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: 7989406
• 负责人: Charles Jeffery WOODBURY
• 金额: $ 30.37万
• 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/7989406
• 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; Health; 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; 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，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觉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端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功能改变的因果机制至关重要。我们最近对新生小鼠的研究表明，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和生理改变；相比之下，其他皮肤伤害感受器在很大程度上未受影响，因此对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。提出的实验将直接研究成年小鼠体内三叉神经制备中髓鞘伤害感受器终末永久变化的可能性。这种新的制备方法首次赋予了标记成年动物生理上识别的皮肤感觉神经元的外周末梢的能力。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，以及新生儿早期的外周炎症是否会导致这些末梢的永久性改变。通过细胞内记录，神经元将使用一套全面的自然皮肤刺激进行生理表征，然后通过神经生物素离子电泳对其进行整体标记。标记神经元的外周末梢将在皮肤切片中重建，以便直接确认个体生理上识别的皮肤感觉神经元的功能形态。对正常（即幼稚）成人的分析将为分析新生儿炎症后这些末梢的潜在变化提供关键背景。在新生小鼠面部皮肤实验诱导炎症的两种不同模型中，将检查外周末梢的潜在长期改变；新生儿佐剂诱导的炎症和卡拉胶诱导的炎症的长期影响将进行比较，以分析持久和急性炎症状态在髓鞘伤害感受器终末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，以确定髓鞘伤害感受器的外周末梢是否保留对成年组织创伤的反应能力，从而在一生中保持可塑性。这些研究的结果将为疼痛系统的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易感性提供前所未有的理解。这一信息将是关键的未来战略的发展，在儿童疼痛管理和这些策略转化为有效的实践。