Synaptic Mechanisms of General Anesthetic Action

全身麻醉作用的突触机制

• 批准号: 8050438
• 负责人: HUGH C HEMMINGS
• 金额: $ 50.88万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050438
• 关键词: Acetylcholine; Adverse effects; Affect; Agonist; Amnesia; Anesthetics; Breathing; Cardiovascular system; Cells; Coupled; Data; Development; Dopamine; Dose; Equilibrium; Exocytosis; Future; General Anesthesia; General anesthetic drugs; Glutamates; Goals; Hippocampus (Brain); Image; Immobilization; Individual; Ion Channel; Isoflurane; Knowledge; Mediating; Mental Depression; Molecular; Nerve; Neuraxis; Neurons; Neurotransmitters; Norepinephrine; Pain; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Pharmacopoeias; Phosphorylation; Preparation; Property; Protein Kinase C; Publishing; Rattus; Regulation; Research; Research Proposals; Role; SCN1A protein; SCN2A protein; Spinal Cord; Synapses; Synaptic Transmission; Synaptic Vesicles; Techniques; Testing; Tetrodotoxin; Text; Therapeutic Effect; Toxic effect; Unconscious State; Ventilatory Depression; age related; aged; channel blockers; gamma-Aminobutyric Acid; high risk; improved; interdisciplinary approach; neurochemistry; neurotoxicity; neurotransmitter release; postsynaptic; presynaptic; receptor; voltage; young adult

DESCRIPTION (provided by applicant): The pharmacology and toxicology of general anesthetics are remarkably incomplete for such a widely used and medically important class of drugs that are administered to increasingly older and sicker patients. Knowledge of the mechanisms of anesthetic action is insufficient to explain how any anesthetic produces amnesia, unconsciousness or immobilization (with increasing doses), the cardinal features of general anesthesia. Anesthetics have potent and specific effects on synaptic transmission, including both presynaptic actions on the release of neurotransmitters and postsynaptic actions on receptors. The principal objective of this research proposal is to understand the presynaptic mechanisms of anesthetic effects on neurotransmitter release by experimentally isolating these effects from their better understood postsynaptic actions. Presynaptic actions could be involved in therapeutic effects (unconsciousness, amnesia, immobility) and/or their toxic effects (neurotoxicity, respiratory depression, cardiovascular depression) of anesthetics. Understanding synaptic mechanisms of anesthetics is essential for development of anesthetics with improved side-effect profiles and for optimization of current anesthetic techniques in high-risk patients. We have shown that general anesthetics inhibit glutamate release by presynaptic mechanisms and that these effects are transmitter-specific and involve region-specific inhibition of specific Na+ channel subtypes. We now propose to focus on the region- and transmitter-specific actions and Na+ channel blocking mechanisms of volatile anesthetics in order to more fully understand their presynaptic actions. Our central hypothesis is that general anesthetics affect neurotransmitter release by synapse-specific mechanisms due to effects on presynaptic ion channels. We will test this hypothesis using an integrative and collaborative multidisciplinary approach by the following Specific Aims: Aim 1-Determine the mechanisms by which volatile anesthetics differentially affect neurotransmitter release from isolated nerve terminals to test the hypothesis that they have synapse-specific effects on transmitter release due to differences in presynaptic mechanisms; Aim 2-Determine the neurotransmitter-specific effects and mechanisms of volatile anesthetics on exocytosis in intact neurons to test the hypothesis that they differentially inhibit synaptic vesicle exocytosis by neurotransmitter-specific and ion channel-dependent mechanisms; and Aim 3-Determine the mechanisms and regulation of volatile anesthetic effects on voltage- gated Na+ channels to test the hypothesis that they inhibit Na+ channel subtypes by state-dependent mechanisms. Complementary approaches include analysis of anesthetic effects on transmitter release from intact nerve terminals, synaptic vesicle exocytosis from single cultured hippocampal neurons, and biophysical properties of specific Na+ channel subtypes. Such studies are essential to a molecular understanding of presynaptic anesthetic mechanisms and the balance between desirable and potentially toxic anesthetic effects on excitatory and inhibitory synaptic transmission. PUBLIC HEALTH RELEVANCE: The molecular and cellular mechanisms by which anesthetics produce amnesia, unconsciousness and immobilization, the cardinal features of general anesthesia, are unknown despite their critical role in the modern pharmacopoeia. We have shown that inhaled anesthetics inhibit neurotransmitter release from nerve terminals by inhibition of Na+ channels involving mechanisms that vary with the specific anesthetic, neurotransmitter, and region of the central nervous system. We now propose to investigate the specific presynaptic actions and Na+ channel blocking mechanisms of inhaled anesthetics in detail to more fully understand how general anesthetics act so that future anesthetics can be developed with reduced undesirable side-effects and current anesthetics can be used more safely.

