Overexpression of Nerve Growth Factors

对疼痛刺激作出反应的感觉神经元，被称为伤害感受器，对生物体的健康至关重要，因为它们负责启动防止或限制组织损伤的行为反应。在正常情况下，疼痛是一种重要的感觉。然而，在受伤或患病后，疼痛可能会持续，严重扰乱受影响者的生活。已知伤害感受器的发育和维持依赖于两种生长因子，神经生长因子（NGF）和胶质系衍生神经营养因子（GDNF）。此外，有人提出NGF和GDNF支持两种不同的伤害感受器种群，这两种种群负责不同类型的持续疼痛。此外，NGF和GDNF诱导的伤害感受器功能的变化也调节了成人脊髓的伤害感受加工，表明体感觉系统中存在多层次、生长因子驱动的可塑性。在我们之前的研究中，我们确定了NGF在决定伤害感受器的“综合表型”中起着重要作用，影响依赖NGF的伤害感受器的生理、解剖和功能特性。下一步是确定NGF如何影响伤害感受器，NGF和GDNF的变化如何影响接受伤害性输入的脊髓神经元，以及这些变化对持续性疼痛的影响。该建议包括三个具体目标，采用“基因到行为”的方法。特异性目标1检查GDNF水平的增加如何影响伤害感受器的综合表型。这些数据将与NGF研究的结果进行比较，以提供生长因子在伤害感受器发育中的作用的完整分析。特异性目标2研究了NGF和GDNF诱导的伤害感受器的变化如何影响背角解剖和神经化学。脊髓的分析是至关重要的，因为脊髓内稳态的改变可以加剧或补偿持续性疼痛。特异性目的3研究了NGF和GDNF表型肥大的小鼠在两种持续疼痛模型中的反应。整个动物的行为，伤害感受器生理学和背角神经化学的变化将被检查。在完成这些特定目标后，我们预计依赖NGF和依赖gdnf的伤害感受器之间的差异将在解剖学、生理学和神经化学特征方面得到理解。此外，应该有可能确定这两类伤害感受器如何影响背角的发育和功能。最后，我们将深入了解这两类伤害感受器及其脊髓靶点如何对持续疼痛的诱导做出反应。

Sensory neurons responsive to painful stimuli, called nociceptors, are crucial for the health of an organism as they are responsible for initiating behavioral responses that prevent or limit tissue damage. Under normal circumstances pain is an important sensation. However, following injury or disease, pain can become persistent, seriously disrupting the lives of those affected. Development and maintenance of nociceptors is known to be dependent on two growth factors, nerve growth factor (NGF) and glial-line derived neurotrophic factor (GDNF). Furthermore, it has been proposed that NGF and GDNF support two different populations of nociceptors and that these two populations are responsible for different types of persistent pain. In addition, changes in nociceptor function induced by NGF and GDNF also modulate nociceptive processing in the adult spinal cord, suggesting a multi-level, growth factor-driven plasticity in the somatosensory system. In our previous studies we determined that NGF plays a dramatic role in determining the "comprehensive phenotype" of nociceptors, influencing physiological, anatomical and functional properties of NGF-dependent nociceptors. The next step is to determine how GDNF affects nociceptors, how changes in NGF and GDNF affect spinal cord neurons receiving nociceptive input, and what affects these changes have on persistent pain. This proposal consists of three Specific Aims employing a "genes to behavior" approach. Specific Aim 1 examines how increases in the level of GDNF affects the comprehensive phenotype of nociceptors. This data will be compared with the results from the NGF studies to provide a complete analysis of the role of growth factors in nociceptor development. Specific Aim 2 examines how NGF- and GDNF- induced changes in nociceptors affects dorsal horn anatomy and neurochemistry. Analysis of spinal cord is crucial because alteration in spinal cord homeostasis can exacerbate or compensate for persistent pain. Specific Aim 3 examines how mice with hypertrophied NGF and GDNF phenotypes respond in two models of persistent pain. Whole animal behavior, nociceptor physiology and changes in dorsal horn neurochemistry will be examined. Upon completion of these specific aims, we anticipate that the differences between NGF- dependent and GDNF-dependent nociceptors will be understood with respect to their anatomical, physiological and neurochemical traits. In addition, it should be possible to identify how these two classes of nociceptors affect dorsal horn development and function. Finally, we will gain insight into how these two classes of nociceptors and their spinal cord targets, respond to induction of persistent pain.