Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief.
Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief.
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DOI：
10.1517/14728222.2016.1162295
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发表时间：
2016-08
影响因子：
5.8
通讯作者：
Wood JN
中科院分区：
文献类型：
--
作者：
Emery EC;Luiz AP;Wood JN
简介：慢性疼痛是一个巨大的临床问题。我们讨论了亚型选择性钠通道阻滞剂的潜力，可能提供镇痛有限的副作用。 涵盖的领域：钠通道亚型已通过遗传研究与人类疼痛综合征有关。Nav1.7、1.8和1.9中的功能突变的获得可导致疼痛，而Nav1.7突变的功能丧失导致其他正常人的疼痛丧失。有趣的是，人和小鼠Nav1.7无效突变体都增加了阿片驱动，因为阿片拮抗剂纳洛酮可以逆转与Nav1.7表达丧失相关的镇痛作用。 专家观点：我们相信钠通道拮抗剂，特别是Nav1.7拮抗剂在治疗大多数疼痛综合征方面有很好的前景。本文综述了最近开发特异性钠通道阻滞剂的尝试、Nav1.7无效无痛表型的基础机制以及使用基因治疗或与亚型特异性钠通道阻滞剂和阿片类药物联合治疗的镇痛新途径。选择性Nav1.7拮抗剂与脑啡肽酶抑制剂或低剂量阿片类药物一起使用具有无副作用镇痛的潜力，以及可能具有临床意义的重要阿片类药物保留功能。
Introduction: Chronic pain is a massive clinical problem. We discuss the potential of subtype selective sodium channel blockers that may provide analgesia with limited side effects. Areas covered: Sodium channel subtypes have been linked to human pain syndromes through genetic studies. Gain of function mutations in Nav1.7, 1.8 and 1.9 can cause pain, whilst loss of function Nav1.7 mutations lead to loss of pain in otherwise normal people. Intriguingly, both human and mouse Nav1.7 null mutants have increased opioid drive, because naloxone, an opioid antagonist, can reverse the analgesia associated with the loss of Nav1.7 expression. Expert Opinion: We believe there is a great future for sodium channel antagonists, particularly Nav1.7 antagonists in treating most pain syndromes. This review deals with recent attempts to develop specific sodium channel blockers, the mechanisms that underpin the Nav1.7 null pain-free phenotype and new routes to analgesia using, for example, gene therapy or combination therapy with subtype specific sodium channel blockers and opioids. The use of selective Nav1.7 antagonists together with either enkephalinase inhibitors or low dose opioids has the potential for side effect-free analgesia, as well as an important opioid sparing function that may be clinically very significant.