ANESTHETIC EFFECTS ON SPINAL NOCICEPTIVE PROCESSING

脊髓是麻醉剂抑制伤害性刺激引起的运动的主要部位，这是麻醉的基本目标。利用系统分析的方法，这项建议将研究麻醉诱导的不动与(1)脊髓神经元的缠绕；(2)N-甲基-D-天冬氨酸受体(NMDA-R)、甘氨酸受体(Gly-R)和Na+通道的关系；(3)脊髓节段被压低导致后肢和前肢不能动。目的1将验证这样一种假设：与那些对NMDA-R有中等或很少体外作用的麻醉药相比，对NMDA受体有主要或独占作用的麻醉药对发条的影响更大。这一目标将通过检测氙气、异氟醚(ISO)、氟烷(HAL)和异丙酚对大鼠腰椎脊髓神经元上链的影响来实现，使用和不使用NMDA受体阻滞剂MK-801。AIMS 2和AIMS 3将测试一种假设，即与野生型小鼠相比，携带NMDA-R和Na+通道突变使小鼠对ISO或HAL不敏感的小鼠将具有对ISO和HAL同样不敏感的发条反应和神经元反应。具有麻醉耐药的Gly-R突变小鼠将有麻醉敏感的缠绕(因为Gly-R不参与缠绕)，但对热伤害性刺激具有麻醉抗性。目的4将验证这样的假设：异氟醚抑制由尾巴或后肢刺激引起的前肢运动，这是由于颈髓(可能是运动神经元)的作用，而氟烷则阻止类似的前肢运动，因为作用于腰骶髓(可能是在背角神经元)。为了实现这一目标，我们将使用血管搭桥准备，允许ISO或HAL不同地输送到兔的上半身和下半身。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剂诱导的不动很重要。

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.