Dissecting the relative contributions of injured and intact primary afferents to neuronal plasticity and neuropathic pain

剖析受损和完整的初级传入神经对神经元可塑性和神经病理性疼痛的相对贡献

• 批准号: MR/T01072X/1
• 负责人: Greg Weir
• 金额: $ 158.7万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT01072X%2F1
• 关键词: Dissecting; relative; contributions; injured; intact

Normal (nociceptive) pain is generated when specialised nerves (nociceptors) detect noxious stimuli and is a vital warning system that helps us to prevent or limit injury. Nociceptors send signals about the noxious stimuli to the spinal cord. Here, the signal is heavily modified before being transmitted to the brain, where the perception of pain is generated. Unlike nociceptive pain, neuropathic pain, which results from injury or disease of the nervous system, is a condition for which there is no known purpose. It affects over five million people in the UK alone and the majority of these patients are failed by current treatments and live in disabling pain.Neuropathic pain represents a dysfunction of pain transmission that can include spontaneous pain (stabbing or burning pain) and/or enhanced pain perception to both noxious and non-noxious stimuli (termed hyperalgesia and allodynia respectively). Changes in the way nociceptors and spinal circuits function are known to contribute to neuropathic pain. However, we know little about the precise nerves involved in different aspects of neuropathic pain, with the underlying causes of spontaneous pain a particularly understudied example. This is an incredibly important research area for two reasons. Firstly, because spontaneous pain is the major complaint from patients with neuropathic pain and, secondly, because knowing which nerves to target and where to do so, will be vital for the rational design of new drugs capable of ameliorating pain. It is clear from studies in patients that excessive electrical activity in nociceptors generates pain. Following injury to a nerve, injured nerves and intact neighbouring nerves develop spontaneous electrical activity; raising the question of how these two groups contribute to pain. This will be the central question of my research programme. To investigate, I will use a genetically altered mouse in which damaged and intact nerves are targeted separately with a protein capable of turning off electrical activity when a drug is given. I will use new behavioural methods to assess spontaneous pain in mouse models of neuropathic pain. The level of spontaneous pain when injured or intact nerves are switched off will be compared to give an insight into their respective contributions.While electrical activity in nociceptors is vital for spontaneous pain, the way the signal is processed in the spinal cord likely enhances or prolongs the pain experienced. Therefore, to study the changes that occur in the spinal cord, I will measure and compare the relative ease with which injured and intact nociceptors can activate spinal circuits. To visualise whether there are changes in spinal cord circuit structure following nerve injury, I will use genetically altered mice to label injured and intact nociceptors with different colours of fluorescent protein. In this way, I will be able to compare where these nerves go in the spinal cord and whether their connections with spinal nerves change after injury. These studies will be supported by recording from spinal nerves in tissue preparations while activating injured or intact nociceptors. By doing so, I will answer whether either pathway is strengthened following injury. Finally, I will study whether electrical activity in injured or intact nerves activates immune cells in the spinal cord, which are known to contribute to chronic pain. This will give us important information on whether activation of the immune system, independent of nociceptor electrical activity, should be an important consideration for drug development.This work will provide important information on the nerves involved in generating pain and how their activity can result in long-lasting and enhanced pain. In doing so, I will define new therapeutic targets that allow us to better design novel drugs for the treatment of neuropathic pain.

