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）：全身麻醉剂的药理学和毒理学对于这样一种广泛使用的和医学上重要的药物类别来说非常不完整，这些药物用于越来越多的老年人和病情加重的患者。对麻醉剂作用机制的了解不足以解释任何麻醉剂如何产生遗忘、无意识或固定（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强而特异的作用，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。这项研究的主要目的是了解麻醉剂对神经递质释放的影响的突触前机制，通过实验将这些影响与更好地理解的突触后作用分离开来。突触前作用可能参与麻醉药的治疗作用（无意识、遗忘、不动）和/或其毒性作用（神经毒性、呼吸抑制、心血管抑制）。了解麻醉药的突触机制对于开发具有改善副作用的麻醉药和优化高危患者的当前麻醉技术至关重要。我们已经表明，全身麻醉剂抑制谷氨酸释放突触前机制，这些影响是特定的递质，并涉及特定的Na+通道亚型的区域特异性抑制。我们现在建议集中在区域和递质特异性行动和Na+通道阻滞机制的挥发性麻醉药，以更充分地了解他们的突触前行动。我们的中心假设是，全身麻醉剂通过突触特异性机制影响神经递质的释放，这是由于对突触前离子通道的影响。我们将通过以下具体目的，使用综合和协作的多学科方法来检验这一假设：目的1-确定挥发性麻醉剂差异影响神经递质从分离的神经末梢释放的机制，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作用的假设;目的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效应和机制，以验证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囊泡胞吐的假设;目的3-确定挥发性麻醉剂对电压门控Na+通道作用的机制和调节，以验证它们通过状态依赖性机制抑制Na+通道亚型的假设。补充方法包括分析麻醉剂对完整神经末梢递质释放的影响，单个培养海马神经元的突触囊泡胞吐作用，以及特定Na+通道亚型的生物物理特性。这样的研究是必不可少的突触前麻醉机制的分子理解和理想的和潜在的毒性麻醉对兴奋性和抑制性突触传递的影响之间的平衡。 公共卫生关系：尽管麻醉剂在现代药典中起着关键作用，但麻醉剂产生遗忘、无意识和固定（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的神经递质释放，其机制随特定麻醉剂、神经递质和中枢神经系统区域而变化。我们现在建议详细研究吸入麻醉剂的特异性突触前作用和Na+通道阻断机制，以更全面地了解全身麻醉剂的作用方式，以便未来的麻醉剂可以减少不良副作用，并且可以更安全地使用当前的麻醉剂。