Volatile Anesthetics and Respiratory Neurotransmission

挥发性麻醉剂和呼吸神经传递

• 批准号: 7047376
• 负责人: ECKEHARD A STUTH
• 金额: $ 25.06万
• 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 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047376
• 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

DESCRIPTION (provided by applicant): Subanesthetic concentrations of volatile anesthetics potently depress upper airway defense mechanisms. In particular, hypoglossal motor control of the tongue that maintains airway patency during inspiration is severely compromised. The overall goal of this proposal is to characterize the actions of volatile anesthetics on specific synaptic mechanisms and neuronal excitability within spontaneously active mammalian inspiratory hypoglossal motoneurons (IHMNs) in vivo. While in vitro studies have identified potential mechanisms for anesthetic-induced depression, this proposal is unique because we focus on functionally identified IHMNs in an intact neuronal network under in vivo conditions, where neurotransmitters are released at physiologically relevant levels. Our overall hypothesis is 1) that the activity of IHMNs is dependent on synaptic inputs mediated by ligand-gated glutamatergic, GABAergic, and glycinergic and G-protein coupled serotonergic and adrenergic receptors, and 2) the effects of volatile anesthetics on neuronal activity are due to depression of excitatory and enhancement of inhibitory synaptic neurotransmission, rather than non-synaptically mediated intrinsic membrane mechanisms such as changes in K+conductance. Recordings of action potentials from IHMNs 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 intrinsic neuronal excitability. Three specific aims have been developed to test our hypothesis in a decerebrate canine model. In specific aim 1, we will identify the key contributing neurotransmitters in IHMNs and determine their physiological receptor activity. In specific aim 2, we will determine the effect of subanesthetic concentrations of volatile anesthetics on overall synaptic transmission of the key neurotransmitter systems in IHMNs. In specific aim 3, we will determine the effects of volatile anesthetics on the postsynaptic receptor responses for the key contributing neurotransmitters in IHMNs. The insights that will be gained from our proposed studies will contribute to our understanding of the effects of volatile anesthetics on upper airway function in the perioperative period and may suggest rational mechanism-based therapeutic interventions to mitigate these effects in the postoperative setting when patients are at high risk of airway- related morbidity.

描述（由申请人提供）：亚麻醉浓度的挥发性麻醉药有效抑制上呼吸道防御机制。特别是，在吸气过程中保持气道通畅的舌下神经运动控制严重受损。本提案的总体目标是表征挥发性麻醉剂在体内自发活动的哺乳动物吸气舌下神经运动神经元（IHMN）内对特定突触机制和神经元兴奋性的作用。虽然体外研究已经确定了麻醉诱导抑郁症的潜在机制，但该建议是独特的，因为我们专注于在体内条件下完整神经元网络中功能鉴定的IHMN，其中神经递质以生理相关水平释放。我们的总体假设是1）IHMN的活性依赖于由配体门控的谷氨酸能、GABA能和甘氨酸能以及G蛋白偶联的多巴胺能和肾上腺素能受体介导的突触输入，以及2）挥发性麻醉剂对神经元活性的影响是由于兴奋性突触神经传递的抑制和抑制性突触神经传递的增强，而不是非突触介导的内在膜机制，如K+电导的变化。将使用IHMN的动作电位记录结合神经递质激动剂和拮抗剂的局部压力微喷射来检查麻醉诱导的改变对兴奋性和抑制性神经传递以及内在神经元兴奋性的相对重要性。三个具体的目标已经开发，以测试我们的假设在去大脑犬模型。在具体目标1中，我们将确定IHMN中的关键神经递质并确定其生理受体活性。在具体目标2中，我们将确定亚麻醉浓度的挥发性麻醉剂对IHMN中关键神经递质系统的整体突触传递的影响。在具体目标3中，我们将确定挥发性麻醉剂对IHMN中关键神经递质的突触后受体反应的影响。从我们拟定的研究中获得的见解将有助于我们了解挥发性麻醉药对围手术期上气道功能的影响，并可能建议合理的基于机制的治疗干预措施，以减轻患者在术后气道相关发病率高风险时的这些影响。