Devor M, Govrin-Lippmann R, Angelides K
Department of Cell and Animal Biology, Life Sciences Institute, Hebrew University of Jerusalem, Israel.
J Neurosci. 1993 May;13(5):1976-92. doi: 10.1523/JNEUROSCI.13-05-01976.1993.
Nerve injury frequently triggers hyperexcitability and the ectopic initiation of impulses in primary afferent axons. An important consequence is neuropathic paresthesias and pain. Electrogenesis in normal afferents depends on appropriate Na+ channel concentrations. Therefore, we have asked whether injury might trigger changes in axolemmal Na+ channel distribution that could account for neuropathic hyperexcitability. We used an Na+ channel-specific antibody, 7493, to immunolocalize Na+ channels ultrastructurally in membranes of normal rat axons, and to assess remodeling following nerve section and neuroma formation. Selective labeling of nodal axolemma and, more weakly, of Schwann cell membrane, confirmed the efficacy of our immunolabeling protocol. In neuromas at postoperative times associated with peak ectopic activity, we found clear evidence of Na+ channel accumulation. Specifically, soon after myelin was stripped from large-diameter axons, the exposed, formerly internodal axolemma became immunopositive. Small-diameter unmyelinated axons and axon sprouts in the neuroma were also marked with 7493 IgG. Activated phagocytic macrophages and endothelial cells were 7493 negative. Both large- and small-diameter axons in neuromas end in swollen, organelle-packed "end bulbs." Most, but not all, of these acquired Na+ channel immunolabeling. We propose that remodeling results from a modification of the normal process of Na+ channel turnover in neural membranes. Na+ channel protein accumulates in preterminal axolemma and neuroma end bulbs due to a combination of permissive factors (especially myelin removal) and promotional factors (removal of normal downstream targets). This accumulation is a likely precursor of afferent hyperexcitability in injured nerve.
神经损伤常常引发初级传入轴突的兴奋性过高以及冲动的异位起始。一个重要的后果就是神经性感觉异常和疼痛。正常传入神经的电发生取决于适当的钠离子通道浓度。因此，我们探究了损伤是否会引发轴膜钠离子通道分布的变化，而这种变化可能是神经性兴奋性过高的原因。我们使用一种钠离子通道特异性抗体7493，通过超微结构免疫定位法来确定正常大鼠轴突膜中钠离子通道的位置，并评估神经切断和神经瘤形成后的重塑情况。对结区轴膜以及较弱的施万细胞膜进行选择性标记，证实了我们免疫标记方案的有效性。在术后与异位活动高峰期相关的神经瘤中，我们发现了钠离子通道积累的确切证据。具体而言，在大直径轴突的髓鞘被剥去后不久，暴露的、以前的结间轴膜就呈免疫阳性。神经瘤中的小直径无髓轴突和轴突芽也被7493 IgG标记。活化的吞噬性巨噬细胞和内皮细胞呈7493阴性。神经瘤中的大直径和小直径轴突末端均为肿胀的、充满细胞器的“终球”。其中大多数，但并非全部，都获得了钠离子通道免疫标记。我们认为重塑是由神经膜中钠离子通道正常周转过程的改变引起的。由于允许性因素（尤其是髓鞘去除）和促进性因素（正常下游靶点的去除）的共同作用，钠离子通道蛋白在终末前轴膜和神经瘤终球中积累。这种积累很可能是损伤神经传入性兴奋性过高的先兆。
