ANESTHETIC EFFECTS ON SPINAL NOCICEPTIVE PROCESSING

麻醉对脊髓伤害性处理的影响

• 批准号: 6807221
• 负责人: JOSEPH ANTOGNINI
• 金额: $ 14.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807221
• 关键词: NMDA receptors; anesthesia; anesthetics; dorsal horn; electrophysiology; gene mutation; glycine receptors; halothane; heat stimulus; inhalation anesthesia; inhibitor /antagonist; isoflurane; laboratory rabbit; laboratory rat; limb movement; neural information processing; neurons; pain; pharmacokinetics; single cell analysis; sodium channel; spinal cord; spinal cord mapping; xenon

The spinal cord is the predominant site where anesthetics act to suppress movement that occurs as the result of noxious stimulation--a fundamental anesthetic goal. Using a systems analysis approach, this proposal will investigate the relationship of anesthetic-induced immobility to (1) wind-up in spinal neurons; (2) the N-methyI-D-aspartate receptor (NMDA-R), the glycine receptor (Gly-R) and the Na+ channel; (3) spinal cord segments that are depressed to result in hindlimb and forelimb immobility. Aim 1 will test the hypothesis that anesthetics with a predominant or exclusive in vitro action at NMDA receptors will affect wind-up more as compared to those that have moderate or little in vitro actions at the NMDA-R. This aim will be accomplished by examining the effects of xenon, isoflurane (ISO), halothane (HAL) and propofol on wind-up in lumbar spinal cord neurons in rats, with and without MK-801, an NMDA receptor blocker. Aims 2 and 3 will test the hypothesis that mice with NMDA-R and Na+ channel mutations which render the mice insensitive to ISO or HAL will have wind-up responses and neuronal responses to thermal stimulation that are likewise less sensitive to ISO and HAL, as compared to wild-type mice. A Gly-R mutant mouse with anesthetic resistance will have anesthetic sensitive wind-up (because Gly-R is not involved in wind-up) but will have anesthetic resistance vis-a-vis thermal noxious stimulation. Aim 4 will test the hypothesis that isoflurane suppresses forelimb movement resulting from tail or hindlimb stimulation because of action in the cervical spinal cord (presumably at motoneurons), while halothane prevents similar forelimb movement because of action in the lumbosacralcoccygeal cord (presumably at dorsal horn neurons). To accomplish this Aim we will use a vascular bypass preparation that permits differential delivery of either ISO or HAL to the upper and lower torso in rabbits. These proposed studies will further elucidate what spinal cord sites and physiological processes are important to anesthetic-induced immobility.

脊髓是麻醉剂抑制有害刺激引起的运动的主要部位--这是麻醉剂的基本目标。本研究拟采用系统分析的方法，探讨麻醉诱导的不动与下列因素之间的关系：（1）脊髓神经元的卷曲;（2）N-甲基-D-天冬氨酸受体（NMDA-R）、甘氨酸受体（Gly-R）和Na+通道;（3）脊髓节段被抑制导致后肢和前肢不动。目的1将检验以下假设：与对NMDA-R具有中等或很少体外作用的麻醉剂相比，对NMDA受体具有主要或排他性体外作用的麻醉剂将更影响发条。这一目的将通过检查氙、异氟烷（ISO）、氟烷（HAL）和丙泊酚对大鼠腰脊髓神经元缠绕的影响来实现，有和没有MK-801，一种NMDA受体阻滞剂。目的2和3将检验以下假设：与野生型小鼠相比，具有使小鼠对ISO或HAL不敏感的NMDA-R和Na+通道突变的小鼠将对热刺激具有同样对ISO和HAL不敏感的发条反应和神经元反应。具有麻醉剂抗性的Gly-R突变小鼠将具有麻醉剂敏感性发条（因为Gly-R不参与发条），但将具有相对维斯热伤害性刺激的麻醉剂抗性。目的4将检验以下假设，即异氟烷由于作用于颈脊髓（推测作用于运动神经元）而抑制由尾部或后肢刺激引起的前肢运动，而氟烷由于作用于腰骶髓（推测作用于背角神经元）而阻止类似的前肢运动。为了实现这一目标，我们将使用血管旁路制备，允许ISO或HAL差异输送到家兔的上部和下部躯干。这些拟议的研究将进一步阐明脊髓部位和生理过程是重要的麻醉诱导的不动。