Defining the primary afferent circuitry that drives neuropathic pain

神经性疼痛是神经系统受损的结果，其特征是感觉丧失，如麻木，以及不愉快的积极感觉特征，如自发疼痛和“异常性疼痛”，即通常不疼痛的刺激，如刷牙，变得疼痛。神经性疼痛很常见，几乎影响到十分之一的人，其原因包括糖尿病或化疗引起的神经病变，以及神经的创伤性损伤，例如幻肢痛。不幸的是，目前的治疗方法是无效的，并且可能有明显的副作用，例如强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。我们的重点将放在初级感觉神经元上，这些神经元被设计用来检测施加于身体（如皮肤）的感觉刺激，并将这些信息传递到脊髓。这些神经元大致可分为低阈值机械感受器（对皮肤的摩擦或压痕/拉伸作出反应）、热感受器（对温暖或冷却作出反应）和伤害感受器（对可能造成伤害的刺激作出反应），如极端温度/机械压力或化学物质（如酸）。这些神经元具有不同的终止模式（在其神经支配目标和脊髓内）和基因表达谱。损伤后感觉神经元产生超兴奋性，包括对刺激的反应增强和自发活动的发展（在没有刺激时产生的动作电位）。这代表了一个重要的治疗目标，然而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，我们可以选择性地针对它们，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，如热感或愉快的触摸。为了了解哪种感觉神经元亚型驱动神经性疼痛，我们将使用新技术来控制它们的活动，特别是“化学遗传学”，我们使用病毒或转基因技术在小鼠的特定感觉神经元亚型中表达修饰的受体基因。然后，这种受体可以被一种无毒的化学物质激活，从而可逆地使这些神经元沉默。我们将利用这个来“关闭”特定的感觉神经元亚群，并确定这些神经元如何对神经性疼痛相关行为的特定方面做出贡献，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，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，导致神经元高度兴奋性，并了解这些神经元的活动如何影响脊髓回路。我们希望确定这些亚群的分子/病理生理变化，以提高治疗的准确性。最后，我们将探讨使用这种化学发生方法作为神经性疼痛治疗的转化潜力。我们将比较我们在小鼠和人类DRG中发现的感觉神经元亚群，这将是未来针对这些神经元所需的信息。我们还将在动物模型和人类神经性疼痛细胞模型中测试新开发的完全人性化的化学发生系统。因此，这不仅将提供有关驱动神经性疼痛的关键电路变化的信息，而且还提供了化学发生基因治疗方法可应用于神经性疼痛患者的概念证明。

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.