ANESTHETIC EFFECTS ON SENSORIMOTOR INTEGRATION

描述(申请人提供)：最近的证据支持脊髓是麻醉剂抑制由有害刺激引起的运动的地方的概念。虽然我们对麻醉药调节的特定神经递质受体的了解已经取得了进展，但我们在综合水平上缺乏对这些麻醉作用的了解-例如，在哪些脊髓位置和类型的神经元上，麻醉效应相互作用而产生不动？为了阐明麻醉对感觉运动加工的影响，本提议将使用神经生理学方法来评估异氟醚(ISO)、氟烷(HAL)和异丙酚(Prop)在几个脊髓部位(背角、中间角和腹角)以及对解剖学或功能上不同的神经元类型(大动态范围、伤害性特异性神经元、具有上升投射的感觉神经元、运动前中间神经元)的影响。在目标1中，我们将测试麻醉剂对脊髓不同深度神经元的不同影响这一假设。我们假设ISO在脊髓腹侧部位起主要作用，而HAL和PROP对脊髓背侧和腹侧部位都有影响。在目标2中，我们将检验这样的假设：与局部节段性神经元相比，具有上升投射的神经元(如脊髓丘脑神经元)对麻醉剂更敏感。此外，在目标2中，我们将测试这一假设，即与伤害性特定神经元相比，大动态范围神经元对麻醉更具抵抗力。在目标3中，我们将验证GABA-A拮抗剂(印防己毒素)、甘氨酸拮抗剂(士的宁)和谷氨酸激动剂(NMDA)将以麻醉特异性的方式逆转麻醉抑制脊髓神经元功能的假设，其中GABA拮抗剂对丙氨酸和谷氨酸更具特异性，甘氨酸拮抗剂对ISO和HAL更具特异性。这一结果将有助于更好地理解麻醉剂如何在综合系统水平上调节神经元功能。了解麻醉药的作用方式和部位将最终导致更好和更安全的麻醉药的开发，从而降低围手术期的发病率和死亡率，并改善公众健康。

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.