Modulation of Developing Spinal Nociceptive Circuits by Sensory Input

描述(申请人提供)：拟议研究的总体目标是更好地理解新生儿脊柱疼痛网络的成熟。现在很清楚，了解影响中枢神经系统(CNS)伤害性回路形成的环境和遗传因素对于改善儿童疼痛的治疗是至关重要的。最近的行为证据表明，新生儿期的感觉体验调节中枢疼痛网络的成熟，并可能对疼痛处理产生长期影响。在细胞水平上理解感觉输入是如何调制新出现的中枢痛觉回路的，将对这些疼痛敏感性持续变化的机制产生至关重要的见解。不幸的是，目前尚不清楚初级感觉传入通路的活动水平如何影响突触功能，从而形成伤害性感觉回路。由于CNS内伤害性信号的突触整合始于脊髓浅背角(SDH)，详细描述出生后早期初级传入如何塑造SDH中的突触网络是解决这一问题的合乎逻辑和重要的第一步。我们假设SDH的兴奋性突触功能在出生后发育的关键时期受到来自外周的感觉输入的调节，因此组织损伤对SDH突触网络的影响具有高度的年龄依赖性。这项建议将通过控制出生后早期初级传入通路的活动水平，并随后使用电生理学、免疫组织化学和生化方法表征大鼠背角谷氨酸能突触信号的特性，来检验这一假说。这将涉及两个特定的目标：(1)确定大鼠脊髓SDH中谷氨酸能突触的有效性是否取决于出生后关键时期初级传入输入的水平；(2)确定外周炎症对发育中的SDH突触功能的影响是否取决于出生后的年龄。由于对婴儿的重症监护治疗通常需要多个侵入性程序，在未成熟的神经系统具有显著可塑性的时候，这些程序会改变躯体感觉输入到脊髓的正常模式，因此了解感觉体验如何影响背角的突触发育对于充分认识这些程序对痛觉的短期和长期后果是必要的。与公共卫生相关：现在全世界都认识到，人类婴儿可能会因为疾病、手术或重症监护治疗而经历相当大的痛苦。然而，成人疼痛的临床治疗并不容易移植到儿童身上，因为很明显，不成熟的神经系统不仅是成熟形式的简化版本，而且是以根本不同的方式组织起来的。在细胞水平上增加我们对疼痛系统成熟的了解，不仅有助于深入了解那些已经给儿童开出的止痛药的作用机制，而且有助于设计适合发育的新的止痛策略。

Description (provided by applicant): The overall goal of the proposed research is to better comprehend the maturation of spinal pain networks in the neonate. It is now clear that knowledge of the environmental and genetic factors which influence the formation of nociceptive circuits in the central nervous system (CNS) is essential to improving the treatment of pain in children. Recent behavioral evidence suggests that sensory experience during the neonatal period regulates the maturation of central pain networks and can have long-term effects on pain processing. An understanding of how emergent central pain circuits are modulated by sensory input at the cellular level will yield crucial insights into the mechanisms underlying these persistent changes in pain sensitivity. Unfortunately, nothing is currently known about how the level of activity in primary sensory afferent pathways influences synaptic function in developing nociceptive circuits. Since the synaptic integration of nociceptive signals within the CNS begins in the superficial dorsal horn (SDH) of the spinal cord, a detailed characterization of how synaptic networks in the SDH are shaped by primary afferent input during the early postnatal period represents a logical and important first step towards addressing this issue. We hypothesize that excitatory synaptic function in the SDH is modulated by sensory input from the periphery during a critical period of postnatal development and that the effects of tissue injury on SDH synaptic networks are therefore highly age-dependent. This proposal will test this hypothesis by manipulating the level of activity in primary afferent pathways during the early postnatal period and subsequently characterizing the properties of glutamatergic synaptic signaling in the rat dorsal horn using electrophysiological, immunohistochemical and biochemical approaches. This will involve two specific aims: (1) To determine if the efficacy of glutamatergic synapses in the SDH of the rat spinal cord depends on the level of primary afferent input during a critical postnatal period; and (2) To determine whether the consequences of peripheral inflammation for synaptic function in the developing SDH depend on postnatal age. Since the intensive care treatment of infants often requires multiple invasive procedures which alter the normal pattern of somatosensory input to the spinal cord at a time when the immature nervous system is capable of significant plasticity, understanding how sensory experience affects synaptic development in the dorsal horn is necessary to fully realize the short and long-term consequences of these procedures for pain sensation. PUBLIC HEALTH RELEVANCE: It is now universally recognized that human infants can experience considerable pain as a result of disease, surgery or intensive care therapies. However, the clinical treatment of pain in adults cannot easily be translated to children, as it is clear that the immature nervous system is not merely a simplified version of the mature form but rather organized in a fundamentally different manner. Increasing our understanding of the maturation of pain systems at the cellular level will not only provide insight into the mechanisms of action of those analgesics already prescribed to children, but also aid in the design of novel analgesic strategies which are developmentally appropriate.