Nociceptor Maturation & Response to Peripheral Injury

伤害感受器成熟

• 批准号: 7084459
• 负责人: Charles Jeffery WOODBURY
• 金额: $ 17.15万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-05 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7084459
• 关键词: action potentials; axon; biotin; confocal scanning microscopy; developmental neurobiology; dorsal horn; electrophysiology; immunocytochemistry; inflammation; injury; laboratory mouse; myelination; neural growth associated protein; neuroanatomy; neurochemistry; neurogenesis; newborn animals; nociceptors; nontherapeutic iontophoresis; pain; peripheral nervous system; skin; somatic afferent nerve; somesthetic sensory cortex; spinal ganglion

DESCRIPTION (provided by applicant): Pain circuitry in the spinal cord develops over a prolonged period of late fetal and early postnatal life and is particularly vulnerable to tissue trauma and inflammation during this time. Over the first few weeks of postnatal life, the central terminals of myelinated primary afferents undergo significant reorganization to generate the stereotypical laminar termination patterns seen in the adult dorsal horn. Recent findings in newborn mice have revealed that tactile afferents generate strikingly adult laminar termination patterns early on and thus undergo little central reorganization postnatally. By contrast, myelinated nociceptors give rise to widespread, inappropriate central projections in early postnatal life and thus the characteristic adult termination patterns of these afferents appear to mature later. Due to the relative immaturity of myelinated nociceptor central projections in newborns, the subsequent postnatal maturation of this group of afferents may be acutely susceptible to early perturbations of the periphery. The proposed experiments will examine the postnatal time course over which myelinated nociceptors achieve maturity to determine the potential window of this vulnerability. These studies will address the hypothesis that this early central exuberance is normally transient but that early tissue trauma, such as that caused by persistent tissue inflammation, arrests the normal postnatal reorganization of their central anatomy, leading to permanent structural alterations in spinal pain circuitry. An isolated somatosensory system preparation developed for comprehensive analyses of individual skin sensory neurons will be used to study the postnatal maturation of myelinated nociceptors in both hairy and glabrous skin of mice. A model of adjuvant-induced inflammation in glabrous skin of newborn mice will be used to examine the effects of early tissue trauma on the anatomical, physiological, and neurochemical maturation of individual neurons. Through intracellular recordings, neurons will be physiologically characterized using a variety of natural skin stimuli and then labeled in their entirety through iontophoresis of Neurobiotin. Their central projections will be reconstructed and analyzed morphometrically for changes taking place throughout postnatal maturation. Somata will be analyzed immunocytochemically to determine neurochemical changes, and peripheral endings will be analyzed for correlated structural changes in both normal and traumatized skin. The results of these studies will provide a detailed understanding of the early maturation of this vital component of the pain system, and the susceptibility of these afferents to early perturbation. This information will be pivotal to the development of future strategies in pediatric pain management and the translation of these strategies into effective practice.

描述（由申请人提供）：脊髓中的疼痛回路在胎儿晚期和产后早期的较长时间内形成，并且在此期间特别容易受到组织创伤和炎症的影响。在出生后的最初几周，有髓鞘初级传入神经的中央末端经历显着的重组，以产生在成人背角中看到的典型的层状终止模式。最近对新生小鼠的研究表明，触觉传入神经在早期就产生了明显的成年层状终止模式，因此在出生后几乎没有发生中枢重组。相比之下，有髓鞘伤害感受器在出生后早期产生广泛的、不适当的中枢投射，因此这些传入神经的特征性成人终止模式似乎成熟得较晚。由于新生儿有髓伤害感受器中枢投射相对不成熟，这组传入神经在出生后的成熟可能非常容易受到周围早期扰动的影响。 拟议的实验将检查有髓鞘伤害感受器成熟的出生后时间过程，以确定这种脆弱性的潜在窗口。这些研究将提出这样的假设：这种早期中枢旺盛通常是短暂的，但早期组织损伤，例如由持续性组织炎症引起的损伤，会阻碍中枢解剖结构的正常产后重组，导致脊髓疼痛回路的永久性结构改变。为综合分析个体皮肤感觉神经元而开发的分离体感系统制剂将用于研究小鼠多毛和无毛皮肤中有髓鞘伤害感受器的出生后成熟。新生小鼠无毛皮肤佐剂诱导的炎症模型将用于检查早期组织创伤对单个神经元的解剖学、生理学和神经化学成熟的影响。通过细胞内记录，神经元将使用各种自然皮肤刺激进行生理学表征，然后通过神经生物素的离子电渗疗法对其进行整体标记。它们的中心投影将被重建并进行形态测量分析，以了解出生后成熟过程中发生的变化。将通过免疫细胞化学分析体细胞以确定神经化学变化，并分析外周末梢以了解正常和受伤皮肤的相关结构变化。这些研究的结果将提供对疼痛系统这一重要组成部分的早期成熟以及这些传入神经对早期扰动的敏感性的详细了解。这些信息对于制定儿科疼痛管理未来策略以及将这些策略转化为有效实践至关重要。