ANESTHETIC ACTIONS ON SYNAPTIC TRANSMISSION

对突触传递的麻醉作用

• 批准号: 6240524
• 负责人: JOAN J KENDIG
• 金额: $ 11.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240524
• 关键词: GABA receptor; NMDA receptors; anesthetics; calcium channel; computational neuroscience; gamma aminobutyrate; ganglions; glutamate receptor; halothane; laboratory rat; neural transmission; neurotransmitter receptor; pharmacokinetics; spinal cord; synapses; voltage /patch clamp

Although anesthetic agents have been indispensable in health care for nearly a century and a half, there is no consensus on their essential actions. In addition, undesirable side effects are common. The compounds synthesized and tested for anesthetic potency in the core project provide an unique means to identify which of the many actions of anesthetic agents are essential and to exclude those which are irrelevant side effects. Anesthetic, transitional and non-anesthetic compounds which deviate from the Meyer-Overton Rule will be compared in respect to their effects in two systems: intact isolated neonatal rat spinal cord and dissociated dorsal root ganglion cells. Dorsal and ventral root population evoked responses in spinal cord are mediated by 3 neurotransmitter receptor subtypes which have been implicated in anesthesia: glutamate non-NMDA, glutamate NMDA and GABA/A. This preparation will be used to test the hypothesis that depression of one or another glutamate receptor and/or enhancement of GABA/A receptor activity is a necessary and sufficient mechanism of anesthetic action. Two alternative hypotheses will also be tested. One is that some anesthetics may act by increasing GABA release; this hypothesis will be tested by measuring spontaneous and evoked GABA release from spinal cord. The other is that anesthesia may be related to inhibition of calcium currents. Patch clamp studies on dissociated dorsal root ganglion cells will examine the extent to which anesthetic potency is correlated with effects on calcium currents. The results will provide a rigorous test of proposed mechanisms of anesthesia, and will be useful in designing optimal anesthetic drugs and drug combinations.

尽管麻醉剂在医疗保健中是必不可少的 将近一个半世纪，他们的基本就没有共识 动作。另外，不良的副作用很常见。化合物 在核心项目中合成并测试了麻醉效力的合成和测试 一种独特的手段来识别麻醉剂的多种作用中的哪一个 代理是必不可少的，排除了那些无关的一面 效果。麻醉，过渡性和非动理化合物，这些化合物 将偏离迈耶（Meyer-Overton）规则的偏离 在两个系统中的影响：完整的孤立的新生大鼠脊髓和 解离背根神经节细胞。背部和腹根 脊髓中诱发的反应由3介导 神经递质受体亚型与已与 麻醉：谷氨酸非NMDA，谷氨酸NMDA和GABA/A。这 准备工作将用于检验以下假设。 或其他谷氨酸受体和/或GABA/A受体的增强 活动是麻醉作用的必要和足够的机制。 还将测试两个替代假设。一个是有些 麻醉药可以通过增加GABA释放来起作用；这个假设将是 通过测量自发和诱发的GABA从脊髓释放进行测试。 另一个是麻醉可能与钙的抑制有关 电流。斑块夹在解离的背根神经节细胞上的研究 将检查麻醉效力与 对钙电流的影响。结果将提供严格的测试 提议的麻醉机制，将在设计中有用 最佳麻醉药物和药物组合。