The Effects of Local Anesthetics on Peripheral Nerve Injury and Repair

与周围神经病相关的感觉和运动障碍导致身体状况不佳 功能、姿势控制和平衡。这些变化影响了人们的日常生活活动，增加了 跌倒的风险，随后导致发病率增加和生活质量下降。[为了努力 最大限度地从伤病中恢复功能，许多退伍军人都会接受手术来治疗他们的伤病 四肢。]麻醉师通常使用局麻药(LAS)来进行周围神经阻滞，结果 在手术过程中或之后暂时控制疼痛。周围神经损伤可发生为 周围神经阻滞的并发症和损伤机制尚不清楚。一切都很好 证明了所有的LAS对神经元都是有毒的。因为LAS经常应用于我们退伍军人的网站 在周围神经有疾病或损伤的情况下，了解它们对受损神经元的影响是重要的 对临床实践的影响。 我们的长期目标是[最大限度地促进患有神经损伤的退伍军人的功能恢复] 通过了解LAS如何影响先前存在的周围神经损伤。目标是确定LAS是否 [在慢性模型中]加重周围神经细胞死亡和/或周围神经功能恢复缓慢 受伤。我们的中心假设是，先前损伤的神经元将更容易受到 作用时间更长的LAS，这将导致神经细胞死亡增加，功能恢复延迟或缺失 在有周围神经损伤的小鼠和没有周围神经损伤的小鼠中进行比较。该计划的基本原理 拟议的研究是，对LAS对神经元影响的更好理解将有助于识别 退伍军人周围神经阻滞后永久性神经功能障碍的风险较高和/或降低了 周围神经阻滞后出现神经功能障碍。为了测试我们的中心假设，我们将执行以下操作 具体目标： 具体目标1：确定选择性LAS是单独导致外周神经细胞死亡还是加重 周围神经切断或挤压后周围神经细胞死亡的成熟小鼠模型 周围神经损伤。选择LAS或安慰剂(生理盐水)将应用于完整的面神经(假损伤)，1 面神经切断后一周，面神经挤压伤后一周。神经元存活将是 在LA治疗4周后，通过比较损伤神经和未损伤神经之间的细胞计数来确定。 具体目标2：确定选择LAS是否会削弱周围神经挤压后的功能恢复 建立完善的小鼠周围神经损伤模型。选择LAS或安慰剂(生理盐水) 适用于面神经挤压伤后1周的面神经。神经元再生将通过以下方式进行衡量 每日两次神经挤压伤后的功能恢复分析。 [特定目标3：探讨LAS处理受损神经元基因表达的变化 来自AIMS 1和AIMS 2。小鼠将接受面神经轴突切断，然后选择局部麻醉剂应用于神经 伤后1周。然后在治疗后0、1、3、7和28天处死动物，并使用激光 捕捉显微解剖从损伤和未损伤的面神经核中收集组织以分析基因 与再生、细胞凋亡、应激反应和钠通道成分有关。] 拟议研究的预期结果是确定恶化的常用LAS 周围神经损伤后神经细胞死亡和/或功能恢复缓慢，并进一步表征 基因表达的变化。这些结果预计将产生重要的积极影响，通过确定 永久性神经缺陷风险较高的患者或帮助识别具有更安全神经毒性特征的LAS。这个 从这些研究中获得的知识可能会影响临床医生如何选择合适的患者接受治疗 周围神经阻滞和/或对高危患者使用LAS的影响。

The sensory and motor impairments associated with peripheral neuropathy lead to poor physical functioning, postural control and balance. These changes affect the activities of daily living and increase the risk of falling, subsequently leading to increased morbidity and decreased quality of life. [In an effort to maximize functional recovery from injuries, many veterans will undergo surgical procedures to their affected limbs.] Anesthesiologists commonly use local anesthetics (LAs) to perform peripheral nerve blocks that result in temporary control of pain during or after a surgical procedure. Peripheral nerve damage can occur as a complication from peripheral nerve blocks and the mechanism of injury remains unknown. It has been well documented that all LAs are toxic to neurons. Because LAs are frequently applied to sites in our veterans where peripheral nerves are diseased or injured, understanding their effects on injured neurons has important implications for clinical practice. Our long-term goal is [to maximize functional recovery in veterans suffering from nerve impairments] by understanding how LAs affect pre-existing peripheral nerve injuries. The objective is to determine if LAs worsen peripheral neuron cell death and/or slow functional recovery [in a chronic model] of peripheral nerve injury. Our central hypothesis is that previously injured neurons will be more susceptible to the toxicity of longer-acting LAs and this will result in increased neuron cell death and delayed or absent functional recovery in mice with a previous peripheral nerve injury compared to mice with no injury. The rationale for the proposed research is that an improved understanding of the effects of LAs on neurons will help identify veterans at higher risk for permanent neural deficits after peripheral nerve blocks and/or decrease the risk of neural deficit following peripheral nerve blocks. To test our central hypothesis we will pursue the following specific aims: Specific Aim 1: Determine if select LAs cause peripheral neuron cell death alone or exacerbate peripheral nerve cell death after a peripheral nerve axotomy or crush in a well-established mouse model of peripheral nerve injury. Select LAs or placebo (saline) will be applied to an intact facial nerve (sham injury), 1 week after a facial nerve axotomy, and 1 week after a facial nerve crush injury. Neuron survival will be determined 4-weeks after LA treatment by cell counts that compare between injured and uninjured nerves. Specific Aim 2: Determine if select LAs attenuate functional recovery after a peripheral nerve crush injury in a well-established mouse model of peripheral nerve injury. Select LAs or placebo (saline) will be applied to the facial nerve 1 week after a facial nerve crush injury. Neuronal regeneration will be measured by twice daily analysis of functional recovery from a nerve crush injury. [Specific Aim 3: Explore changes in gene expression of injured neurons treated with LAs identified from Aims 1 and 2. Mice will undergo a facial nerve axtotomy then select local anesthetic applied to the nerve 1 week after injury. We will then sacrifice animals at 0, 1, 3, 7, and 28 days following treatment and use laser capture microdissection to collect tissue from the injured and uninjured facial nuclei to analyze genes associated with regeneration, apoptosis, stress response and sodium channel components.] The expected outcomes of the proposed research are to identify commonly used LAs that worsen neuron cell death and/or slow functional recovery after a peripheral nerve injury, and to further characterize changes in gene expression. Such results are expected to have an important positive impact, by identifying patients at higher risk for permanent neural deficits or help identify LAs with safer neurotoxicity profiles. The knowledge gained from these studies may impact how clinicians choose appropriate patients to receive peripheral nerve blocks and/or influence which LAs are used on at-risk patients.