine the role of the activation gate in modulating use-dependent block (a) by comparing the voltage dependence of use-dependent block to that for the activation of the Na channels, and (b) by comparing the voltage dependence for recovery from use-dependent block to that for the activation of the Na channels. (3) To determine the potency and voltage dependency of local anesthetic blocking action in the presence of different species of permenant ions at various concentrations in pronase-treated axons. These results will be interpreted using a barrier model with a provision for multi-ion occcupancy. (4) To define the role of external or internal H+ ions in modulating the recovery from use-dependent block. (5) To determine the effects of local anesthetics and other membrane perturbating agents on the artificial gating current induced by hydrophobic ions and compare these effects to their effects on the Na gating currents. Our understanding of mechanisms for producing local anesthetic action will also provide an understanding of how antiarrhythmic and anticonvulsant action is brought about by those agents exhibiting local anesthetic action.