ANESTHETIC EFFECTS ON SPINAL NOCICEPTIVE PROCESSING

脊髓是麻醉药抑制因有害刺激而产生的运动的主要部位，这是麻醉药的基本目标。采用系统分析的方法，本研究将探讨麻醉诱导的不动与(1)脊髓神经元上发条的关系；(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)脊髓节段凹陷导致后肢和前肢不活动。目的1将检验一种假设，即与那些在NMDA- r有中等或很少的体外作用的麻醉药相比，对NMDA受体有主要或唯一的体外作用的麻醉药会更大程度地影响缠绕。这一目标将通过检查氙气、异氟烷（ISO）、氟烷（HAL）和异丙酚对大鼠腰椎脊髓神经元上弦的影响来实现，有和没有MK-801，一种NMDA受体阻断剂。目标2和目标3将验证这样的假设：与野生型小鼠相比，NMDA-R和Na+通道突变导致小鼠对ISO或HAL不敏感，因此小鼠对热刺激的上锁反应和神经元反应同样对ISO和HAL不敏感。具有麻醉抗性的Gly-R突变小鼠将具有麻醉敏感的上弦（因为Gly-R不参与上弦），但对热有害刺激具有麻醉抗性。目的4将验证一种假设，即异氟醚抑制由尾或后肢刺激引起的前肢运动，这是由于颈脊髓的作用（可能是在运动神经元上），而氟烷则由于腰骶尾椎索的作用（可能是在背角神经元上）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准备，允许将ISO或HAL分别输送到兔子的上半身和下半身。这些拟议的研究将进一步阐明哪些脊髓部位和生理过程对麻醉诱导的静止是重要的。

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.