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: 8629852
• 负责人: Mark L Baccei
• 金额: $ 34.67万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629852
• 关键词: Action Potentials; Adult; Age; Brain; Cells; Child; Childhood; Clinical Treatment; Data; Development; Developmental Biology; Environment; 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; Pathway interactions; Physiology; Process; Public Health; Research; Research Personnel; Risk; Rodent; Sensory; Sensory Thresholds; Signal Transduction; Slice; Spinal; Spinal Cord; Spinal cord posterior horn; Surgical incisions; Synapses; Synaptic plasticity; Techniques; Testing; Tissues; Universities; Work; base; central pain; chronic pain; computerized data processing; critical period; design; dorsal horn; experience; feeding; improved; innovation; insight; novel; patch clamp; postsynaptic; public health relevance; research study; response; sensory integration; synaptic function; transmission process

Project Summary/Abstract 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 efficacy 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.

项目概要/摘要 尽管组织损伤通常发生在新生儿重症监护治疗期间并且可以改变疼痛 整个生命过程中的敏感性，这种早期损伤是否会引起突触功能的长期变化 成熟的伤害感受途径仍然未知。因此，细胞和分子机制 导致新生儿损伤后疼痛敏感性持续改变的因素尚不清楚。长- 长期目标是通过确定新生儿组织损伤如何影响来改善疼痛的临床治疗 整个发展过程中的伤害性加工。该应用程序的总体目标是识别变化 在早期组织损伤后，成熟啮齿动物浅表背角（SDH）网络内，促进 伤害性突触上行投射神经元的活动依赖性可塑性，构成 脊髓疼痛网络的输出。中心假设是新生儿组织损伤会引起持续的 脊髓抑制回路功能缺陷，导致成人前馈抑制减少 层 I 投射神经元，导致伤害感受的长时程增强 (LTP) 增强 突触到这些细胞上。拟议研究的基本原理是通过阐明早期组织如何 损伤调节成年投射神经元突触的未来可塑性，这些实验将 揭示潜在机制，通过该机制，发展中的脊髓疼痛回路可以“启动”以产生更大的 晚年受伤后过度兴奋的程度。在强有力的初步数据指引下，中央 将测试假设，并通过追求以下具体目标来实现本申请的总体目标 目的：(1) 确定新生儿组织损伤对 GABA 能和甘氨酸能的功效的长期影响 向成熟的第一层投射神经元发出信号； (2) 阐明早期组织损伤如何调节 成年期脊髓板 I 投射神经元内感觉输入的整合； (3) 确定 新生儿损伤改变成熟脊髓投射神经元突触可塑性的程度。这些目标将 通过使用体外电生理学、免疫组织化学和纤维束追踪技术来完成 描述新生儿组织损伤对成人 SDH 内突触信号传导的影响，并确定 上行投射神经元内信号处理的早期损伤的总体后果。这 这些调查的结果将是确定突触组织的永久性改变 早期组织损伤后的脊柱疼痛网络，促进上行疼痛的放大 随后的有害刺激后中枢神经系统中的信号。因此，本文提出的研究具有重要意义 因为它将增强我们对中枢疼痛通路中伤害性突触可塑性的理解 受到新生儿时期痛苦经历的调节，从而提供了对 儿科和成人慢性疼痛之间的新联系。