Primary and Secondary Nociceptors in Persistent Pain

描述(申请人提供)：拟议研究的目标是检查与炎症和神经病理性疼痛状态的发展和维持有关的已识别的皮肤感觉神经元和脊髓神经元的变化的时间进程。这些神经元在处理疼痛信息方面起着关键作用。这些研究将涉及三个具体目标。在第一个目标中，我们将使用生理学和解剖学相结合的技术来确定正常小鼠的初级传入细胞和浅层背角细胞的特性。在第二个目标中，我们将确定炎症和神经病理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识别出的神经元中看到的任何变化进行比较。在第三个目标中，我们将使用两个转基因小鼠系(一个是辣椒素/热通道TRPV1被敲除，另一个是Mas基因相关的G蛋白偶联受体D(MRgdprd)被敲除，绿色荧光蛋白被敲除)。TRPV1已被证明在某些方面调节热敏感性，而MRGPrd仅在皮肤感觉性伤害性感受器中发现。我们最近发现，在mrgprd基因敲除小鼠中，这些皮肤伤害性感受器可以减弱热反应。我们将在炎症和神经病理性损伤后确定这两个小鼠系的初级传入和次级伤害性感受器的特性。通过比较行为和神经数据，我们将能够评估这些基因操作在两种类型的损伤后诱导和维持疼痛状态方面的效果。在所有三个特定目标中收集的数据将被用来开发在这些疼痛状态中必不可少的神经回路模型。通过对这三组神经元的比较，我们希望阐明在这一过程中起关键作用的初级传入神经元和次级伤害感受神经元的特定群体。

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.