Developmental Regulation of Intrinsic Excitability in Spinal Pain Networks

项目总结/摘要 尽管儿科疼痛的患病率很高，最常见的是肌肉骨骼疼痛， 关于未成熟的中枢神经系统如何处理不同类型的有害感觉信息，特别是 在脊髓损伤早期，调节伤害性信号从脊髓到大脑的上行流的机制 生活仍不明朗。由于板层I投射神经元代表脊髓伤害性感受神经元的基本输出， 电路和慢性疼痛的产生是至关重要的，更好地了解离子电导 在生命早期控制这些神经元的内在膜兴奋性， 人口形状的成熟突触输入从不同类别的感觉传入，代表了一个 为解决这一问题迈出了重要一步。长期目标是促进设计基于证据的 通过提高中枢神经系统发育神经生物学知识来治疗儿童疼痛的方法 伤害感受网络本应用程序的总体目标是确定调节点火的关键因素 的上升投射神经元在生命早期，并确定这种活动的作用，在调节初级 传入突触连接到这些细胞上中心假设是经典的内向整流K+（Kir 2）和 NALCN Na+漏通道联合调节新生投射神经元动作电位放电， 从而影响来自皮肤和肌肉的功能不同的突触输入的出生后发育 感觉传入提出这项研究的基本原理是，了解内在和突触 决定未成熟投射神经元（PN）兴奋性的机制是实现神经元兴奋性的第一步。 控制发育中的脊髓伤害感受回路的信号“增益”，这将有助于设计 缓解小儿疼痛的新策略。在强有力的初步数据的指导下，中心假设将是 通过以下具体目标来实现本申请的总体目标：（1）确定 在生命早期，离子通道塑造了上行脊髓PN的内在膜兴奋性;（2） 阐明皮肤和肌肉传入突触到发育中的PN上的特性;以及（3）确定 发育中的PN的内在膜兴奋性影响初级神经元成熟的程度 传入突触输入这些目标将通过使用多学科实验方法来实现 包括体外电生理学、遗传学和免疫组织化学技术。成果的 研究将是第一次确定哪些电压无关的（即“泄漏”）离子通道塑造了 新生脊髓投射神经元的内在膜兴奋性，以及建立一个 这些细胞的放电和来自皮肤的突触输入的成熟之间的功能关系， 肌肉传入神经因此，拟议的研究是重要的，因为它将揭示机制， 控制从脊髓到发育中的大脑的上行伤害性传递，也将产生新的 深入了解为什么肌肉传入更能引起中枢疼痛回路的过度兴奋。

Project Summary/Abstract Despite the high prevalence of pediatric pain, most commonly seen as musculoskeletal pain, little is known about how the immature CNS processes distinct types of noxious sensory information. In particular, the mechanisms regulating the ascending flow of nociceptive signals from the spinal cord to the brain during early life remain unclear. Since lamina I projection neurons represent an essential output of the spinal nociceptive circuit and are critical for the generation of chronic pain, a better understanding of the ionic conductances which control the intrinsic membrane excitability of these neurons during early life, and how the firing of this population shapes the maturation of synaptic inputs from different classes of sensory afferents, represents an important step towards addressing this issue. The long-term goal is to facilitate the design of evidence-based approaches to treat pediatric pain by advancing the knowledge of the developmental neurobiology of central nociceptive networks. The overall objective of this application is to identify the key factors regulating the firing of ascending projection neurons during early life and to determine the role of this activity in modulating primary afferent synapses onto these cells. The central hypothesis is that classic inward-rectifying K+ (Kir2) and NALCN Na+ leak channels jointly regulate action potential discharge in neonatal projection neurons and thereby influence the postnatal development of functionally distinct synaptic inputs from cutaneous and muscle sensory afferents. The rationale of the proposed research is that understanding the intrinsic and synaptic mechanisms that dictate the excitability of immature projection neurons (PNs) is the first step towards controlling the signaling “gain” of developing spinal nociceptive circuits, which would facilitate the design of novel strategies to alleviate pediatric pain. 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 ion channels shaping the intrinsic membrane excitability of ascending spinal PNs during early life; (2) Elucidate the properties of cutaneous and muscle afferent synapses onto developing PNs; and (3) Determine the extent to which the intrinsic membrane excitability of developing PNs influences the maturation of primary afferent synaptic inputs. These aims will be accomplished by using a multidisciplinary experimental approach that includes in vitro electrophysiological, genetic and immunohistochemical techniques. The outcome of these investigations will be the first identification of which voltage-independent (i.e. “leak”) ion channels shape the intrinsic membrane excitability of neonatal spinal projection neurons, as well as the establishment of a functional relationship between the firing of these cells and the maturation of synaptic inputs from skin and muscle afferents. As a result, the proposed research is significant because it will reveal mechanisms that control ascending nociceptive transmission from the spinal cord to the developing brain, and will also yield new insight into why muscle afferents are more capable of evoking hyperexcitability within central pain circuits.