STUDY OF ACTIVITY-DEPENDENT SYMPATHETIC SPROUTING

描述（由申请人提供）：我们研究的总体目标是研究交感神经萌芽的机制及其与源自轴突断裂的感觉神经元或损伤的外周轴突（神经瘤）的异位自发活动的相关性。在外周轴突切断后，交感神经轴突发芽进入腰背根神经节（DRG），这是涉及神经性疼痛的主要现象（例如，复杂性局部疼痛综合征[CRPS]）。虽然有证据表明，某些胶质细胞源性神经营养因子参与交感神经萌芽，触发，并可能指导，交感神经末梢萌芽的因果因素仍然在很大程度上是未知的。然而，有证据表明，交感神经萌芽主要与大型和中型感觉神经元，这往往是神经损伤后的高频率和/或爆发性放电。我们的初步研究结果表明，全身利多卡因（钠通道阻滞剂）显着降低交感神经发芽的程度，而全身给药的4-氨基吡啶（4-AP，钾离子通道阻滞剂），这增强了自发活动，增加了发芽。我们推测，周围神经或DRG的损伤导致高频率和/或爆发性放电，在大型和中型DRG神经元，触发发芽的交感神经纤维可能通过增强表达的神经营养因子从卫星胶质细胞。本研究利用实验性神经瘤动物模型，结合电生理、免疫组化和Western blot技术，从以下三个方面验证我们的假设。具体目标1。检查外周轴突切断后DRG中的交感神经发芽是否显示出对具有高频和/或爆发性放电或过度兴奋的自发活动神经元的偏好。具体目标2。确定交感神经萌芽是否可以诱发自发活动的DRG无轴突切断。具体目标3。评估胶质细胞源性神经营养因子在活动依赖性交感神经发芽中的作用。如果确定了自发活动、神经营养因子和交感神经萌芽之间的关系，则可以开发涉及对自发活动进行药理学调节的新治疗方法来抑制感觉神经元的过度兴奋。这种疗法可以为神经性疼痛患者提供更有效的非阿片类镇痛。

DESCRIPTION (provided by applicant): The overall goal of our research is to investigate the mechanisms underling sympathetic sprouting and its correlation with ectopic, spontaneous activity originating from axotornized sensory neurons or injured peripheral axons (neuroma). After peripheral axotomy, sympathetic axons sprout into the lumbar dorsal root ganglia (DRGs), a major phenomenon implicated in neuropathic pain (e.g., complex regional pain syndrome [CRPS]). Although there is evidence that certain glial-cell-derived neurotrophins are involved in the sympathetic sprouting, the causal factor that triggers, and possibly guides, the sprouting of sympathetic nerve endings remains largely unknown. However, evidence exists that sympathetic sprouting is associated predominately with large- and medium-sized sensory neurons, which often present with high frequency and/or bursting discharges after nerve injury. Results from our preliminary study revealed that systemic lidocaine (a Na* channel blocker) significantly reduced the extent of sympathetic sprouting, whereas systemic administration of 4-aminopyridine (4-AP, a K+ channel blocker), which enhances spontaneous activity, increased the sprouting. We hypothesize that injury of the peripheral nerve or the DRG causes high frequency and/or bursting discharges in large- and medium-sized DRG neurons that trigger the sprouting of sympathetic nerve fibers possibly through the enhanced expression of neurotrophins from satellite glial cells. Using animal models of experimental neuroma combining with electrophysiological, immunohistochemical and Western blot techniques, we will test our hypothesis via the following 3 Specific Aims. Specific Aim 1. Examine whether sympathetic sprouting in DRGs with peripheral axotomy shows any preference for spontaneously active neurons with high frequency and/or bursting discharges or hyperexcitability. Specific Aim 2. Determine whether sympathetic sprouting may be evoked by spontaneous activity in DRGs without axotomy. Specific Aim 3. Assess the role of glial cell-derived neurotrophins in activity-dependent sympathetic sprouting. If a relationship among spontaneous activity, neurotrophins, and sympathetic sprouting is identified, then new therapeutic approaches involving pharmacological modulation of spontaneous activity could be developed to suppress the hyperexcitability of sensory neurons. Such therapies could provide more effective non-opioid analgesia to patients with neuropathic pain.