Nociceptor Maturation and Response to Peripheral Injury

伤害感受器的成熟和对周围损伤的反应

• 批准号: 7753179
• 负责人: Charles Jeffery WOODBURY
• 金额: $ 30.43万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753179
• 关键词: Acute; Address; Adjuvant; Adult; Afferent Neurons; Age; Behavior; Birth; Carrageenan; Childhood; Chronic; Cutaneous; Development; Epidermis; Exhibits; Face; Foundations; Future; Goals; Hair follicle structure; In Vitro; Individual; Inflammation; Inflammatory; Injury; Iontophoresis; Knowledge; Label; Lead; Life; Long-Term Effects; Modeling; Morphology; Mus; Neonatal; Neurons; Newborn Infant; Nociception; Nociceptors; Pain; Pain management; Perception; Peripheral; Physiological; Physiology; Plastics; Predisposition; Preparation; Process; Property; Ruffinis Corpuscles; Skin; Staining method; Stains; Stimulus; Structure; System; Tactile; Testing; Time; Translations; Trigeminal System; Work; in vivo; mature animal; neonate; neurobiotin; novel; postnatal; public health relevance; research study; response; somatosensory; tissue trauma

DESCRIPTION (provided by applicant): Pain sensory neurons, or nociceptors, are particularly vulnerable to tissue trauma and inflammation during early life, and there is mounting evidence that peripheral inflammation in newborns can lead to permanent alterations in central nociceptive circuitry and pain-related behaviors. The extent to which these changes reflect permanent local alterations in the peripheral terminals of nociceptors is unknown, although such knowledge is critical to understanding causal mechanisms that either drive or help maintain altered nociceptive functioning in adults. Our recent work in neonatal mice has shown that the peripheral terminals of myelinated nociceptors undergo dramatic anatomical and physiological alterations within days of an inflammatory insult; by contrast, other cutaneous nociceptors were largely unaffected, and thus effects on myelinated nociceptors may be key to understanding altered adult pain states following early tissue trauma. The proposed experiments will directly examine the potential for permanent changes in myelinated nociceptor terminals using an in vivo trigeminal preparation in adult mice. This new preparation confers the ability, for the first time, to label the peripheral terminals of physiologically identified skin sensory neurons in adult animals. The overall goals of these studies are to determine the morphological diversity of myelinated nociceptor terminals in the skin of normal adult animals, and whether peripheral inflammation in early neonatal life results in permanent alterations of these endings. Through intracellular recordings, neurons will be physiologically characterized using a comprehensive suite of natural skin stimuli and then labeled in their entirety through iontophoresis of Neurobiotin. The peripheral terminals of labeled neurons will be reconstructed in skin sections to allow direct confirmation of functional morphology of individual physiologically identified skin sensory neurons. Analyses in normal (i.e., naove) adults will provide a critical backdrop for analyzing potential changes in these endings following neonatal inflammation. Potential long-term alterations in peripheral endings will be examined in two different models of experimentally induced inflammation in facial skin of newborn mice; the long-term effects of neonatal adjuvant-induced and carrageenan-induced inflammation will be compared to analyze potential differences between persistent versus acute inflammatory states in producing permanent alterations in myelinated nociceptor terminals. These results will be compared with the effects of experimentally induced inflammation in adulthood to determine whether the peripheral terminals of myelinated nociceptors retain the ability to respond to adult tissue trauma and therefore remain plastic throughout life. The results of these studies will provide an unprecedented 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. PUBLIC HEALTH RELEVANCE There is mounting evidence that peripheral inflammation in newborns can lead to permanent alterations in pain circuitry and behaviors. The extent to which these permanent effects are driven by irreversible effects of early inflammation on the terminals of pain-sensing, or nociceptive sensory neurons in the skin is unknown. The proposed work will determine the morphological diversity of nociceptor terminals in the skin of normal adult mice, and determine whether early inflammation leads to in permanent alterations in these endings.

描述（由申请人提供）：疼痛感觉神经元或伤害感受器在生命早期特别容易受到组织创伤和炎症的影响，并且有越来越多的证据表明新生儿的外周炎症可导致中枢伤害感受回路和疼痛相关行为的永久性改变。这些变化在多大程度上反映了伤害感受器外周末梢的永久性局部改变尚不清楚，尽管这些知识对于理解驱动或帮助维持成人伤害感受功能改变的因果机制至关重要。我们最近在新生小鼠中的研究表明，有髓鞘伤害感受器的外周末梢在炎症损伤的几天内发生了巨大的解剖学和生理学变化;相比之下，其他皮肤伤害感受器基本上不受影响，因此对有髓鞘伤害感受器的影响可能是理解早期组织创伤后成人疼痛状态改变的关键。拟议的实验将直接检查永久性变化的潜力，在有髓鞘的伤害性感受器终端在成年小鼠体内使用三叉神经制剂。这种新的制剂赋予的能力，第一次，标记生理上确定的皮肤感觉神经元在成年动物的外周终端。这些研究的总体目标是确定正常成年动物皮肤中有髓鞘伤害感受器末梢的形态多样性，以及新生儿早期外周炎症是否导致这些末梢的永久性改变。通过细胞内记录，将使用一套全面的天然皮肤刺激对神经元进行生理学表征，然后通过Neurobiotin的离子电渗法对其进行整体标记。将在皮肤切片中重建标记神经元的外周末梢，以直接确认生理学鉴定的单个皮肤感觉神经元的功能形态。正常情况下的分析（即，naove）成人将为分析新生儿炎症后这些结局的潜在变化提供关键背景。将在新生小鼠面部皮肤实验诱导炎症的两种不同模型中检查外周末梢的潜在长期改变;将比较新生清洁剂诱导和角叉菜胶诱导炎症的长期影响，以分析持续性与急性炎症状态在有髓鞘伤害感受器末端产生永久性改变方面的潜在差异。这些结果将与成年期实验诱导炎症的影响进行比较，以确定有髓鞘伤害感受器的外周末端是否保留对成人组织创伤的反应能力，从而在整个生命过程中保持可塑性。这些研究的结果将提供一个前所未有的了解早期成熟的疼痛系统的重要组成部分，这些传入神经的敏感性，早期扰动。这些信息将是关键的发展，未来的战略，在儿科疼痛管理和翻译这些战略转化为有效的做法。 越来越多的证据表明，新生儿外周炎症可导致疼痛回路和行为的永久性改变。这些永久性效应在多大程度上是由早期炎症对皮肤中疼痛感受或伤害感受神经元末梢的不可逆效应驱动的尚不清楚。这项工作将确定正常成年小鼠皮肤中伤害感受器末端的形态多样性，并确定早期炎症是否会导致这些末端的永久性改变。