Volatile Anesthetic Action in Vertebrate Locomotor Systems

描述（由申请人提供）：全麻的固定效力由消融由最大有害刺激引起的多节段、有节奏的运动型运动所需的最小浓度决定。然而，几乎没有关于麻醉对运动系统的作用的数据存在。拟议的研究旨在了解挥发性麻醉剂（氟烷和异氟烷）如何影响特定类别的运动产生脊髓运动和髓质神经元。项目包括在大鼠体内和七鳃鳗分离脊髓制备的单单元细胞外电生理学，以及应用于七鳃鳗的药理学方法。目的1：我们将确定挥发性药物是否直接破坏运动网络。我们假设麻醉药阻断了脊髓运动神经元对最大上有害刺激和中脑运动区（MLR）电微刺激的反应，其浓度足以阻断运动。在七鳃鳗，我们将识别兴奋性和抑制性中枢模式生成（CPG）神经元使用峰值触发平均和反dromic激活。我们假设麻醉剂对兴奋性CPG神经元的抑制作用大于抑制性神经元。目的2：使用七鳃鳗的药理学方法，我们将确定挥发性麻醉剂是否主要通过直接抑制兴奋性CPG网络起作用。我们假设GABAA和甘氨酸受体拮抗剂不会显著改变麻醉需求，并且挥发性麻醉剂对运动节律的影响与I组代谢性谷氨酸受体拮抗剂的作用一致，但与AMPA和NMDA受体拮抗剂的作用不一致。目的3：在大鼠和七鳃鳗制剂中，我们将确定挥发性药物是否通过棘上作用抑制下行运动驱动到脊髓。我们假设麻醉剂抑制了大鼠网状脊髓髓神经元对有害刺激和MLR微刺激的反应，并且在七鳃鳗中，选择性地向脑干输送麻醉剂抑制了网状脊髓神经元对MLR微刺激的反应和运动反应。全麻是危险的，在临床浓度下会降低血压、呼吸和体温调节。这些项目的结果将增加我们对麻醉药在神经系统中的作用方式和位置的理解，有助于开发更安全的麻醉药和临床实践。

DESCRIPTION (provided by applicant): The immobilizing potencies of general anesthetics are determined by the minimum concentration necessary to ablate multisegmental, rhythmic locomotor-type movements elicited by supramaximal noxious stimuli. However, almost no data exist regarding anesthetic action on locomotor systems that mediate this movement. The proposed studies aim to understand how volatile anesthetics (halothane and isoflurane) affect specific classes of movement-generating spinal locomotor and medullary neurons. Projects entail single-unit extracellular electrophysiology in both rat in vivo and lamprey isolated spinal cord preparations, with pharmacological approaches applied to lamprey. Aim 1: We will determine if volatile agents direcly disrupt locomotor networks. We hypothesize that anesthetics block responses of spinal locomotor neurons to both supramaximal noxious stimuli and electrical microstimulation of the mesencephalic locomotor region (MLR) at concentrations necessary to block movement. In lamprey, we will identify excitatory and inhibitory central pattern generating (CPG) neurons using spike-triggered averaging and antidromic activation. We hypothesize that anesthetics suppress excitatory CPG neurons more than inhibitory neurons. Aim 2: Using pharmacological approaches in lamprey, we will determine if volatile anesthetics act largely by direct suppression of excitatory CPG networks. We hypothesize that GABAA and glycine receptor antagonists do not significantly change anesthetic requirements, and that volatile anesthetics affect the locomotor rhythm consistent with effects on group I metabotropic glutamate receptor antagonists, but not consistent with effects of AMPA and NMDA receptor antagonists. Aim 3: In both rat and lamprey preparations, we will determine if volatile agents depress descending locomotor drive to the spinal cord by a supraspinal action. We hypothesize that anesthetics depress responses of rat reticulospinal medullary neurons to noxious stimuli as well as to MLR microstimulation, and that in the lamprey, selective delivery of anesthetics to the brainstem depresses reticulospinal neuronal responses and motor responses to MLR microstimulation. General anesthetics are dangerous, depressing blood pressure, respiration, and thermoregulation at clinical concentrations. Results from these projects will increase our understanding of how and where anesthetics act in the nervous system, contributing to the development of safer anesthetics and clinical practices.