当专门的神经（伤害感受器）检测到有害刺激时，就会产生正常的（伤害性）疼痛，这是一个重要的警告系统，可以帮助我们预防或限制伤害。痛觉感受器向脊髓发送有关有害刺激的信号。在这里，信号在传输到大脑之前被大量修改，在那里产生了对疼痛的感知。与痛觉性疼痛不同，神经性疼痛是由神经系统损伤或疾病引起的，是一种没有已知目的的病症。仅在英国就有超过500万人受到影响，其中大多数患者目前的治疗失败，生活在致残的疼痛中。神经性疼痛是一种疼痛传递功能障碍，可包括自发性疼痛（刺痛或灼痛）和/或对有害和无害刺激（分别称为痛觉过敏和异常痛觉）的疼痛感知增强。伤害感受器和脊髓回路功能的改变是导致神经性疼痛的原因。然而，我们对神经性疼痛的不同方面所涉及的确切神经知之甚少，自发性疼痛的潜在原因是一个特别缺乏研究的例子。这是一个非常重要的研究领域，原因有二。首先，因为自发性疼痛是神经性疼痛患者的主要抱怨，其次，因为知道应该针对哪些神经以及在哪里进行，对于合理设计能够减轻疼痛的新药至关重要。从对病人的研究中可以清楚地看出，伤害感受器的过度电活动会产生疼痛。神经损伤后，损伤的神经和周围完整的神经发生自发电活动；这就提出了这两个群体是如何导致疼痛的问题。这将是我研究计划的中心问题。为了进行调查，我将使用一只转基因老鼠，在老鼠身上，受损和完整的神经分别被一种蛋白质靶向，这种蛋白质能够在给药时关闭电活动。我将使用新的行为学方法来评估神经性疼痛小鼠模型中的自发性疼痛。当受伤或完整的神经被关闭时，自发疼痛的水平将被比较，以深入了解它们各自的贡献。虽然痛觉感受器的电活动对自发性疼痛至关重要，但脊髓处理信号的方式可能会增强或延长所经历的疼痛。因此，为了研究脊髓中发生的变化，我将测量和比较受伤和完整的伤害感受器激活脊髓回路的相对容易程度。为了观察神经损伤后脊髓回路结构是否有变化，我将使用转基因小鼠用不同颜色的荧光蛋白标记受伤和完整的伤害感受器。通过这种方式，我将能够比较这些神经在脊髓中的位置以及它们与脊髓神经的连接是否在损伤后发生变化。这些研究将通过脊髓神经在组织准备中激活受伤或完整的伤害感受器的记录来支持。通过这样做，我将回答是否这两种途径在损伤后得到加强。最后，我将研究损伤或完整神经的电活动是否会激活脊髓中的免疫细胞，这是已知的导致慢性疼痛的原因。这将为我们提供重要的信息，说明独立于伤害感受器电活动的免疫系统的激活是否应该是药物开发的重要考虑因素。这项工作将为产生疼痛的神经以及它们的活动如何导致持久和增强的疼痛提供重要信息。在此过程中，我将定义新的治疗靶点，使我们能够更好地设计治疗神经性疼痛的新药。

项目成果

Cellular models of pain: New technologies and their potential to progress preclinical research.

疼痛的细胞模型：新技术及其进行临床前研究的潜力。

• DOI: 10.1016/j.ynpai.2021.100063
• 发表时间: 2021-08
• 期刊: Neurobiology of pain (Cambridge, Mass.)
• 作者: Chrysostomidou L;Cooper AH;Weir GA
• 通讯作者: Weir GA

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

• DOI: 10.1101/2023.02.10.528013
• 发表时间: 2023-03
• 期刊: bioRxiv
• 作者: K. Boyle;E. Polgár;M. Gutierrez-Mecinas;A. Dickie;Andrew H. Cooper;Andrew M. Bell;M. Evelline Jumolea;Adrián Casas-Benito;Masahiko Watanabe;D. Hughes;Gregory A Weir;J. Riddell;A. Todd

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling.

• DOI: 10.7554/elife.86633
• 发表时间: 2023-07-25
• 期刊: eLife
• 影响因子: 7.7
• 作者: Boyle KA;Polgar E;Gutierrez-Mecinas M;Dickie AC;Cooper AH;Bell AM;Jumolea E;Casas-Benito A;Watanabe M;Hughes DI;Weir GA;Riddell JS;Todd AJ
• 通讯作者: Todd AJ

Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.

• DOI: 10.1093/brain/awab482
• 发表时间: 2022-10-21
• 期刊: Brain : a journal of neurology