ANESTHETIC EFFECTS ON SENSORIMOTOR INTEGRATION

描述（由申请人提供）：最近的证据支持脊髓是麻醉剂抑制有害刺激引起的运动的部位的观点。虽然我们对麻醉剂调节的特定神经递质受体的理解已经取得了进展，但我们缺乏对这些麻醉作用在综合水平上的理解-例如，在脊髓的哪些位置和神经元类型上，麻醉作用相互作用而产生不动性？为了阐明麻醉剂对感觉运动处理的影响，本提案将使用神经生理学方法评估异氟烷（ISO）、氟烷（HAL）和丙泊酚（PROP）在几个脊髓部位（背角;中间角和腹角）以及在解剖学或功能上不同的神经元类型（宽动态范围、伤害感受特异性神经元、具有上行投射的感觉神经元、运动前中间神经元）的影响。在目标1中，我们将检验麻醉剂对脊髓不同深度神经元的影响不同的假设。我们假设ISO将在腹侧脊髓部位具有主要作用，而HAL和PROP将对背侧和腹侧脊髓部位均有作用。在目标2中，我们将检验具有上行投射的神经元（如脊髓丘脑神经元）比局部节段神经元对麻醉剂更敏感的假设。此外，在目标2中，我们将检验宽动态范围神经元比伤害性特异性神经元对麻醉更耐受的假设。在目标3中，我们将检验以下假设：GABA-A拮抗作用（印防己毒素）、甘氨酸拮抗作用（士的宁）和谷氨酸激动作用（NMDA）将以麻醉特异性方式逆转脊髓神经元功能的麻醉抑制，其中GABA拮抗作用对PROP和谷氨酸更特异，甘氨酸拮抗作用对ISO和HAL更特异。结果将导致更好地了解麻醉剂如何调节神经元功能的综合系统水平。了解麻醉剂的作用方式和作用部位将最终导致更好、更安全的麻醉剂的开发，从而降低围手术期的发病率和死亡率，改善公众健康。

DESCRIPTION (provided by applicant): Recent evidence supports the notion that the spinal cord is the site where anesthetics suppress movement resulting from noxious stimuli. While gains have been made in our understanding of specific neurotransmitter receptors that are modulated by anesthetics, we lack understanding of these anesthetic actions at an integrative level-e.g., at which spinal cord locations and types of neurons do anesthetic effects interact to produce immobility? To shed light on anesthetic effects on sensorimotor processing, the present proposal will use neurophysiological methods to assess the effects of isoflurane (ISO), halothane (HAL) and propofol (PROP) at several spinal sites (dorsal horn; intermediate and ventral horn) and on anatomically or functionally different neuronal types (wide-dynamic range, nociceptive specific neurons, sensory neurons with ascending projections, pre-motor interneurons). In Aim 1 we will test the hypothesis that anesthetics differ in their effects on neurons at different depths in the spinal cord. We hypothesize that ISO will have predominant effects at ventral spinal cord sites, whereas HAL and PROP will have effects on both dorsal and ventral spinal cord sites. In Aim 2 we will test the hypothesis that neurons with ascending projections (such as spinothalamic neurons) are more sensitive to anesthetics as compared to local segmental neurons. Furthermore, in Aim 2, we will test the hypothesis that wide-dynamic range neurons are more resistant to anesthesia compared to nociceptive specific neurons. In Aim 3, we will test the hypothesis that GABA-A antagonism (picrotoxin), glycine antagonism (strychnine) and glutamate agonism (NMDA) will reverse anesthetic depression of spinal cord neuronal function in an anesthetic-specific way, with GABA antagonism being more specific for PROP and glutamate and glycine antagonism being more specific for ISO and HAL. The results will lead to a better understanding of how anesthetics modulate neuronal function at an integrative systems level. Understanding how and where anesthetics act will eventually lead to the development of better and safer anesthetics, thereby decreasing peri-operative morbidity and mortality and improving public health.