描述（由申请人提供）：对于如此广泛使用且医学上重要的一类药物（这些药物被用于年龄越来越大、病情越来越重的患者），全身麻醉药的药理学和毒理学是非常不完整的。对麻醉作用机制的了解不足以解释任何麻醉剂如何产生健忘症、意识丧失或不动（随着剂量的增加），这是全身麻醉的主要特征。麻醉剂对突触传递具有有效且特定的作用，包括对神经递质释放的突触前作用和对受体的突触后作用。本研究提案的主要目的是通过实验将麻醉作用与更好理解的突触后作用分离出来，了解麻醉作用对神经递质释放的突触前机制。突触前作用可能涉及麻醉剂的治疗效果（意识不清、遗忘、不动）和/或其毒性作用（神经毒性、呼吸抑制、心血管抑制）。了解麻醉剂的突触机制对于开发具有改善副作用的麻醉剂以及优化当前高危患者的麻醉技术至关重要。我们已经证明，全身麻醉药通过突触前机制抑制谷氨酸释放，并且这些效应是递质特异性的，并且涉及特定 Na+ 通道亚型的区域特异性抑制。我们现在建议重点关注挥发性麻醉剂的区域和递质特异性作用以及 Na+ 通道阻断机制，以便更全面地了解其突触前作用。我们的中心假设是，全身麻醉剂由于对突触前离子通道的影响，通过突触特异性机制影响神经递质释放。我们将通过以下具体目标，使用综合和协作的多学科方法来检验这一假设： 目标 1-确定挥发性麻醉剂对孤立神经末梢神经递质释放产生差异影响的机制，以检验由于突触前机制的差异，它们对递质释放具有突触特异性影响的假设；目标 2-确定挥发性麻醉剂对完整神经元胞吐作用的神经递质特异性作用和机制，以检验它们通过神经递质特异性和离子通道依赖性机制差异抑制突触小泡胞吐作用的假设；目标3-确定挥发性麻醉剂对电压门控Na+通道的影响的机制和调节，以检验它们通过状态依赖性机制抑制Na+通道亚型的假设。补充方法包括分析对完整神经末梢递质释放的麻醉作用、单个培养海马神经元突触小泡胞吐作用以及特定 Na+ 通道亚型的生物物理特性。这些研究对于从分子角度理解突触前麻醉机制以及对兴奋性和抑制性突触传递的理想麻醉效果和潜在毒性麻醉效果之间的平衡至关重要。 公共卫生相关性：尽管麻醉剂在现代药典中发挥着重要作用，但麻醉剂产生遗忘、意识丧失和固定（全身麻醉的主要特征）的分子和细胞机制尚不清楚。我们已经证明，吸入麻醉剂通过抑制 Na+ 通道来抑制神经末梢释放神经递质，其机制随特定麻醉剂、神经递质和中枢神经系统区域的不同而变化。我们现在建议详细研究吸入麻醉剂的特定突触前作用和Na+通道阻断机制，以更全面地了解全身麻醉剂的作用方式，以便可以开发出减少不良副作用的未来麻醉剂，并可以更安全地使用现有麻醉剂。