NEURAL MECHANISMS OF ANESTHESIA

麻醉的神经机制

• 批准号: 2771907
• 负责人: JOAN J KENDIG
• 金额: $ 39.76万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-05-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2771907
• 关键词: GABA receptor; afferent nerve; analgesics; anesthetics; benzodiazepine receptor; benzodiazepines; disease /disorder model; drug interactions; evoked potentials; general anesthesia; glycine receptors; hyperalgesia; inhalation anesthesia; interneurons; intravenous anesthesia; laboratory rat; long term potentiation; motor neurons; neural transmission; spinal cord; stimulus /response; synapses; thalamus; voltage /patch clamp; voltage gated channel

The cellular and molecular basis of general anesthesia has not been satisfactorily defined. Recent evidence points to the spinal cord as the locus of one common anesthetic endpoint, namely absence of movement in response to a painful stimulus. Specific Aim l of the proposed studies tests the hypothesis that motor neurons participate in the cellular determination of this endpoint,.and probes the molecular basis of anesthetic effects on these cells as it relates to specific voltage-gated and ligand-gated ion channels. Analgesia is another desirable anesthetic endpoint. Anesthetic agents and adjuvants vary in respect to analgesic effect, from potent analgesia through ineffectiveness to hyperalgesia. Specific Aim 2 tests the hypothesis that spinal actions in addition-to supraspinal effects contribute to these differences. Agents used in anesthesia will be probed to compare their effects on motor output with effects on nociceptive interneurons that project cepahalad in the spinothalamic tract. Inhibition of activity in this tract would contribute both to analgesia and to diminution of arousal in response to painful stimuli. A significant problem in pain management is the hyperalgesia that often follows a tissue injury which produces prolonged noxious stimulation. Changes in synaptic transmission at the spinal level, termed spinal sensitization, are in part responsible. We have discovered and partially characterized two forms of lone term potentiation (LTP) in an in vitro spinal cord preparation which may be related to injury-induced hyperalgesia and a third which may be related to the hyperalgesia observed on abrupt opioid withdrawal. Specific Aim 3 will characterize these novel forms of LTP, define their mechanisms, and compare their pharmacology to that of animal models of hyperalgesia. The results will increase understanding of this important problem and provide an in vitro model for testing therapeutic strategies. All the proposed studies employ spinal cord isolated from 3 - 12 day old rats. Drugs to be tested include both inhalation and intravenous general anesthetic and hypnotic agents as well as opioid and alpha2 adrenergic analgesics. Methods include extracellular recording of population evoked potentials and single unit responses to stimuli to a peripheral nerve or dorsal root; whole cell ruptured patch electrode recording in current clamp mode from cells identified by physiological characteristics in whole cord; and whole cell ruptured patch voltage clamp of visually identified cells in thin spinal cord slices.

全身麻醉的细胞和分子基础尚未 令人满意的定义。最近的证据表明脊髓是 一个常见的麻醉终点的基因座，即没有运动 对痛苦刺激的反应。拟议研究的特定目的l 测试运动神经元参与细胞的假设 确定该终点，并探测 与特定电压门控有关这些细胞的麻醉作用 和配体门控离子通道。镇痛是另一种理想的麻醉 端点。麻醉剂和佐剂在镇痛药方面有所不同 效果，从有效的镇痛到无效性到痛觉过敏。 特定目标2检验了脊柱作用的假设。 脊柱上的效应有助于这些差异。代理使用 麻醉将进行探测以将其对电机输出的影响与 对在cepahalad投射的伤害性中间神经元的影响 脊柱丘脑。抑制这一区域的活动将 既有助于镇痛和唤醒的减少 痛苦的刺激。疼痛管理中的一个重大问题是 通常跟随组织损伤产生延长的组织损伤 有害刺激。脊柱突触传播的变化 水平，称为脊柱敏化，部分负责。我们有 发现并部分表征了两种形式的唯一术语 在体外脊髓制剂中的增强（LTP）可能是 与损伤引起的痛觉过敏有关，三分之一可能相关 在突然提取阿片类药物时观察到的痛觉过敏。具体目标 3将表征这些新型LTP的形式，定义其机制， 并将其药理学与痛觉过敏模型的药理学进行比较。 结果将增加对这个重要问题的理解， 提供一个用于测试治疗策略的体外模型。 所有拟议的研究采用从3-12天大的脊髓分离出的脊髓 老鼠。要测试的药物包括吸入和静脉注射 麻醉和催眠剂以及阿片类药物和α2肾上腺素能 镇痛药。方法包括唤起人口的细胞外记录 对刺激对周围神经的势和单位反应 背根；全细胞破裂的斑块电极记录电流 通过生理特征鉴定的细胞中的夹具模式 整根绳子；整个细胞在视觉上破裂的斑块电压夹 鉴定出细胞中的细胞中的脊髓切片。