LOCAL ANESTHETIC NEUROTOXICITY

脊髓及硬膜外术后神经系统损伤的近期报道 麻醉突出了我们目前对麻醉的理解中的巨大差距， 局部麻醉神经毒性。 具体来说，损伤的机制是 未知，解剖相关性不明确，以及促进 或减弱损害，我们对此知之甚少。尽管在这一时期取得了重大进展， 近十年来在神经营养因子纯化和表征方面， 不存在特定的治疗。由于缺乏相关的实验模型， 一直是研究脊髓神经毒性损伤的主要障碍， 神经根修改经验证的鞘内注射技术 导管插入术，药物输送和大鼠的感觉评估，我们有 开发了一种适合于这种研究的体内模型。拟议 项目将使用该模型来描述潜在的结构变化 功能障碍，是应用组织学技术研究 毒性的基本机制。 拟议的研究还将使用该模型，沿着 体外方法学，以确定是否“治疗指数”， 功能缺陷和不可逆传导阻滞的安全范围 不同的是目前使用的局部麻醉剂。拟议的研究将 确定麻醉剂的组合是否在添加剂、亚 添加或协同方式。持续时间增加的影响 将研究麻醉剂暴露，以确定神经毒性是否 仅是浓度依赖性功能。拟议的研究还将 确定神经生长因子（NGF）是否可以最小化或消除 损害初级传入神经的中枢过程，或促进 恢复功能。阳性结果表明 以神经营养为基础的脊髓神经根损伤治疗。 最后，为了确定局部麻醉神经毒性是否由 阻断电压门控钠离子通道本身，我们将建立 局麻药的神经毒性是否超过 河豚毒素，一种高选择性钠离子通道阻滞剂。积极的 研究结果表明，局部麻醉作用和神经毒性是 由不同的机制介导，并肯定了一个更安全的麻醉剂， 可以基于河豚毒素药效团进行开发。拟议 该项目是一个更大的努力，包括正在进行的临床研究的一部分 蛛网膜下腔麻醉剂分布的体外研究 旨在提高脊髓和硬膜外麻醉的安全性和有效性， 麻醉

Recent reports of neurologic injury occurring after spinal and epidural anesthesia highlight substantial gaps in our current understanding of local anesthetic neurotoxicity. Specifically, the mechanism of injury is unknown, the anatomic correlates ill-defined, and the factors that promote or attenuate damage, poorly understood. Despite major advances during the last decade in purification and characterization of neurotrophic factors, no specific therapy exists. The lack of a relevant experimental model has been a major barrier to study of neurotoxic damage to the spinal cord and nerve roots. Modifying well-validated techniques for intrathecal catheterization, drug delivery and sensory assessment in the rat, we have developed an in vivo model suitable for such investigation. The proposed project will use this model to delineate the structural changes underlying dysfunction, a prerequisite to applying histologic techniques to study basic mechanisms of toxicity. The proposed studies will also use this model along with established in vitro methodology to determine whether the "therapeutic index" for functional deficit and the safety margin for irreversible conduction block differ for currently used local anesthetics. The proposed studies will determine whether combinations of anesthetic interact in an additive, sub- additive or synergistic fashion. The effect of increasing duration of anesthetic exposure will be studied to determine if neurotoxicity is solely a concentration-dependent function. The proposed studies will also determine whether nerve growth factor (NGF) can minimize or eliminate damage to the central process of a primary afferent, or facilitate recovery of function. A positive finding would indicate potential for neurotrophic-based treatment of spinal cord nerve root injury. Finally, to determine whether local anesthetic neurotoxicity results from blockade of the voltage-gated sodium channel, per se, we will establish whether the neurotoxic potential of local anesthetics exceed that of tetrodotoxin, a highly selective sodium channel blocker. A positive finding would indicate that local anesthetic effect and neurotoxicity are mediated by different mechanisms and would affirm that a safer anesthetic can be developed based on the tetrodotoxin pharmacophore. The proposed project is part of a larger effort that includes ongoing clinical studies and in vitro investigations of subarachnoid anesthetic distribution directed at improving the safety and efficacy of spinal and epidural anesthesia.