Synaptic Mechanisms of General Anesthetic Action

全身麻醉作用的突触机制

• 批准号: 7937433
• 负责人: HUGH C HEMMINGS
• 金额: $ 4.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937433
• 关键词: Adverse effects; Affect; Anesthetics; Biochemical; Brain region; Cardiovascular system; Catecholamines; Clinical; Corpus striatum structure; Coupling; Development; Dopamine; Exocytosis; General anesthetic drugs; Glutamates; Goals; Heterogeneity; Hippocampus (Brain); Ion Channel; Isoflurane; Methods; Nerve; Norepinephrine; Potassium Channel; Preparation; Property; Radiolabeled; Rattus; Recombinants; Relative (related person); Research Personnel; Rodent; Spinal Cord; Subcellular Fractions; Sucrose; Synapses; Synaptic Transmission; Synaptic Vesicles; Techniques; Testing; Tetrodotoxin; Therapeutic; Work; age related; aged; channel blockers; gamma-Aminobutyric Acid; neurochemistry; neurotransmitter release; patch clamp; potassium channel protein TREK-1; presynaptic; programs; radiotracer; research study; respiratory; voltage; voltage gated channel; young adult

DESCRIPTION (provided by applicant): The long-term goal of this competing continuation proposal is to understand the mechanisms of action of general anesthetics on synaptic transmission. Understanding the mechanisms of both the therapeutic and undesired effects of existing general anesthetics will facilitate their safe clinical use while enabling the rational development of more specific agents with reduced side-effects. Our central hypothesis is that general anesthetics affect neurotransmitter release by agent- and transmitter-specific presynaptic mechanisms involving effects on presynaptic ion channels. The project will be accomplished through a combination of neurochemical, electrophysiological and biochemical techniques via the following proposed Specific Aims: 1) Determine the mechanisms by which volatile anesthetics affect glutamate and GABA release from isolated nerve terminals to test the hypothesis that the effects of volatile anesthetics on glutamate and GABA release result from actions on presynaptic ion channels. 2) Characterize the electrophysiological effects of volatile anesthetics on voltage-gated Na+ channels to test the hypothesis that volatile anesthetics have state-dependent effects on voltage-gated Na+ channels at clinical concentrations. 3) Elucidate brain region-, transmitter- and age-dependent effects of volatile anesthetics on transmitter release in the CNS to test the hypothesis that heterogeneity in transmitter release mechanisms between various nerve terminal types results in differential presynaptic sensitivities to general anesthetics. Experiments will employ rodent nerve terminals isolated from various CNS regions to study presynaptic anesthetic effects in a subcellular fraction free of intercellular interactions and amenable to pharmacological, electrophysiological and biochemical analysis. Methods will include analysis of volatile anesthetic effects on basal and evoked release of radiolabeled glutamate, GABA, norepinephrine, and dopamine; comparison of the effects of isoflurane and other Na+ channel blockers on native, recombinant and bacterial Na+ channel biophysical properties; and immunochemical analysis of ion channels expressed in isolated nerve terminal preparations. Despite widespread clinical use, our understanding of how general anesthetics work is incomplete. Better understanding of their mechanisms will allow safer use of current anesthetics and facilitate development of anesthetics with fewer dangerous cardiovascular and respiratory side-effects.

描述（由申请人提供）：该竞争性延续建议的长期目标是了解一般麻醉药在突触传播方面的作用机制。了解现有全身麻醉药的治疗和不希望作用的机制将有助于其安全的临床用途，同时使更具体的药物的合理发展具有降低的副作用。我们的中心假设是，全身麻醉剂会影响涉及对突触前离子通道影响的药物和发射器特异性的前突触前机制的神经递质释放。该项目将通过以下提出的特定目的结合通过神经化学，电生理学和生化技术来完成：1）确定挥发性麻醉剂会影响谷氨酸和GABA从分离的神经终末释放的机制，以测试对迁移量和GABASATERIS pRIESHATIES和GABASATES的影响，以测试孔疗中的作用和GABASATERIS intheTAMES和GABAATAMATIES的作用。 2）表征挥发性麻醉药对电压门控的Na+通道的电生理影响，以测试挥发性麻醉药对临床浓度下电压门控的Na+通道具有状态依赖性的假设。 3）阐明挥发性麻醉药对中枢神经系统中发射机释放的脑区域，发射机和年龄依赖性影响，以检验以下假说：各种神经终末类型之间发射机释放机制的异质性导致对一般麻醉的差异前敏感性。实验将采用从各个中枢神经系统区域分离出的啮齿动物神经末端，以研究无细胞间相互作用的亚细胞分数中的突触前麻醉作用，并且可与药理学，电生理和生物化学分析相提并论。方法将包括分析挥发性麻醉对基底和诱发的放射性标记谷氨酸，GABA，去甲肾上腺素和多巴胺的释放的分析；异氟烷和其他Na+通道阻滞剂对天然，重组和细菌Na+通道生物物理特性的影响的比较；以及在分离的神经末端制剂中表达的离子通道的免疫化学分析。尽管临床广泛使用，但我们对一般麻醉的工作方式的理解是不完整的。更好地了解它们的机制将使使用当前麻醉药更安全，并促进危险性心血管和呼吸副作用较少的麻醉药的发展。