Epigenetic Gene Silencing Underlies C-Fiber Dysfunctions in Neuropathic Pain
Epigenetic Gene Silencing Underlies C-Fiber Dysfunctions in Neuropathic Pain
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DOI：
10.1523/jneurosci.5541-09.2010
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发表时间：
2010-03-31
影响因子：
5.3
通讯作者：
Ueda, Hiroshi
中科院分区：
文献类型：
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作者：
Uchida, Hitoshi;Ma, Lin;Ueda, Hiroshi
周围神经损伤会引发神经性疼痛，其特点是同时出现正负两种看似矛盾的感觉症状。临床上，阴性体征较为常见，然而，其潜在的分子机制在很大程度上仍不明确。C纤维功能障碍被认为是阴性症状的基础，同时伴有背根神经节（DRG）中Na(v)1.8钠通道和μ阿片受体（MOP）的长期下调。在本研究中，我们发现神经损伤通过表观遗传机制上调了DRG神经元中神经元限制性沉默因子（NRSF）的表达。此外，染色质免疫沉淀分析显示，神经损伤促使NRSF与MOP和Na(v)1.8基因内的神经元限制性沉默元件结合，从而导致表观遗传沉默。再者，敲低NRSF能显著阻断神经损伤诱导的MOP和Na(v)1.8基因表达下调、C纤维感觉减退，以及外周吗啡镇痛作用的丧失和Na(v)1.8选择性阻滞剂诱导的感觉减退。综上所述，这些数据表明NRSF导致了C纤维的病理和药理功能障碍，这是神经性疼痛阴性症状的基础。
Peripheral nerve injury causes neuropathic pain, which is characterized by the paradoxical sensations of positive and negative symptoms. Clinically, negative signs are frequently observed; however, their underlying molecular mechanisms are largely unknown. Dysfunction of C-fibers is assumed to underlie negative symptoms and is accompanied by long-lasting downregulation of Na(v)1.8 sodium channel and mu-opioid receptor (MOP) in the dorsal root ganglion (DRG). In the present study, we found that nerve injury upregulates neuron-restrictive silencer factor (NRSF) expression in the DRG neurons mediated through epigenetic mechanisms. In addition, chromatin immunoprecipitation analysis revealed that nerve injury promotes NRSF binding to the neuron-restrictive silencer element within MOP and Na(v)1.8 genes, thereby causing epigenetic silencing. Furthermore, NRSF knockdown significantly blocked nerve injury-induced downregulations of MOP and Na(v)1.8 gene expressions, C-fiber hypoesthesia, and the losses of peripheral morphine analgesia and Na(v)1.8-selective blocker-induced hypoesthesia. Together, these data suggest that NRSF causes pathological and pharmacological dysfunction of C-fibers, which underlies the negative symptoms in neuropathic pain.