Synaptic function within mature central pain networks after neonatal injury

描述（由申请人提供）：尽管组织损伤通常发生在新生儿重症监护治疗期间，并且可以改变整个生命的疼痛敏感性，但这种早期损伤是否可以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性感受过程来改善疼痛的临床治疗。本申请的总体目标是确定早期组织损伤后成熟啮齿动物浅表背角（SDH）网络内的变化，这些变化促进伤害性突触到上行投射神经元上的活性依赖性可塑性，上行投射神经元构成脊髓疼痛网络的输出。中心假设是，新生儿组织损伤引起脊髓抑制回路功能的持续缺陷，这导致成人I层投射神经元的前馈抑制减少，导致这些细胞上的伤害性突触的长时程增强（LTP）。这项研究的基本原理是，通过阐明早期组织损伤如何调节突触在成年投射神经元上的未来可塑性，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被“启动”，在以后的年龄损伤后产生更大程度的过度兴奋。在强有力的初步数据的指导下，将检验中心假设，并且通过追求以下具体目标来实现本申请的总体目标：（1）鉴定新生组织损伤对GABA能和甘氨酸能信号传导到成熟板层I投射神经元上的效力的长期影响;（2）阐明早期组织损伤如何调节成年期脊髓第一层投射神经元内感觉输入的整合;和（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，并确定上行投射神经元内信号处理的早期损伤的总体后果来实现。这些研究的结果将是鉴定早期组织损伤后脊髓疼痛网络突触组织的永久性改变，其促进随后的伤害性刺激后CNS中上行疼痛信号的放大。因此，拟议的研究是重要的，因为它将增强我们对中枢疼痛通路中的伤害性突触可塑性如何被新生儿时期的疼痛经历所调制的理解，从而为儿童和成人慢性疼痛状况之间的新兴联系提供机械见解。

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.