Primary and Secondary Nociceptors in Persistent Pain

描述（由申请人提供）：拟议研究的目标是检查已识别的负责炎症和神经性疼痛状态的发展和维持的皮肤感觉神经元和脊髓神经元的变化的时间过程。这些神经元在处理疼痛信息中发挥着关键作用。这些研究将解决 3 个具体目标。在第一个目标中，我们将采用生理学和解剖学相结合的技术来确定正常小鼠初级传入神经和浅表背角细胞的特性。在第二个目标中，我们将确定炎症和神经性损伤后相同细胞的特性。机械和热敏感性的行为测试将与已识别的神经元中看到的任何变化进行比较。在第三个目标中，我们将使用 2 个转基因小鼠品系（1 个已敲除辣椒素/热通道 TRPV1，1 个已敲除 Mas 基因相关的 G 蛋白偶联受体 D (Mrgdprd) 并敲入绿色荧光蛋白）。 TRPV1 已被证明可以介导热敏感性的某些方面，而 Mrgprd 只存在于皮肤感觉伤害感受器群体中。我们最近发现 Mrgprd 敲除小鼠的这些皮肤伤害感受器减弱了热反应。我们将确定这两个小鼠系在炎症和神经性损伤后初级传入和次级伤害感受器的特性。通过比较行为和神经数据，我们将能够评估这些基因操作对两种类型损伤后疼痛状态的诱导和维持的影响。在所有 3 个具体目标中收集的数据将用于开发在这些疼痛状态下至关重要的神经回路模型。通过比较这三组，我们希望阐明对此过程至关重要的初级传入和次级伤害性神经元的特定群体。

DESCRIPTION (provided by applicant): The goal of the proposed studies is to examine the time course of changes in identified cutaneous sensory neurons and spinal cord neurons responsible for the development and maintenance of inflammatory and neuropathic pain states. These neurons play critical roles in processing of pain information. These studies will address 3 specific aims. In the first aim we will employ combined physiological and anatomical techniques to determine the properties of primary afferents and superficial dorsal horn cells in normal mice. In the second aim we will determine the properties of the same cells after inflammatory and neuropathic injury. Behavioral tests of mechanical and heat sensitivity will be compared with any changes seen in the identified neurons. In the third aim, we will use 2 trangenic mouse lines (1 that has the capsaicin/heat channel TRPV1 knocked out, 1 that has the Mas-gene related G-protein coupled receptor D (Mrgdprd) knocked out and green fluorescent protein knocked in). TRPV1 has been shown to mediate some aspects of heat sensitivity, and Mrgprd is found exclusively in a population of cutaneous sensory nociceptors. We have recently found that these cutaneous nociceptors in Mrgprd-knock-out mice, have attenuated heat responses. We will determine the properties of primary afferent and secondary nociceptors in these 2 mouse lines following inflammatory and neuropathic injury. By comparing behavioral and neural data, we will be able to assess the effect of these genetic manipulations on the induction and maintenance of pain states following 2 types of injury. The data gathered in all 3 specific aims will be used to develop a model of neural circuits that are essential during these pain states. By comparing the 3 groups, we hope to elucidate the specific populations of primary afferent and secondary nociceptive neurons crucial to this process.