Nociceptor Maturation & Response to Peripheral Injury

伤害感受器成熟

• 批准号: 6606876
• 负责人: Charles Jeffery WOODBURY
• 金额: $ 17.56万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6606876
• 关键词: action potentials; axon; biotin; confocal scanning microscopy; developmental neurobiology; dorsal horn; electrophysiology; immunocytochemistry; inflammation; injury; iontophoresis therapy; laboratory mouse; myelination; neural growth associated protein; neuroanatomy; neurochemistry; neurogenesis; newborn animals; nociceptors; 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，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内，有髓鞘初级传入神经的中枢末梢经历了重大的重组，形成了成人背角中常见的典型层状末梢模式。最近对新生小鼠的研究发现，触觉传入事件在早期产生了惊人的成年层流终止模式，因此在出生后很少进行中枢重组。相比之下，有髓鞘的伤害感受器在出生后早期会产生广泛的、不适当的中枢投射，因此这些传入事件的典型成年终止模式似乎更晚成熟。由于新生儿髓鞘伤害感受器中枢投射相对不成熟，这组传入神经的随后出生后成熟可能极易受到外围神经早期扰动的影响。