HCN ion channels and pain

HCN离子通道与疼痛

• 批准号: BB/J009180/1
• 负责人: Peter Anthony McNaughton
• 金额: $ 53.1万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ009180%2F1
• 关键词: HCN; ion; channels; pain

Pain is critical for survival, as shown by the bodily damage and short lives of the rare humans who lack a sensation of pain. Pain also has a downside, however, because chronic pain causes severe limitations in mobility and quality of life of those who suffer from it. Three modes of pain can be distinguished: acute pain, caused by an initial injury; inflammatory pain, in which tissue damage releases inflammatory mediators which enhance the sensation of pain; and neuropathic pain, caused by direct nerve damage. Acute pain is essential to protect us from injury. Inflammatory pain can be beneficial in protecting damaged areas from further harm, but when chronic it can cause a major reduction in quality of life. Neuropathic pain serves no obvious protective function and is a severe handicap for those who suffer from it. It is also the most poorly understood mode of pain, and the most difficult to treat.Recent work in the applicant laboratory has found that a single ion channel, HCN2, which is expressed in the surface membranes of nociceptive (pain-sensitive) neurons, controls their rate of firing of action potentials in response to inflammatory mediators. Selective genetic deletion of HCN2 in a subset of nociceptors abolishes the heat sensitivity seen in inflammatory pain, and also abolishes neuropathic pain. This work showed for the first time that a single molecular entity underlies both forms of pain, and moreover it opens up possibilities for new treatments of pain by the development of selective blockers of HCN2. This last will be a particularly welcome development, as all current analgesics in common use have major side effects.The present application aims to build on this advance by extending our scientific understanding of the involvement of HCN2 in pain. We have identified a particular population of nociceptors where the expression of HCN2 is critical for pain. The method that we used to achieve the genetic deletion tells us that these neurons must express a voltage-dependent sodium channel, NaV1.8. What are the other electrophysiological and histological properties of these neurons that make them critical for pain? We will mark these neurons genetically and will isolate them for further study. In two further lines of enquiry we will investigate which inflammatory mediators are crucial for modulating HCN2. Our previous work has identified prostaglandin E2 as one such mediator, but we have strong indications that others are important, in particular for neuropathic pain. We will test candidate mediators in isolated neurons, and we will elucidate their intracellular signalling pathways. We will then test inhibitors of these mediators, or of their signalling pathways, in in vivo experiments. This work may open up therapeutic possibilities for controlling pain by attacking the modulation of HCN2 rather than directly blocking the channel.A fourth area will investigate how the expression of HCN2 in neurons, and its expression in the neuronal membrane itself, may be modulated in a more long-term way by inflammatory mediators of the growth factor family, such as NGF and GDNF. There is evidence that these factors are released following nerve injury, and they may be important in the long-term maintenance of neuropathic pain.The work outlined above will put our understanding of the role of HCN2 in pain ona firm basis. There are two other members of the HCN ion channel family, HCN3 and HCN4, which remain to be investigated (previous work in our group has already ruled out HCN1 as a major contributor to pain). In the final phase of the project we will construct animals with genetic deletions of these two ion channels and will examine the effect of the deletion on pain. This work will tell us in a straightforward fashion whether either channel plays an important role in either inflammatory or neuropathic pain.

