Developmental Regulation of Intrinsic Excitability in Spinal Pain Networks

项目摘要/摘要 尽管儿科疼痛的发病率很高，最常见的是肌肉骨骼疼痛，但很少有 知道不成熟的中枢神经系统如何处理不同类型的有害感觉信息。尤其是， 早期脊髓伤害性信号上行流向大脑的调控机制 生活仍不明朗。由于I板层投射神经元是脊髓伤害性感受器的基本输出 回路对慢性疼痛的产生至关重要，对离子电导有更好的了解 在早期生命中控制这些神经元固有的膜兴奋性的是什么，以及这种兴奋是如何被激发的 群体塑造了来自不同类别感觉传入的突触输入的成熟，代表了 朝着解决这一问题迈出的重要一步。长期目标是促进基于证据的设计 通过提高对中枢发育神经生物学的认识来治疗儿童疼痛的方法 伤害性网络。此应用程序的总体目标是确定控制射击的关键因素 早期生命中上升投射神经元的变化，并确定这一活动在调节初级 传入突触与这些细胞相连。中心假设是经典的内向整流性K+(Kir2)和 NALCN Na+泄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不同功能突触输入的出生后发育 感官传入。这项拟议的研究的基本原理是理解固有的和突触的 决定未成熟投射神经元兴奋性的机制是迈向 控制脊髓伤害性环路的信号“增益”，将有助于设计 减轻儿科疼痛的新策略。在强劲的初步数据指引下，核心假设将是 经过测试，并通过追求以下具体目标实现了本应用程序的总体目标：(1)确定 离子通道对早期脊髓PNS内源性膜兴奋性的影响；(2) 阐明皮肤和肌肉传入突触在发育中的三叉神经节的特性；以及(3)确定 发育中的三叉神经节固有的膜兴奋性对原代细胞成熟的影响程度 传入突触输入。这些目标将通过使用多学科的实验方法来实现 这包括体外电生理、遗传和免疫组织化学技术。这些措施的结果 调查将是第一次确定哪些与电压无关的(即“泄漏”)离子通道塑造了 新生脊髓投射神经元固有的膜兴奋性以及建立 这些细胞的放电与来自皮肤的突触输入成熟之间的功能关系 肌肉传入。因此，拟议的研究具有重要意义，因为它将揭示 控制从脊髓到发育中的大脑的上行伤害性传递，并将产生新的 洞察为什么肌肉传入更能在中枢痛觉回路中引起超兴奋性。

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.