Anesthetic actions on GABA(A) fast, slow, tonic and GABA(B) receptors

对 GABA(A) 快、慢、强直和 GABA(B) 受体的麻醉作用

基本信息

批准号：
8186361
负责人：
M. Bruce MacIver
金额：
$ 27.88万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8186361
关键词：
Address Agonist Anesthesia procedures Anesthetics Barbiturates Behavioral Behavioral inhibition Brain region Calcium Channel Complement Confusion Data Depressed mood Drug Design Drug usage Frequencies GABA Receptor GABA-B Receptor General anesthetic drugs Goals Individual Intravenous Isoflurane Learning Link Measures Mediating Memory Mental Depression Modeling Modern Medicine Molecular Target Neocortex Nervous system structure Operative Surgical Procedures Pain Pattern Pentobarbital Pharmaceutical Preparations Physiological Play Potassium Channel Presynaptic Receptors Propofol Reflex action Research Role SNAP receptor Signal Transduction Site Spinal Cord Synapses Synaptic Receptors System Testing Therapeutic Therapeutic Effect Time Unconscious State Ventilatory Depression Work barbituric acid salt base design gamma-Aminobutyric Acid in vivo receptor research study response sodium channel proteins synaptic inhibition

项目摘要

DESCRIPTION (provided by applicant): The long term goal of our research is to define the role played in anesthesia by various forms of GABA-mediated inhibition. There is great controversy at present regarding anesthetic-enhanced GABA inhibition for various anesthetic end-points. Good evidence points to considerable involvement, for several end-points, including loss of recall, loss of consciousness and even immobility, but other experiments have suggested little or no involvement. Nor is it clear whether GABA inhibition mediated by synaptic receptors or extrasynaptic tonic receptors play the more important role in depressing circuit level signaling. Our recent discovery of important effects on GABAB, in addition to well documented effects on GABAA systems, have added to the confusion about relevant effects for a growing array of new anesthetic target sites (e.g TREK and TASK potassium channels, calcium channels, other transmitter receptors, presynaptic SNARE proteins, and sodium channels). We will focus this study on GABAA and GABAB mediated inhibition, because these appear to contribute most to depression (over 60% when combined) from our preliminary studies, but our new circuit level analysis has already provided evidence for other key sites of action as well. Three specific aims will be addressed: 1 - to assess the role that fast and slow synaptic as well as tonic GABAA inhibition plays in CA1 circuit integration, 2 - to assess the roles these forms of inhibition play for anesthetic- induced circuit depression, and 3 - to assess the role GABAB mediated inhibition plays for anesthetics. Information from these aims is essential for designing safer and more effective anesthetics that selectively target the most relevant GABA receptors. In the immediate-term, we will contribute quantitative assessments to resolve current controversies, and assess new GABAB contributions for three classes of general anesthetics. Our results will provide the best quantitative data available upon which to model anesthetic effects using computational approaches - current models use estimates of the involvement of GABA systems that range from ~ 20 to 90 %, and there is little evidence upon which to base these estimates. As the GABA receptor subtypes underlying various forms of inhibition become known, our results will help link desired and unwanted anesthetic effects to these molecular targets. PUBLIC HEALTH RELEVANCE: General anesthetics are essential in modern medicine, especially for surgery, but these drugs remain among the most dangerous and poorly understood among clinically used drugs. Our research will address fundamental mechanisms of action for three important classes of anesthetics, including the intravenous agent propofol, the barbiturate pentobarbital, and volatile anesthetic isoflurane - to provide a scientific basis for safer drug design.

描述（由申请人提供）：我们研究的长期目标是定义通过各种形式的GABA介导的抑制作用在麻醉中起作用的作用。目前，关于各种麻醉终点的麻醉增强GABA的GABA抑制存在很大争议。充分的证据表明，有几个终点，包括失去召回，意识丧失甚至不动，但其他实验几乎没有参与。突触受体或突触外强调受体介导的GABA抑制是否在抑制电路水平信号传导中起着更重要的作用。除了对GABAA系统的影响充分，我们最近发现了对GABAB的重要影响，这加剧了人们对越来越多的新麻醉靶位点（例如Trek和Tast钾通道，钙通道，其他发射机受体，突触前的SNARE SNARE蛋白质和Sodium通道）的相关影响的困惑。我们将将这项研究重点放在GABAA和GABAB介导的抑制上，因为这些研究似乎对抑郁症最大（超过60％的合并），我们的初步研究中，我们的新电路水平分析也已经为其他关键作用部位提供了证据。将解决三个具体目标：1-评估快速和缓慢突触的作用以及在CA1电路整合中起作用的强度GABAA抑制作用，2- - 评估这些形式的抑制作用在麻醉诱发的电路抑郁症上和3--评估GABAB介导的抑制作用可在麻醉方面发挥作用。来自这些目标的信息对于设计最相关的GABA受体的更安全，更有效的麻醉剂至关重要。在即时期间，我们将贡献定量评估以解决当前的争议，并评估三类全身麻醉剂的新GABAB贡献。我们的结果将提供可用的最佳定量数据，以使用计算方法对麻醉效应进行建模 - 当前模型使用估计的GABA系统的参与度，该GABA系统的参与度在约20％至90％之间，几乎没有证据可以基于这些估计。由于已知各种形式的抑制作用的GABA受体亚型，我们的结果将有助于将所需的和不必要的麻醉作用与这些分子靶标联系起来。公共卫生相关性：一般麻醉在现代医学中是必不可少的，尤其是对于手术，但这些药物仍然是临床使用药物中最危险和最差的药物之一。我们的研究将针对三种重要类麻醉剂的基本作用机制，包括静脉注射剂丙泊酚，巴比妥酸盐五核和挥发性麻醉异氟烷 - 为更安全的药物设计提供科学基础。