Glutamate receptors in pain and addictive behaviors

描述（由申请人提供）： 这是一个高级科学家奖的续期请求，这将使我能够继续获得分子遗传学和神经科学技术，并利用它们来实现两个NIDA资助的研究项目的目标。这两个项目的目的是测试的假设，NR 1或GluR 2亚基组成的多巴胺能受体是必要的神经元的可塑性，表现为损伤引起的疼痛（伤害性）和适应过程中发生的可卡因或阿片类药物的重复使用，并表现为药物奖励和复发以及阿片类药物的耐受性和依赖性。第一个项目将使用我们开发的时空敲除（KO）来确定脊髓背角NMDAR 1（NMDA受体）和/或GluR 2（AMPA受体）亚基在炎症和脊髓神经损伤引起的持续性疼痛中的作用。第二个项目将使用相同的Cre-loxP技术产生NMDA和AMPA受体的KO，其局限于成年小鼠中选定的脊髓上CNS区域，包括延髓核、腹侧被盖区和腹侧下托（空间KO）（时间KO）。我们将通过免疫细胞化学，原位杂交和电子显微镜技术，展示与靶受体亚基缺失相关的基因表达变化的空间定位和时间特征。我们还将确定上述选定CNS区域中这些受体亚基的靶向缺失是否会减弱多巴胺能电流，并减少或阻止对可卡因和阿片类药物使用的行为适应，包括药物奖励和复发以及阿片类药物耐受性和依赖性。 这些技术的获得和应用将通过合作安排和利用补充我的实验室现有专门知识的机构核心设施来完成。 这个SSA奖也将使我能够继续减少教学和行政责任，这大大增加了我能够投入到提高我的科学技能的时间。

DESCRIPTION (provided by applicant): This is a request for a renewal of a Senior Scientist Award that will allow me to continue to acquire molecular genetic and neuroscience techniques and to use them to achieve the goals of two NIDA funded research projects. Both projects are designed to test the hypothesis that glutamatergic receptors composed of NR1 or GluR2 subunits are necessary for the neuronal plasticity that is manifest as injury-induced pain (nociception) and the adaptations that occur during repeated cocaine or opioid use and are manifest as drug reward and relapse as well as opioid tolerance and dependence. The first project will use the spatial-temporal knockout (KO) that we have developed to determine the role of spinal cord dorsal horn of NMDAR1 (NMDA receptor) and/or GluR2 (AMPA receptor) subunits in persistent pain resulting from inflammation and spinal nerve injury. The second project will use this same Cre-loxP technology to produce a KO of the NMDA and AMPA receptors that is confined to selected supraspinal CNS areas including the nucleus accumbens, ventral tegmental area and ventral subiculum (a spatial KO) in adult mice (a temporal KO). We will demonstrate by immunocytochemical, in situ hybridization and electron microscopy techniques, the spatial localization and temporal characteristics of the changes in gene expression that are associated with the deletion of the target receptor subunits. We will also determine whether the targeted deletion of these receptor subunits in the selected CNS areas given above will attenuate glutamatergic currents and decrease or prevent the behavioral adaptations to cocaine and opioid use including drug reward and relapse and opioid tolerance and dependence. The acquisition and application of these techniques will be accomplished through collaborative arrangements and through the utilization of institutional core facilities that complement the expertise available in my laboratory. This SSA award will also allow me to continue the reduction in teaching and administrative responsibilities that has significantly increased the time I was able to devote to enhancing my scientific skills.