钠通道 Nav1.7、Nav1.8 与疼痛;Nav1.7 空镇痛的两种不同机制

Q2 Medicine
Federico Iseppon , Alexandros H. Kanellopoulos , Naxi Tian , Jun Zhou , Gozde Caan , Riccardo Chiozzi , Konstantinos Thalassinos , Cankut Çubuk , Myles J. Lewis , James J. Cox , Jing Zhao , Christopher G. Woods , John N. Wood
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引用次数: 0

摘要

基因缺失和药理抑制是揭示疼痛机制、确定靶点和开发新型镇痛药的不同方法。这两种方法都适用于电压门控钠通道 Nav1.7 和 Nav1.8。在小鼠中遗传性缺失 Nav1.8 会导致疼痛消失,而拮抗剂是有效的镇痛剂。Nav1.7 的情况则更为复杂。人类或小鼠感觉神经元胚胎期完全缺失 Nav1.7,会导致无嗅觉以及因神经递质释放减少而产生的深度镇痛。在人类和小鼠中,这是由内源性阿片信号增强介导的。相比之下,嗅觉缺失则与阿片无关。感觉神经元的兴奋性和自律神经功能似乎正常。成人感觉神经元中 Nav1.7 的缺失也会导致镇痛,但这是通过降低感觉神经元和自律神经元的兴奋性来实现的。纳洛酮(Naloxone)缺乏作用表明,镇痛或嗅觉失灵中没有阿片类成分。在小鼠和人体内对 Nav1.7 进行药理抑制既会导致镇痛,又会对自律神经系统产生剧烈的副作用,而且没有治疗窗口期。这些数据表明,特异性 Nav1.7 通道阻断剂不能作为镇痛药物。胚胎空突变体的存活率表明,存在代偿性变化以替代失去的 Nav1.7 通道。在这里,我们展示了通过质谱法检测到的感觉神经元钠通道 Nav1.1、Nav1.2 和 β4 亚基在 Nav1.7 胚胎无效神经元中上调,连同其他蛋白质组的变化,有可能补偿 Nav1.7 的损失。 有趣的是,许多上调的蛋白质已知与 Nav1.7 相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sodium channels Nav1.7, Nav1.8 and pain; two distinct mechanisms for Nav1.7 null analgesia
Genetic deletion and pharmacological inhibition are distinct approaches to unravelling pain mechanisms, identifying targets and developing new analgesics. Both approaches have been applied to the voltage-gated sodium channels Nav1.7 and Nav1.8. Genetic deletion of Nav1.8 in mice leads to a loss of pain and antagonists are effective analgesics. The situation with Nav1.7 is more complex. Complete embryonic loss of Nav1.7 in humans or in mouse sensory neurons leads to anosmia as well as profound analgesia as a result of diminished neurotransmitter release. This is mediated by enhanced endogenous opioid signaling in humans and mice. In contrast, anosmia is opioid-independent. Sensory neuron excitability and autonomic function appear to be normal.
Adult deletion of Nav1.7 in sensory neurons also leads to analgesia, but through diminished sensory and autonomic neuron excitability. There is no opioid component of analgesia or anosmia as shown by a lack of effect of naloxone. Pharmacological inhibition of Nav1.7 in mice and humans leads both to analgesia and dramatic side-effects on the autonomic nervous system with no therapeutic window. These data demonstrate that specific Nav1.7 channel blockers will fail as analgesic drugs. The viability of embryonic null mutants suggests that there are compensatory changes to replace the lost Nav1.7 channel. Here we show that sensory neuron sodium channels Nav1.1, Nav1.2 and β4 subunits detected by Mass Spectrometry are upregulated in Nav1.7 embryonic null neurons and, together with other proteome changes, potentially compensate for the loss of Nav1.7. Interestingly, many of the upregulated proteins are known to interact with Nav1.7.
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来源期刊
Neurobiology of Pain
Neurobiology of Pain Medicine-Anesthesiology and Pain Medicine
CiteScore
4.40
自引率
0.00%
发文量
29
审稿时长
54 days
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