MOLECULAR BASIS OF OPIOID PHARMACODYNAMICS

描述：(申请人摘要) 这是一项续签研究科学家奖的请求，以允许我 继续追求分子生物学技术的获得和 并允许我将它们应用于NIDA资助的两项研究 项目。这两个项目都是为了检验这样一种假设，即兴奋性 氨基酸(EAA)受体介导明显的神经元可塑性 作为阿片类药物耐受和依赖，或作为某些类型的伤害性感受器 行为。第一个项目将使用NMDA和非NMDA受体拮抗剂 和激动剂以及针对NMDA受体的反义或核酶 动物行为范例精选以展示EAA的作用 阿片耐受性和伤害性感受的受体。分子和生化 技术将被用来识别和定位神经解剖学区域， 与阿片类药物耐受或相关的基因表达变化 伤害性行为。为了补充和推广这些方法，阿片类药物 耐受性、依赖性和伤害性行为将在淘汰赛中进行测量 携带缺失或突变的EAA受体的小鼠。 第二个项目将确定，在培养的细胞中表达功能 NMDA和阿片(Mu或Delta)受体，NMDA受体在 阿片受体信号转导的变化 这些细胞暴露在阿片类药物中。 分子技术的获得，包括与基因有关的技术 目标将通过实验室中的休假研究来完成 在那里我可以直接参与设计、生产和评估 EAA受体基因敲除小鼠。 这个RSA奖项还将使我继续减少教学和 过去四年来的行政责任， 大大增加了我可以用于提高我的科学能力的时间 技能。

DESCRIPTION: (Applicant's Abstract) This is a request for a renewal of a Research Scientist Award to allow me to continue to pursue the acquisition of techniques of molecular biology and neuroscience and to allow me to apply them to two NIDA funded research projects. Both projects are designed to test the hypothesis that Excitatory Amino Acid (EAA) receptors mediate the neuronal plasticity that is manifest as opioid tolerance and dependence or as certain types of nociceptive behavior. The first project will use NMDA and non-NMDA receptor antagonists and agonists as well as antisense or ribozymes targeted to NMDA receptors in selected animal behavioral paradigms to demonstrate the role of EAA receptors in opioid tolerance and nociception. Molecular and biochemical techniques will be used to identify and localize to neuroanatomical areas, the changes in gene expression that are associated with opioid tolerance or nociceptive behaviors. To complement and extend these approaches, opioid tolerance, dependence and nociceptive behaviors will be measured in knockout mice engineered with an absent or mutated EAA receptor. The second project will determine, in cultured cells expressing functional NMDA and opioid (mu or delta) receptors, the role of NMDA receptors in the changes that occur in opioid receptor signal transduction as a result of the exposure of these cells to opioids. The acquisition of molecular techniques, including, those related to gene targeting will be accomplished through sabbatical research in a laboratory where I can be directly involved in the design, production and evaluation of EAA receptor knockout mice. This RSA award will also allow me to maintain the reduction in teaching and administrative responsibilities that have for the past four years, significantly increased the time I can devote to enhancing my scientific skills.