Conditional knockout of Na(V)1.6 in adult mice ameliorates neuropathic pain.
Conditional knockout of Na(V)1.6 in adult mice ameliorates neuropathic pain.
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DOI：
10.1038/s41598-018-22216-w
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发表时间：
2018-03-01
影响因子：
4.6
通讯作者：
Dib-Hajj SD
中科院分区：
文献类型：
--
作者：
Chen L;Huang J;Zhao P;Persson AK;Dib-Hajj FB;Cheng X;Tan A;Waxman SG;Dib-Hajj SD
电压门控钠离子通道NaV1.7、NaV1.8和NaV1.9一直是疼痛研究的焦点，因为它们的突变与人类疼痛障碍有关，但NaV1.6在疼痛中的作用尚不清楚。在这项研究中，我们选择性地敲除背根神经节（DRG）神经元中的NaV1.6，使用NaV1.8-Cre定向或腺相关病毒（AAV）-Cre介导的方法，并检查NaV1.6对这些神经元中河豚毒素敏感（TTX-S）电流的特异性贡献及其在神经病理性疼痛中的作用。我们在这里报告说，NaV1.6在大的DRG神经元中贡献了高达60%的TTX-S电流，在小的DRG神经元中贡献了34%。我们还发现，在保留神经损伤（SNI）后，NaV1.6在神经瘤内的Ranvier结处积聚。尽管NaV1.8-Cre驱动的NaV1.6敲除不改变急性、炎性或神经性疼痛行为，但成年小鼠中AAV-Cre介导的NaV1.6敲除部分减弱SNI诱导的机械性异常性疼痛。此外，AAV-Cre介导的NaV1.6敲除（主要在大DRG神经元中）显著减弱SNI后这些神经元的兴奋性，并减少神经瘤Ranvier结处的NaV1.6积累。总之，在正常或病理条件下，NaV1.8阳性神经元中的NaV1.6不影响痛阈，但在大的NaV1.8阴性DRG神经元中的NaV1.6在神经病理性疼痛中起重要作用。
Voltage-gated sodium channels NaV1.7, NaV1.8 and NaV1.9 have been the focus for pain studies because their mutations are associated with human pain disorders, but the role of NaV1.6 in pain is less understood. In this study, we selectively knocked out NaV1.6 in dorsal root ganglion (DRG) neurons, using NaV1.8-Cre directed or adeno-associated virus (AAV)-Cre mediated approaches, and examined the specific contribution of NaV1.6 to the tetrodotoxin-sensitive (TTX-S) current in these neurons and its role in neuropathic pain. We report here that NaV1.6 contributes up to 60% of the TTX-S current in large, and 34% in small DRG neurons. We also show NaV1.6 accumulates at nodes of Ranvier within the neuroma following spared nerve injury (SNI). Although NaV1.8-Cre driven NaV1.6 knockout does not alter acute, inflammatory or neuropathic pain behaviors, AAV-Cre mediated NaV1.6 knockout in adult mice partially attenuates SNI-induced mechanical allodynia. Additionally, AAV-Cre mediated NaV1.6 knockout, mostly in large DRG neurons, significantly attenuates excitability of these neurons after SNI and reduces NaV1.6 accumulation at nodes of Ranvier at the neuroma. Together, NaV1.6 in NaV1.8-positive neurons does not influence pain thresholds under normal or pathological conditions, but NaV1.6 in large NaV1.8-negative DRG neurons plays an important role in neuropathic pain.
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DOI：
10.1073/pnas.95.15.8963
发表时间：
1998-07-21
影响因子：
11.1
作者：
Dib-Hajj, SD;Tyrrell, L;Waxman, SG
通讯作者：
Waxman, SG
影响因子：
11.2
作者：
Faber, Catharina G.;Hoeijmakers, Janneke G. J.;Merkies, Ingemar S. J.
通讯作者：
Merkies, Ingemar S. J.
影响因子：
14.5
作者：
Cheng, Xiaoyang;Dib-Hajj, Sulayman D.;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.
影响因子：
7.4
作者：
Deuis JR;Zimmermann K;Romanovsky AA;Possani LD;Cabot PJ;Lewis RJ;Vetter I
通讯作者：
Vetter I
影响因子：
5.3
作者：
Amaya, Fumimasa;Wang, Haibin;Woolf, Clifford J.
通讯作者：
Woolf, Clifford J.