Defining the primary afferent circuitry that drives neuropathic pain

定义驱动神经性疼痛的主要传入回路

• 批准号: MR/T020113/1
• 负责人: David Bennett
• 金额: $ 268.27万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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%2FT020113%2F1
• 关键词: Defining; primary; afferent; circuitry; drives

Neuropathic pain occurs as a consequence of damage to the nervous system and is characterise by both loss of sensation such as numbness as well as unpleasant positive sensory features such as spontaneous pain and 'allodynia' whereby stimuli which are not normally painful such as brushing the skin become painful. Neuropathic pain is common, affecting almost 1 in 10 people and causes include neuropathy due to diabetes or chemotherapy treatment and traumatic injury to the nerves for instance phantom limb pain. Unfortunately, current treatments are ineffective and can have significant side effects for instance the addictive potential of strong opioids. Our over-arching aim is to understand the neural circuits driving neuropathic pain and to develop means to suppress aberrant activity in these circuits in order to inform new treatment approaches in neuropathic pain. Our focus will be the primary sensory neurons which are those neurons designed to detect sensory stimuli applied to the body (such as the skin) and transmit this information to the spinal cord. These neurons can be broadly classified into low threshold mechanoreceptors which respond to brushing the skin or skin indentation/stretch, thermoceptors responding to warmth or cooling and nociceptors which respond to stimuli which could cause injury such as extremes of temperature/mechanical pressure or chemicals such as acid. These neurons have distinct termination patterns (within their innervation targets and spinal cord) and gene expression profiles. After injury sensory neurons develop hyper-excitability including enhanced responses to stimulation and the development of spontaneous activity (action potentials generated in the absence of a stimulus). This represents an important treatment target however we need to understand exactly which sensory neurons are driving specific features of neuropathic pain. We can then target them selectively in order to treat neuropathic pain whilst not impairing other important aspects of neural function such as movement or useful sensations such as thermoception or pleasant touch.In order to understand which sensory neuron sub-types drive neuropathic pain we will use new technologies to control their activity and in particular 'chemogenetics' in which we express a modified receptor gene in a desired specific sensory neuron sub-type in mice using viruses or transgenic techniques. This receptor can then be activated by a non-toxic chemical to reversibly silence these neurons. We will use this to 'switch off' specific sensory neuron sub-populations and determine how these neurons contribute to specific aspects of neuropathic pain related behaviour such as brush evoked allodynia or assays of spontaneous pain. Once we have identified the key sensory neuron populations driving neuropathic pain we will investigate the pathophysiological changes specifically within these neurons for instance: defining the gene expression changes evoked by nerve injury that result in neuronal hyper-excitability and understanding how activity in these neurons impacts on spinal cord circuits. We hope to identify molecules/pathophysiological changes specific to these sub-populations in order to enhance the precision of treatment. Finally we will explore the translational potential of using this chemogenetic approach as a treatment for neuropathic pain. We will compare the sensory neuron sub-populations that we have identified in mouse to human DRG, information that would be needed in the future to target these neurons. We will also test a newly developed fully humanised chemogenetic system in both animal models and also human cellular models of neuropathic pain. This will therefore not only be informative regarding the critical circuit changes which drive neuropathic pain but also provide proof of concept that a chemogenetic gene therapy approach could be applied to neuropathic pain patients.