疼痛对生存至关重要，正如罕见的缺乏疼痛感的人的身体损伤和短暂生命所显示的那样。疼痛也有一个缺点，因为慢性疼痛会严重限制患者的活动能力和生活质量。疼痛可以分为三种模式：急性疼痛，由初始损伤引起;炎性疼痛，其中组织损伤释放炎性介质，增强疼痛感;和神经性疼痛，由直接神经损伤引起。剧烈的疼痛对保护我们免受伤害至关重要。炎症性疼痛可以保护受损区域免受进一步伤害，但当慢性时，它会导致生活质量的大幅降低。神经病理性疼痛没有明显的保护功能，对于那些患有神经病理性疼痛的人来说是一种严重的障碍。它也是最不了解的疼痛模式，并且最难治疗。申请人实验室的最近工作发现，在伤害感受性神经元的表面膜中表达的单个离子通道HCN 2，（疼痛敏感）神经元控制它们响应于炎症介质的动作电位的激发速率。在伤害感受器的子集中选择性遗传缺失HCN 2消除了在炎性疼痛中观察到的热敏感性，并且还消除了神经性疼痛。这项工作首次表明，一个单一的分子实体是两种形式的疼痛的基础，此外，它开辟了通过开发HCN 2的选择性阻断剂来治疗疼痛的新方法的可能性。这最后一个将是一个特别受欢迎的发展，因为所有目前常用的镇痛药都有主要的副作用。我们已经确定了一个特定的伤害感受器群体，其中HCN 2的表达对疼痛至关重要。我们用来实现基因缺失的方法告诉我们，这些神经元必须表达电压依赖性钠通道NaV1.8。这些神经元的其他电生理学和组织学特性使它们对疼痛至关重要吗？我们将对这些神经元进行遗传标记，并将它们分离出来进行进一步研究。在两个进一步的调查，我们将调查哪些炎症介质是至关重要的调节HCN 2。我们以前的工作已经确定前列腺素E2作为这样的介质之一，但我们有强烈的迹象表明，其他的是重要的，特别是神经性疼痛。我们将测试候选介质在孤立的神经元，我们将阐明他们的细胞内信号通路。然后，我们将在体内实验中测试这些介质或其信号通路的抑制剂。这项工作可能会打开通过攻击HCN 2的调节而不是直接阻断通道来控制疼痛的治疗可能性。第四个领域将研究HCN 2在神经元中的表达及其在神经元膜本身的表达如何通过生长因子家族的炎症介质（如NGF和GDNF）以更长期的方式进行调节。有证据表明，这些因子在神经损伤后释放，它们可能在神经病理性疼痛的长期维持中起重要作用。HCN离子通道家族中还有另外两个成员HCN 3和HCN 4仍有待研究（我们小组以前的工作已经排除了HCN 1是疼痛的主要贡献者）。在项目的最后阶段，我们将构建这两种离子通道基因缺失的动物，并将检查缺失对疼痛的影响。这项工作将以一种直接的方式告诉我们，无论是在炎症或神经病理性疼痛中，通道是否起着重要作用。

项目成果

How does inducible deletion of HCN2 in sensory neurons affect neuropathic pain?

感觉神经元中 HCN2 的诱导缺失如何影响神经性疼痛？

• 发表时间: 2013
• 期刊: Society for Neuroscience meeting 2013
• 作者: Mooney, Elizabeth

Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy.

• DOI: 10.1126/scitranslmed.aam6072
• 发表时间: 2017-09-27
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Tsantoulas C;Laínez S;Wong S;Mehta I;Vilar B;McNaughton PA
• 通讯作者: McNaughton PA

Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain.

• DOI: 10.1097/pr9.0000000000000967
• 发表时间: 2021-11
• 期刊: Pain reports
• 影响因子: 4.8
• 作者: Bernard Healey SA;Scholtes I;Abrahams M;McNaughton PA;Menon DK;Lee MC
• 通讯作者: Lee MC

Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length.

• DOI: 10.1523/jneurosci.2463-20.2021
• 发表时间: 2021-09-22
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Swire M;Assinck P;McNaughton PA;Lyons DA;Ffrench-Constant C;Livesey MR
• 通讯作者: Livesey MR

A randomised, double-blind, placebo-controlled crossover trial of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model: an enriched population trial

• DOI: 10.1097/j.pain.0000000000001638
• 发表时间: 2019-11-01
• 期刊: PAIN
• 影响因子: 7.4
• 作者: Lee, Michael C.;Bond, Simon;Menon, David
• 通讯作者: Menon, David