Redistribution of NaV1.8 in Uninjured Axons Enables Neuropathic Pain
Redistribution of NaV1.8 in Uninjured Axons Enables Neuropathic Pain
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DOI：
10.1523/jneurosci.23-01-00158.2003
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发表时间：
2003-01
期刊：
影响因子：
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通讯作者：
M. Gold;D. Weinreich;Chang-Sook Kim;Ruizhong Wang;J. Treanor;F. Porreca;J. Lai
中科院分区：
文献类型：
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作者：
M. Gold;D. Weinreich;Chang-Sook Kim;Ruizhong Wang;J. Treanor;F. Porreca;J. Lai
神经性疼痛的潜在机制知之甚少，现有的治疗方法大多无效。我们最近证实，反义介导的钠通道亚型NaV1.8的“敲低”逆转L5/L 6脊神经结扎（SNL）后的神经性疼痛行为，暗示NaV1.8在神经性状态中的关键功能作用。在这里，我们研究了NaV1.8有助于表达实验性神经病理性疼痛的机制。NaV1.8似乎不会通过对受伤传入神经的作用而导致神经性疼痛，因为该通道在受伤神经元的细胞体中功能性下调，并且不会重新分配到受伤的末端。虽然在L4神经节中未损伤神经元的胞体中NaV1.8蛋白或功能通道几乎没有变化，但沿坐骨神经的NaV1.8免疫反应性沿着显著增加。NaV1.8的分布主要反映了无髓鞘轴突中功能通道的存在。100 μ mTTX对SNL大鼠坐骨神经复合动作电位（CAP）的C纤维成分的阻断率>40%，而100 μ mTTX对SNL大鼠坐骨神经CAP的A、C纤维成分的阻断率均>90%。用反义寡脱氧核苷酸减弱NaV1.8的表达可防止NaV1.8在坐骨神经中的再分布，并逆转神经病理性疼痛。这些观察结果表明，未受伤的C-纤维的异常活动是与部分神经损伤相关的疼痛的必要组成部分。他们还表明，阻断NaV1.8将是神经性疼痛的有效治疗方法。
The underlying mechanisms of neuropathic pain are poorly understood, and existing treatments are mostly ineffective. We recently demonstrated that antisense mediated “knock-down” of the sodium channel isoform, NaV1.8, reverses neuropathic pain behavior after L5/L6 spinal nerve ligation (SNL), implicating a critical functional role of NaV1.8 in the neuropathic state. Here we have investigated mechanisms through which NaV1.8 contributes to the expression of experimental neuropathic pain. NaV1.8 does not appear to contribute to neuropathic pain through an action in injured afferents because the channel is functionally downregulated in the cell bodies of injured neurons and does not redistribute to injured terminals. Although there was little change in NaV1.8 protein or functional channels in the cell bodies of uninjured neurons in L4 ganglia, there was a striking increase in NaV1.8 immunoreactivity along the sciatic nerve. The distribution of NaV1.8 reflected predominantly the presence of functional channels in unmyelinated axons. The C-fiber component of the sciatic nerve compound action potential (CAP) was resistant (>40%) to 100 μm TTX after SNL, whereas both A- and C-fiber components of sciatic nerve CAP were blocked (>90%) by 100 μm TTX in sham-operated rats or the contralateral sciatic nerve of SNL rats. Attenuating expression of NaV1.8 with antisense oligodeoxynucleotides prevented the redistribution of NaV1.8 in the sciatic nerve and reversed neuropathic pain. These observations suggest that aberrant activity in uninjured C-fibers is a necessary component of pain associated with partial nerve injury. They also suggest that blocking NaV1.8 would be an effective treatment of neuropathic pain.