The Effects of Local Anesthetics on Peripheral Nerve Injury and Repair

与周围神经病变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。这些变化会影响日常生活活动， 跌倒的风险，随后导致发病率增加和生活质量下降。[In努力 最大限度地从伤病中恢复功能，许多退伍军人将接受手术治疗，以他们的影响 四肢。]麻醉师通常使用局部麻醉剂（LA）进行周围神经阻滞， 在手术过程中或手术后暂时控制疼痛。周围神经损伤可能发生在 周围神经阻滞的并发症和损伤机制仍不清楚。已经充分 所有的LA都对神经元有毒。因为LA经常应用于我们退伍军人中的站点， 在周围神经患病或受伤的情况下，了解它们对受伤神经元的影响具有重要意义。 对临床实践的影响。 我们的长期目标是[最大限度地恢复神经损伤退伍军人的功能] 通过了解LA如何影响预先存在的周围神经损伤。目的是确定LA是否 恶化外周神经元细胞死亡和/或缓慢的外周神经功能恢复[在慢性模型中] 损伤我们的中心假设是，以前受伤的神经元将更容易受到毒性， 长效LA，这将导致神经元细胞死亡增加和功能恢复延迟或缺失 与没有损伤的小鼠相比，先前有外周神经损伤的小鼠。的理由 拟议的研究是，更好地了解LA对神经元的影响将有助于确定 周围神经阻滞后永久性神经缺损风险较高的退伍军人和/或降低 周围神经阻滞后的神经缺损。为了检验我们的中心假设，我们将继续以下内容 具体目标： 具体目标1：确定选择的LA是否单独引起外周神经元细胞死亡或加剧 周围神经轴突切断术或挤压后周围神经细胞死亡在一个良好建立的小鼠模型， 周围神经损伤将选择的LA或安慰剂（生理盐水）应用于完整的面神经（假损伤），1 面神经切断术后1周和面神经挤压伤后1周。神经元的存活将是 在LA治疗后4周，通过比较损伤和未损伤神经之间的细胞计数来确定。 具体目标2：确定选择的LA是否会减弱周围神经挤压后的功能恢复 损伤在良好建立的周围神经损伤的小鼠模型中。将选择LA或安慰剂（生理盐水） 在面神经挤压伤后1周应用于面神经。神经元再生将通过 每天两次分析神经挤压损伤的功能恢复。 [具体目的3：探索用鉴定的LA处理的损伤神经元的基因表达的变化 目标1和2。小鼠将接受面神经轴突切断术，然后选择局部麻醉剂应用于神经 受伤后一周。然后，我们将在治疗后0、1、3、7和28天处死动物，并使用激光 捕获显微切割，从受伤和未受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相关。 拟议研究的预期结果是确定恶化的常用LA 周围神经损伤后神经元细胞死亡和/或缓慢的功能恢复，并进一步表征 基因表达的变化。这些成果预计将产生重要的积极影响， 永久性神经功能缺损风险较高的患者，或帮助识别具有更安全神经毒性特征的LA。的 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 周围神经阻滞和/或影响哪些LA用于高危患者。

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.