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和早期产后寿命的长时间内发育，并且在这段时间尤其容易受到组织创伤和炎症的影响。在产后寿命的前几周，髓鞘的主要传入中央末端经历了显着的重组，以产生成人背角中看到的刻板印象层状终止模式。新生小鼠的最新发现表明，触觉传入在早期就产生了惊人的成年层流终止模式，因此在产后，触觉传入是在中央重组的。相比之下，骨髓的伤害感受器在产后早期生命中引起了广泛的，不适当的中心预测，因此这些传入者的特征成人终止模式在以后似乎成熟。由于新生儿中骨髓伤害感受器中央预测的相对不成熟，随后的产后成熟可能会严重易于早期扰动外围的扰动。 拟议的实验将检查产后时间过程，骨髓伤害感受器达到成熟度，以确定这种脆弱性的潜在窗口。这些研究将解决以下假设：这种早期的中心旺盛通常是短暂的，但是早期的组织创伤（例如持续组织炎症引起的）会阻止其中枢解剖结构的正常后重组，从而导致脊柱疼痛回路的永久性结构改变。开发了用于全面分析单个皮肤感觉神经元的孤立的体感系统制备，将使用小鼠毛骨子和无毛皮肤的骨髓伤害感受器的产后成熟。新生小鼠无毛皮肤辅助诱导的炎症模型将用于检查早期组织创伤对单个神经元解剖，生理和神经化学成熟的影响。通过细胞内记录，神经元将在生理上使用各种天然皮肤刺激来表征，然后通过神经biotin的离子噬菌体进行全部标记。它们的中心预测将进行形态计量的重构和分析，以在产后成熟过程中发生变化。将对SOMATA进行免疫细胞化学分析以确定神经化学的变化，并将分析外周结尾，以了解正常和创伤性皮肤的相关结构变化。这些研究的结果将详细了解疼痛系统的这一重要组成部分的早期成熟，以及这些传入对早期扰动的敏感性。这些信息对于开发小儿疼痛管理中未来策略以及将这些策略转化为有效实践的策略至关重要。