Synaptic function within mature central pain networks after neonatal injury

新生儿损伤后成熟中枢疼痛网络内的突触功能

• 批准号: 9291516
• 负责人: Mark L Baccei
• 金额: $ 34.56万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-21 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291516
• 关键词: Action Potentials; Adult; Age; Brain; Cells; Child; Childhood; Clinical Treatment; Data; Development; Developmental Biology; Electrophysiology (science); Future; Goals; Hyperalgesia; Immunohistochemistry; In Vitro; Injury; Intervention; Investigation; Lead; Life; Link; Long-Term Potentiation; Measures; Mediator of activation protein; Modification; Molecular; Mus; Neonatal; Neonatal Intensive Care; Neurons; Nociception; Outcome; Output; Pain; Pain Research; Pain management; Pathway interactions; Physiology; Public Health; Research; Research Personnel; Risk; Rodent; Sensory; Sensory Thresholds; Signal Transduction; Slice; Spinal; Spinal Cord; Spinal cord posterior horn; Spine pain; Surgical incisions; Synapses; Synaptic plasticity; Techniques; Testing; Tissues; Universities; Work; base; central pain; chronic pain; collaborative environment; critical period; design; dorsal horn; experience; experimental study; feeding; improved; innovation; insight; neonatal injury; novel; patch clamp; postsynaptic; public health relevance; response; sensory input; sensory integration; signal processing; synaptic function; transmission process

DESCRIPTION (provided by applicant): Although tissue damage commonly occurs during neonatal intensive care treatment and can alter pain sensitivity throughout life, whether such early injuries can evoke long-term changes in synaptic function within mature nociceptive pathways remains unknown. As a result, the cellular and molecular mechanisms which contribute to the persistent alterations in pain sensitivity following neonatal injury are still unclear. The long- term goal is to improve the clinical treatment of pain by determining how neonatal tissue injury influences nociceptive processing throughout development. The overall objective of this application is to identify changes within the mature rodent superficial dorsal horn (SDH) network following early tissue damage that facilitate activity-dependent plasticity at nociceptive synapses onto ascending projection neurons, which constitute the output of the spinal pain network. The central hypothesis is that neonatal tissue damage evokes persistent deficits in the function of spinal inhibitory circuits which result in decreased feed-forward inhibition of adult lamina I projection neurons, leading to an enhancement of long-term potentiation (LTP) at nociceptive synapses onto these cells. The rationale of the proposed research is that by elucidating how early tissue damage modulates the future plasticity of synapses onto adult projection neurons, these experiments will reveal potential mechanisms by which developing spinal pain circuits can be "primed" to produce a greater degree of hyperexcitability following injuries at later ages. Guided by strong preliminary data, the central hypothesis will be tested and the overall objective of this application achieved by pursuing the following specific aims: (1) Identify the prolonged effects of neonatal tissue injury on the efficay of GABAergic and glycinergic signaling onto mature lamina I projection neurons; (2) Elucidate how early tissue damage modulates the integration of sensory input within spinal lamina I projection neurons during adulthood; and (3) Determine the extent to which neonatal injury alters synaptic plasticity in mature spinal projection neurons. These aims will be accomplished by using in vitro electrophysiological, immunohistochemical, and tract-tracing techniques to characterize the effects of neonatal tissue damage on synaptic signaling within the adult SDH and determine the overall consequences of early injury for signal processing within ascending projection neurons. The outcome of these investigations will be the identification of permanent alterations in the synaptic organization of spinal pain networks following early tissue damage which promote the amplification of ascending pain signals in the CNS following subsequent noxious stimulation. As a result, the proposed research is significant because it will enhance our understanding of how nociceptive synaptic plasticity in central pain pathways is modulated by painful experience during the neonatal period and thus provide mechanistic insight into the emerging link between pediatric and adult chronic pain conditions.

描述（由申请人提供）：尽管组织损伤通常在新生儿重症监护治疗期间发生，并且可以改变整个生命的疼痛敏感性，但是这种早期伤害是否可以引起成熟伤害感受途径内突触功能的长期变化。结果，新生儿损伤后持续改变疼痛敏感性的细胞和分子机制尚不清楚。长期目标是通过确定新生儿组织损伤如何影响整个发育中的伤害性处理来改善疼痛的临床治疗。该应用的总体目标是确定早期组织损伤后成熟的啮齿动物表面背角（SDH）网络内的变化，从而促进了在升高的投影神经元上依赖活性的可塑性，这构成了脊柱疼痛网络的输出。中心假设是，新生儿组织损伤引起了脊柱抑制回路功能的持续缺陷，从而导致成年层层I投射神经元的前馈抑制作用降低，从而增强了长期增强（LTP）对这些细胞的长期增强（LTP）。拟议研究的基本原理是，通过阐明早期组织损伤如何调节突触对成人投影神经元的未来可塑性，这些实验将揭示潜在的机制，通过这些机制，可以“启动”出现更大程度的过度刺激性的脊柱疼痛电路，以产生更大程度的过度抗性性。在强大的初步数据的指导下，将测试中心假设，并通过追求以下特定目的来实现该应用的总体目标：（1）确定新生儿组织损伤对GABA能和GABA能和甘油能信号效率上对成熟层层层层层的投射神经元的影响； （2）阐明组织损伤如何调节成年期间脊柱I投射神经元内感觉输入的整合； （3）确定新生儿损伤在多大程度上改变成熟的脊柱投射神经元中突触可塑性。这些目标将通过使用体外电生理学，免疫组织化学和道追踪技术来表征新生儿组织损伤对成人SDH内突触信号的影响，并确定早期损伤在升序投射神经元内信号处理的总体后果。这些研究的结果将是鉴定在早期组织损伤后脊柱疼痛网络的突触组织中的永久改变，这在随后的有害刺激后促进了中枢神经系统中上升疼痛信号的扩增。结果，提出的研究很重要，因为它将增强我们对中央疼痛途径中的伤害感受性突触可塑性在新生儿期间如何调节痛苦的经历，从而为小儿和成人慢性疼痛条件之间的新兴联系提供机械洞察力。