Neuronal subtype-specific plasticity in the acute to chronic pain transition

描述（由申请人提供）：疼痛治疗不足给社会带来了巨大的负担，部分原因是对急性疼痛向慢性疼痛转变的生物学事件的理解有限。更好地理解这种转变的障碍包括无法选择性地和有效地可视化或操纵特定的感觉神经元群体，以及在细胞水平上监测伤害感受器功能的可用方法的吞吐量非常低。在这项合作计划中，我们与一位发育神经生物学家和几位疼痛生物学家合作，共同克服这两个障碍。使用新开发的分子遗传学策略，我们将选择性地标记小鼠中低阈值机械感受性（LTMR）神经元以及肽能和MrgprD表达非肽能伤害感受器的四个主要亚群中的每一个。该技术将与小鼠外周感觉神经元中遗传编码的钙指示剂GCAMP3的选择性表达相结合，以允许皮肤和DRG中神经元活动的直接可视化。在我们的前两个目标中，这些工具将使我们能够有效地和高时空分辨率监测神经性疼痛发展过程中明确定义的伤害感受器和LTMR群体的解剖和功能变化。这些变化将与相应的行为变化相关，使用经典和新开发的热和机械敏感性测定进行监测。在目标3中，我们将选择性消融两个LTMR人群，这两个人群是疼痛的候选参与者，并定义其各自对神经性机械超敏反应的建立、维持和表现的贡献。总之，这些研究将为我们提供与慢性疼痛过渡相关的动态过程的前所未有的观点，并为开发改进的镇痛疗法定义细胞靶点。 公共卫生相关性：慢性疼痛影响着数百万人，而且往往很难治疗。部分原因是我们对为什么有些人在神经损伤后会转变为慢性疼痛状态缺乏了解，而另一些人则不然。在这项提案中，我们将利用新技术直接可视化皮肤中特定类别的神经，以了解神经损伤后其结构和功能的变化如何增强对疼痛的感知。这将允许合理开发治疗慢性疼痛的改进疗法。

DESCRIPTION (provided by applicant): Inadequate treatment of pain imposes an enormous burden on society, and is due, in part, to a limited understanding of biological events that underlie the transition from acute to chronic pain. Barriers to a better understanding of this transition have included an inability to selectively and efficiently visualize or manipulate specifc sensory neuron populations and the very low throughput of available methods to monitor nociceptor function at the cellular level. In this collaborative proposal, we have teamed together a developmental neurobiologist and several pain biologists to synergistically overcome both of these barriers. Using newly- developed molecular-genetic strategies, we will selectively label each of the four major subpopulations of low- threshold mechanoreceptive (LTMR) neurons, as well as peptidergic and MrgprD-expressing nonpeptidergic nociceptors, in mice. This technology will be combined with selective expression of the genetically encoded calcium indicator, GCAMP3, in mouse peripheral sensory neurons to permit direct visualization of neuronal activity in the skin and DRG. In our first two aims, these tools will allow us to efficiently and with high spatiotemporal resolution monitor changes in the anatomy and function of unambiguously defined nociceptor and LTMR populations during the development of neuropathic pain. These changes will be correlated with corresponding behavioral changes, monitored using classical and newly developed assays of thermal and mechanical sensitivity. In Aim 3, we will selectively ablate two LTMR populations that are candidate participants in pain and define their respective contributions to the establishment, maintenance, and manifestation of neuropathic mechanical hypersensitivity. Together, these studies will provide us with an unprecedented view of the dynamic processes associated with the transition to chronic pain and define cellular targets for the development of improved analgesic therapies. PUBLIC HEALTH RELEVANCE: Chronic pain affects millions of people and is often difficult to treat. This is due, in part, to our poor understanding of why some people, but not others, transition to a state of chronic pain after nerve injury. In this proposal, we will take advantage f new technology to directly visualize specific classes of nerves in the skin to understand how changes in their structure and function after nerve injury enhances the perception of pain. This will allow the rational development of improved therapies to treat chronic pain.