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: 8739319
• 负责人: Mark L Baccei
• 金额: $ 34.33万
• 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/8739319
• 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; critical period; design; dorsal horn; experience; feeding; improved; innovation; insight; novel; patch clamp; postsynaptic; public health relevance; research study; response; 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）：虽然组织损伤通常发生在新生儿重症监护治疗期间，并且可能改变整个生命周期的疼痛敏感性，但这种早期损伤是否会引起成熟伤害性通路内突触功能的长期变化仍然未知。因此，导致新生儿损伤后疼痛敏感性持续改变的细胞和分子机制仍不清楚。长期目标是通过确定新生儿组织损伤如何影响整个发育过程中的伤害感受处理来改善疼痛的临床治疗。该应用的总体目标是确定成熟啮齿动物浅表背角（SDH）网络在早期组织损伤后的变化，这些变化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。核心假设是，新生儿组织损伤会引起脊髓抑制回路功能的持续缺陷，从而导致成年椎板 I 投射神经元的前馈抑制减少，从而导致这些神经元的伤害性突触的长时程增强 (LTP) 增强。细胞。这项研究的基本原理是，通过阐明早期组织损伤如何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的机制，通过这些机制，发育中的脊髓疼痛回路可以“启动”，以产生更大程度的过度兴奋。晚年受伤。在强有力的初步数据的指导下，将测试中心假设，并通过追求以下具体目标来实现本申请的总体目标：（1）确定新生儿组织损伤对成熟层 I 上 GABA 能和甘氨酸能信号传导功效的长期影响投射神经元； (2) 阐明早期组织损伤如何调节成年期椎板 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表征新生儿组织损伤对成人 SDH 内突触信号传导的影响，并确定早期损伤对上行投射神经元内信号处理的总体影响。这些研究的结果将是确定早期组织损伤后脊髓疼痛网络突触组织的永久性改变，这会促进随后的有害刺激后中枢神经系统中上行疼痛信号的放大。因此，拟议的研究具有重要意义，因为它将增强我们对新生儿期疼痛经历如何调节中枢疼痛通路中的伤害性突触可塑性的理解，从而为儿科和成人慢性疼痛状况之间新出现的联系提供机制见解。