VOLATILE ANESTHETICS AND RESPIRATORY NEUROTRANSMISSION

挥发性麻醉剂与呼吸神经传输

• 批准号: 6181446
• 负责人: ECKEHARD A STUTH
• 金额: $ 21.82万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6181446
• 关键词: AMPA receptors; NMDA receptors; anesthetics; biological signal transduction; decerebration; dogs; electrical measurement; electrophysiology; gamma aminobutyrate; glutamates; halothane; inhalation anesthesia; isoflurane; motor neurons; neural inhibition; neural transmission; neuropharmacology; neurotransmitter agonist; neurotransmitter antagonist; pulmonary respiration; spreading cortical depression; synapses

The overall goal of this proposal is to characterize the actions of the potent, volatile anesthetics on specific synaptic events within the spontaneously active mammalian respiratory system, in vivo. The findings of the proposed research will result in new knowledge that will increase our understanding of the mechanisms by which volatile anesthetics alter neuronal function in the intact central nervous system. This proposal is unique because we propose studies that focus on specific respiratory neurons of known function in an intact neuronal network under in vivo conditions. In our experimental paradigm synaptic neurotransmitters are released at levels that are present during normal function of the respiratory centers. Our overall hypothesis is that the effects of volatile anesthetics on central respiratory output are mainly due to depression of excitatory rather than enhancement of inhibitory synaptic neurotransmission. Recordings of action potentials from premotor neurons in conjunction with localized pressure microejection of neurotransmitter agonists and antagonists will be used to examine the relative importance of anesthetic-induced alterations on excitatory and inhibitory neurotransmission, and on presynaptic vs. postsynaptic mechanisms. Three specific aims have been developed to test our hypothesis. In specific aim 1, we will determine the amount of overall anesthetic-induced alterations of glutamatergic excitation and GABAergic inhibition of inspiratory and expiratory premotor neurons in a decerebrate canine model. In specific aim 2, we will determine the relative contribution of anesthetic-induced presynaptic and postsynaptic effects to the overall depression of these premotor neurons. In specific aim 3, we will characterize and contrast the differential agent-and site-specific effects of halothane, isoflurane, and sevoflurane on the synaptic mechanisms of these premotor neurons. Our model will serve as a paradigm to explore other neuronal circuits in vivo. Furthermore, the insights that will be gained from our proposed studies will allow us to develop rational mechanism- based therapeutic strategies that will minimize the serious side- effects of these agents, such as depression of the cardiorespiratory centers. Such mechanistic knowledge could also help in the design of safer anesthetic agents with the least deleterious effects on respiration.

本提案的总体目标是表征强效挥发性麻醉剂对体内自发活动哺乳动物呼吸系统内特定突触事件的作用。 拟议研究的结果将产生新的知识，这将增加我们对挥发性麻醉剂改变完整中枢神经系统神经元功能的机制的理解。 这一建议是独一无二的，因为我们提出的研究，集中在一个完整的神经元网络在体内条件下的已知功能的特定呼吸神经元。 在我们的实验范例中，突触神经递质的释放水平与呼吸中枢正常功能时相同。 我们的总体假设是，挥发性麻醉药对中枢呼吸输出的影响主要是由于兴奋性突触传递的抑制，而不是抑制性突触传递的增强。记录运动前神经元的动作电位，结合神经递质激动剂和拮抗剂的局部压力微喷射，将用于检查麻醉诱导的兴奋性和抑制性神经传递改变的相对重要性，以及突触前与突触后机制。 为了检验我们的假设，我们提出了三个具体的目标。 在具体目标1中，我们将确定去大脑犬模型中吸气和呼气前运动神经元的GABA能兴奋和GABA能抑制的总体麻醉诱导的改变量。在具体目标2中，我们将确定麻醉诱导的突触前和突触后效应对这些运动前神经元的总体抑制的相对贡献。 在具体目标3中，我们将描述和对比氟烷、异氟烷和七氟烷对这些运动前神经元的突触机制的不同药物和部位特异性作用。 我们的模型将作为一个范例，探索其他神经元回路在体内。此外，从我们提出的研究中获得的见解将使我们能够开发合理的基于机制的治疗策略，这些策略将最大限度地减少这些药物的严重副作用，例如心肺中心的抑制。 这种机制的知识也可以帮助设计更安全的麻醉剂，对呼吸的有害影响最小。