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轴突感觉神经元或外周轴突损伤（神经瘤）引起的异位自发活动的关系。外周轴切开术后，交感轴突萌发进入腰椎背根神经节（DRGs），这是神经性疼痛（如复杂区域疼痛综合征[CRPS]）的主要现象。尽管有证据表明某些神经胶质细胞衍生的神经营养因子参与了交感神经的萌发，但触发并可能引导交感神经末梢萌发的因果因素在很大程度上仍然未知。然而，有证据表明交感神经萌芽主要与大中型感觉神经元相关，在神经损伤后经常出现高频和/或爆发性放电。我们的初步研究结果显示，全身利多卡因（一种Na*通道阻滞剂）显著降低了交感神经发芽的程度，而全身给药4-氨基吡啶（4-AP，一种K+通道阻滞剂）增强了自发活性，增加了交感神经发芽。我们假设周围神经或DRG的损伤会导致大、中型DRG神经元的高频放电和/或爆发性放电，从而触发交感神经纤维的萌发，这可能是通过卫星神经胶质细胞中神经营养因子的表达增强来实现的。利用实验神经瘤动物模型，结合电生理、免疫组织化学和Western blot技术，我们将通过以下3个特定目的来验证我们的假设。具体目标检查外周轴切开术后DRGs的交感神经芽是否表现出对高频和/或爆发性放电或高兴奋性自发活动神经元的偏好。具体目标2。确定在不进行轴切开术的情况下，DRGs的自发活动是否会诱发交感神经萌芽。具体目标3。评估神经胶质细胞来源的神经营养因子在活动依赖性交感神经发芽中的作用。如果自发活动、神经营养因子和交感神经发芽之间的关系被确定，那么涉及自发活动的药理学调节的新治疗方法可能会被开发出来，以抑制感觉神经元的过度兴奋性。这种治疗方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.