VOLATILE ANESTHETICS AND RESPIRATORY NEUROTRANSMISSION

挥发性麻醉剂与呼吸神经传输

• 批准号: 7025243
• 负责人: ECKEHARD A STUTH
• 金额: $ 7.73万
• 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 2005-12-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025243
• 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.

这项建议的总体目标是表征有效的、挥发性麻醉剂对体内自发活动的哺乳动物呼吸系统中特定突触事件的作用。拟议中的研究结果将带来新的知识，将增加我们对挥发性麻醉剂改变完整中枢神经系统神经功能的机制的理解。这一建议是独特的，因为我们提出的研究重点是在活体条件下完整的神经元网络中具有已知功能的特定呼吸神经元。在我们的实验范式中，突触神经递质的释放水平与呼吸中心正常运行时的水平相同。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抑制兴奋性而不是增强抑制性突触神经传递。运动前神经元动作电位的记录结合神经递质激动剂和拮抗剂的局部压力微喷射，将被用来检验麻醉诱导的兴奋性和抑制性神经传递改变的相对重要性，以及突触前和突触后的机制。已经制定了三个具体目标来检验我们的假设。在具体目标1中，我们将在去大脑的犬模型中测定麻醉剂引起的吸气和呼气前运动神经元谷氨酸能兴奋和GABA能抑制的变化。在特定的目标2中，我们将确定麻醉剂诱导的突触前和突触后效应对这些运动前神经元整体抑制的相对贡献。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神经元突触机制的不同药剂和部位特异性作用。我们的模型将作为探索体内其他神经元回路的范例。此外，从我们拟议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，将这些药物的严重副作用降至最低，如心肺中心的抑制。这种机械知识也有助于设计更安全的麻醉剂，对呼吸的有害影响最小。