Genetic manipulation of intraspinal plasticity after spinal cord injury alters the severity of autonomic dysreflexia
Genetic manipulation of intraspinal plasticity after spinal cord injury alters the severity of autonomic dysreflexia
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DOI：
10.1523/jneurosci.4390-05.2006
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发表时间：
2006-03-15
影响因子：
5.3
通讯作者：
Rabchevsky, AG
中科院分区：
文献类型：
--
作者：
Cameron, AA;Smith, GM;Rabchevsky, AG
胸中段以上的严重脊髓损伤可导致称为自主神经反射异常的潜在危及生命的高血压病症，其通常由骨盆内脏（膀胱或肠）的疼痛性膨胀和随后的感觉纤维激活（包括伤害性C纤维）触发。在损伤后，紧张性活跃的髓-脊髓通路的中断引起胸腰交感神经节前神经元的去抑制，并且神经生长因子（NGF）反应性初级传入纤维的椎管内发芽被认为有助于它们的过度活跃。我们研究了脊髓水平，这是关键的诱发自主神经反射障碍，使用模型的伤害性结直肠扩张（CRD）后，完全脊髓横断在大鼠的第四胸段。与对照绿色荧光蛋白（GFP）相比，双侧显微注射编码生长促进性NGF或生长抑制性脑信号蛋白3A（Sema 3a）的腺病毒，在特定脊髓损伤尾侧水平选择性地改变降钙素基因相关肽（CGRP）免疫反应性初级传入纤维的创伤后发芽。两周后，在对注射部位的传入纤维密度进行组织学分析之前，评估了治疗组对CRD的心脏生理反应。与GFP相比，腰骶段中NGF过表达的反射障碍性高血压显著更高，而类似的Sema 3a过表达显著降低了伤害性CRD诱发的高血压。脊髓背角CGRP免疫染色的定量分析表明，纤维发芽到脊髓节段注射和自主神经反射障碍的严重程度之间的显着相关性。这些结果表明，在完全脊髓损伤后，轴突导向分子的定点遗传操作可以改变内源性回路，以调节可塑性诱导的自主神经病理生理学。
Severe spinal cord injuries above mid-thoracic levels can lead to a potentially life-threatening hypertensive condition termed autonomic dysreflexia, which is often triggered by painful distension of pelvic viscera (bladder or bowel) and consequent sensory fiber activation, including nociceptive C-fibers. Interruption of tonically active medullo-spinal pathways after injury causes disinhibition of thoracolumbar sympathetic preganglionic neurons, and intraspinal sprouting of nerve growth factor (NGF)-responsive primary afferent fibers is thought to contribute to their hyperactivity. We investigated spinal levels that are critical for eliciting autonomic dysreflexia using a model of noxious colorectal distension (CRD) after complete spinal transection at the fourth thoracic segment in rats. Post-traumatic sprouting of calcitonin gene-related peptide (CGRP)-immunoreactive primary afferent fibers was selectively altered at specific spinal levels caudal to the injury with bilateral microinjections of adenovirus encoding the growth-promoting NGF or growth-inhibitory semaphorin 3A (Sema3a) compared with control green fluorescent protein (GFP). Two weeks later, cardio-physiological responses to CRD were assessed among treatment groups before histological analysis of afferent fiber density at the injection sites. Dysreflexic hypertension was significantly higher with NGF overexpression in lumbosacral segments compared with GFP, whereas similar overexpression of Sema3a significantly reduced noxious CRD-evoked hypertension. Quantitative analysis of CGRP immunostaining in the spinal dorsal horns showed a significant correlation between the extent of fiber sprouting into the spinal segments injected and the severity of autonomic dysreflexia. These results demonstrate that site-directed genetic manipulation of axon guidance molecules after complete spinal cord injury can alter endogenous circuitry to modulate plasticity-induced autonomic pathophysiology.