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）：疼痛感官神经元或伤害感受器在早期生命中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，新生儿的周围炎症会导致中央致病性回路和与疼痛相关行为的永久变化。这些变化反映了伤害感受器外围终端的永久局部变化的程度尚不清楚，尽管这种知识对于理解驱动或有助于维持成人的伤害感受功能的因果机制至关重要。我们最近在新生儿小鼠中的工作表明，骨髓伤害感受器的外围末端在炎症性侮辱后的几天内经历了戏剧性的解剖和生理改变。相比之下，其他皮肤伤害感受器在很大程度上不受影响，因此对髓鞘的伤害感受器的影响可能是早期组织创伤后成人疼痛状态改变的关键。提出的实验将直接检查使用成年小鼠中体内三叉神经药物的髓鞘伤害感受器末端永久变化的潜力。这种新的制剂首次赋予了成年动物中生理上鉴定出的皮肤感觉神经元的外围末端的能力。这些研究的总体目标是确定正常动物皮肤中髓鞘伤害终末的形态多样性，以及新生儿早期的周围炎症是否会导致这些结局的永久改变。通过细胞内记录，神经元将在生理上使用全面的天然皮肤刺激套件来表征，然后通过神经蛋白的离子噬菌体进行全部标记。标记神经元的外围末端将在皮肤切片中重建，以直接确认单个生理鉴定的皮肤感觉神经元的功能形态。正常（即NAOVE）成年人的分析将为分析新生儿炎症后这些结局的潜在变化提供关键的背景。在新生小鼠面部皮肤的两种不同模型中，将检查外围末端的潜在长期改变。将比较新生儿辅助诱导的炎症和角叉菜胶引起的炎症的长期影响，以分析持续性与急性炎症状态之间在产生骨髓伤害感受器末端的永久变化中的潜在差异。这些结果将与实验引起的成年后的炎症的影响进行比较，以确定髓鞘伤害感受器的外围末端是否保留对成年组织创伤的反应能力，因此一生都保持塑性。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和这些传入对早期扰动的敏感性提供前所未有的理解。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。 公共卫生相关性有越来越多的证据表明，新生儿的周围炎症会导致疼痛回路和行为的永久改变。这些永久作用是由早期炎症对皮肤疼痛感应或伤害感受感官神经元的末端的不可逆影响驱动的程度。拟议的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导致这些结局的永久性改变。