MOLECULAR BASIS OF OPIOID PHARMACODYNAMICS

描述：（申请人摘要） 这是一个研究科学家奖续期的请求，让我能够 继续追求分子生物学技术的收购， 并允许我将其应用于两个NIDA资助的研究 项目 这两个项目都是为了测试兴奋性的假设， 氨基酸（EAA）受体介导神经元可塑性， 阿片类药物耐受性和依赖性或某些类型的伤害性 行为 第一个项目将使用NMDA和非NMDA受体拮抗剂 和激动剂以及靶向NMDA受体的反义或核酶， 选择动物行为范例来证明EAA的作用 受体在阿片耐受和伤害感受中的作用。 分子和生化 技术将用于识别和定位到神经解剖区域， 与阿片类药物耐受相关的基因表达变化， 伤害性行为 为了补充和扩展这些方法，阿片类药物 耐受性、依赖性和伤害感受行为将在敲除中测量。 用缺失或突变的EAA受体改造小鼠。 第二个项目将确定，在培养的细胞中表达功能 NMDA和阿片样物质（μ或δ）受体，NMDA受体在神经元凋亡中的作用， 阿片受体信号转导中发生的变化， 这些细胞暴露于阿片类药物。 获得分子技术，包括与基因相关的技术 目标的确定将通过在实验室的休假研究来完成 在那里我可以直接参与设计，生产和评估 EAA受体敲除小鼠。 这个RSA奖也将使我能够保持减少教学， 在过去四年里， 大大增加了我可以投入到提高我的科学的时间 skills.

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.