Cameron Adrian A, Smith George M, Randall David C, Brown David R, Rabchevsky Alexander G
Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536, USA.
J Neurosci. 2006 Mar 15;26(11):2923-32. doi: 10.1523/JNEUROSCI.4390-05.2006.
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.
胸中段以上的严重脊髓损伤可导致一种潜在危及生命的高血压病症，称为自主神经反射异常，其通常由盆腔脏器（膀胱或肠道）的疼痛性扩张以及随之而来的感觉纤维激活（包括伤害性C纤维）所触发。损伤后紧张性活动的延髓 - 脊髓通路中断会导致胸腰段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脊髓内芽生被认为促成了它们的过度活动。我们使用大鼠第四胸段完全脊髓横断后有害性结肠扩张（CRD）模型，研究了引发自主神经反射异常的关键脊髓节段。与对照绿色荧光蛋白（GFP）相比，通过双侧微量注射编码促生长NGF或生长抑制性信号素3A（Sema3a），在损伤尾侧的特定脊髓节段选择性地改变了降钙素基因相关肽（CGRP）免疫反应性初级传入纤维的创伤后芽生。两周后，在对注射部位传入纤维密度进行组织学分析之前，评估各治疗组对CRD的心脏生理反应。与GFP相比，腰段NGF过表达时反射异常性高血压显著更高，而Sema3a的类似过表达显著降低了有害CRD诱发的高血压。脊髓背角CGRP免疫染色的定量分析表明，向注射脊髓节段内纤维芽生的程度与自主神经反射异常的严重程度之间存在显著相关性。这些结果表明，完全脊髓损伤后对轴突导向分子进行定点基因操作可改变内源性神经回路，以调节可塑性诱导的自主神经病理生理学。
