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

描述(申请人提供)：疼痛治疗不当给社会带来了巨大的负担，部分原因是对从急性疼痛向慢性疼痛过渡的生物学事件了解有限。更好地理解这一转变的障碍包括无法选择性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性感受器功能的现有方法的吞吐量非常低。在这项合作提案中，我们联合了一位发育神经生物学家和几位疼痛生物学家，以协同克服这两个障碍。使用新开发的分子遗传学策略，我们将选择性地标记小鼠低阈值机械感受性(LTMR)神经元的四个主要亚群中的每一个，以及表达肽能和MRGPrD的非肽能伤害性感受器。这项技术将与基因编码的钙指示剂GCAMP3在小鼠外周感觉神经元中的选择性表达相结合，从而直接显示皮肤和背根节中的神经元活动。在我们的前两个目标中，这些工具将使我们能够高效地以高时空分辨率监测明确定义的伤害性感受器和LTMR群体在神经病理性疼痛发展过程中的解剖和功能变化。这些变化将与相应的行为变化相关联，使用经典的和新开发的热和机械灵敏度分析进行监测。在目标3中，我们将有选择地消融两个LTMR群体，它们是疼痛的候选参与者，并确定它们在神经病理性机械超敏反应的建立、维持和表现中各自的贡献。总之，这些研究将为我们提供一个前所未有的视角，了解与向慢性疼痛过渡相关的动态过程，并为改进的止痛疗法的开发确定细胞靶点。 与公共卫生相关：慢性疼痛影响着数百万人，而且往往难以治疗。这在一定程度上是由于我们对为什么有些人，而不是其他人，在神经损伤后过渡到慢性疼痛状态的理解不足。在这项建议中，我们将利用新技术直接显示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疼痛的感知。这将允许合理开发改进的治疗方法来治疗慢性疼痛。

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.