神经性疼痛由于神经系统损伤而发生，并且由于感觉丧失（例如麻木）以及令人不快的积极感觉特征（例如自发性疼痛和"异常性疼痛"，由此通常不疼痛的刺激（例如刷洗皮肤）变得疼痛）而引起。神经性疼痛是常见的，影响几乎十分之一的人，原因包括由于糖尿病或化疗治疗引起的神经病变和神经创伤性损伤，例如幻肢痛。不幸的是，目前的治疗方法是无效的，并且可能具有显著的副作用，例如强效阿片类药物的成瘾潜力。我们的首要目标是了解驱动神经性疼痛的神经回路，并开发抑制这些回路中异常活动的方法，以便为神经性疼痛的新治疗方法提供信息。我们的重点将是初级感觉神经元，这些神经元旨在检测施加到身体（如皮肤）的感觉刺激并将此信息传递到脊髓。这些神经元可以广泛地分类为响应于刷擦皮肤或皮肤压痕/拉伸的低阈值机械感受器、响应于温暖或冷却的温度感受器和响应于可能导致损伤的刺激（例如极端温度/机械压力或化学物质（例如酸））的伤害感受器。这些神经元具有不同的终止模式（在其神经支配靶和脊髓内）和基因表达谱。损伤后，感觉神经元产生过度兴奋性，包括对刺激的反应增强和自发活动的发展（在没有刺激的情况下产生的动作电位）。这代表了一个重要的治疗目标，但是我们需要确切地了解哪些感觉神经元驱动神经性疼痛的特定特征。然后，我们可以选择性地靶向它们，以治疗神经性疼痛，同时不损害神经功能的其他重要方面，如运动或有用的感觉，如热觉或愉快的触觉。类型驱动神经性疼痛，我们将使用新技术来控制它们的活性，特别是“化学遗传学”，其中我们在所需的特定感觉中表达修饰的受体基因，神经元亚型的小鼠使用病毒或转基因技术。然后，这种受体可以被一种无毒的化学物质激活，使这些神经元可逆地沉默。我们将利用这一点来"关闭"特定的感觉神经元亚群，并确定这些神经元如何促进神经性疼痛相关行为的特定方面，如刷诱发的异常性疼痛或自发性疼痛的测定。一旦我们确定了驱动神经性疼痛的关键感觉神经元群体，我们将研究这些神经元内的病理生理变化，例如：定义神经损伤引起的基因表达变化，导致神经元过度兴奋，并了解这些神经元的活动如何影响脊髓回路。我们希望识别这些亚群特有的分子/病理生理学变化，以提高治疗的精确度。最后，我们将探讨使用这种化学遗传学方法作为治疗神经性疼痛的翻译潜力。我们将比较我们在小鼠和人类DRG中识别的感觉神经元亚群，这些信息将在未来针对这些神经元。我们还将在神经性疼痛的动物模型和人类细胞模型中测试新开发的完全人源化的化学遗传系统。因此，这将不仅是关于驱动神经性疼痛的关键回路变化的信息，而且还提供了化学遗传基因治疗方法可以应用于神经性疼痛患者的概念证明。

项目成果

Towards prevention of diabetic peripheral neuropathy: clinical presentation, pathogenesis, and new treatments.

• DOI: 10.1016/s1474-4422(22)00188-0
• 发表时间: 2022-10
• 期刊: LANCET NEUROLOGY
• 影响因子: 48
• 作者: Elafros, Melissa A.;Andersen, Henning;Bennett, David L.;Savelieff, Masha G.;Viswanathan, Vijay;Callaghan, Brian C.;Feldman, Eva L.
• 通讯作者: Feldman, Eva L.

Deep RNA-seq of male and female murine sensory neuron subtypes after nerve injury

神经损伤后雄性和雌性小鼠感觉神经元亚型的深度 RNA-seq

• DOI: 10.1101/2022.11.21.516781
• 发表时间: 2022
• 作者: Barry A

Deep RNA-seq of male and female murine sensory neuron subtypes after nerve injury.

• DOI: 10.1097/j.pain.0000000000002934
• 发表时间: 2023-10-01
• 期刊: Pain
• 影响因子: 7.4

Epidemiology of neuropathic pain: an analysis of prevalence and associated factors in UK Biobank.

• DOI: 10.1097/pr9.0000000000001066
• 发表时间: 2023-03
• 期刊: Pain reports
• 影响因子: 4.8
• 作者: Baskozos G;Hébert HL;Pascal MM;Themistocleous AC;Macfarlane GJ;Wynick D;Bennett DL;Smith BH
• 通讯作者: Smith BH