OPIATE RECEPTOR PHARMACOLOGY

这是对研究科学家奖(KO5)的申请。尽管他们 在疼痛管理中的重要性，阿片类药物被滥用，这一点仍然存在 这是个大问题。通过了解许多阿片受体的作用 在疼痛控制和成瘾行为中的亚型，可能有可能 开发无滥用潜力的止痛药。阿片受体多样性 已经扩展到三个主要的受体类别(Mu、Delta和kappa) 每个类中都有子类型。这些受体亚型一直是 与体内的特定药理作用有关，并已被 在传统的结合分析中进行了研究。Delta、Mu、和的最新克隆 Kappa1受体极大地促进了阿片受体的研究 异质性。例如，我们已经确认了脊髓三角洲的作用 脑啡肽受体在脑啡肽反义寡核苷酸镇痛中的作用 DOR-L并鉴定了一个新的可能的kappa3受体克隆 序列同源。一种基于此的反义寡核苷酸 克隆可以通过kappa3配体阻止体内的止痛，但不能阻止吗啡。 这些关于阿片受体异质性的研究将继续进行， 集中在Mu和kappa3受体上。它们将包括绑定， 细胞内Mu和kappa3受体的调节及第二信使系统 使用传统的生化和分子生物学方法的品系， 以及我的实验室合成的新型配体。与组织不同 文化背景下，大脑是一个高度复杂的神经系统网络。这个 不同脑干核团之间显著的区域协同作用的描述 大脑和脊髓之间的关系强调了在体内 学习。我们对中枢神经系统内协同作用的研究将 继续，将定义各种受体亚型的作用。 对耐受性和一氧化氮(NO)作用的研究也将 在寻找一种重要的吗啡的其他研究期间继续进行 代谢产物吗啡6β-葡萄糖醛酸苷将被扩大。我们最近 识别大脑中的抗阿片类药物Sigma1系统可能会有所帮助 解释不同品系的小鼠对阿片类药物反应的广泛差异 可能还有人类。探索这些Sigma1/阿片类药物的更多研究 互动是有计划的。虽然了解阿片类药物的药理作用 至关重要的是，将这一知识传播给医务人员是很重要的 社区和普通公众。这只会带来更有效的 控制疼痛的方法和减少滥用这些药物的方法 重要的药物。

This is a request for a Research Scientist Award (KO5). Despite their importance in the management of pain, opiates are abused and this remains a major problem. By understanding the roles of the many opioid receptor subtypes in pain control and addictive behavior, it may be possible to develop analgesics without abuse potentia. Opiate receptor multiplicity has expanded to three major classes of receptors (mu, delta and kappa) with subtypes within each class. These receptor subtypes have been associated with specific pharmacological actions in vivo and have been studied in traditional binding assays. The recent cloning of delta, mu and kappa1 receptors has greatly facilitated the study of opioid receptor heterogeneity. For example, we have confirmed the role of spinal delta receptors in enkephalin analgesia using an antisense oligodeoxynucleotide to DOR-l and identified a new putative kappa3 receptor clone based upon sequence homologies. An antisense oligodeoxynucleotide based upon this clone prevents analgesia in vivo by a kappa3 ligand but not morphine. These investigations into opioid receptor heterogeneity will be continued, focusing upon mu and kappa3 receptors. They will include the binding, regulation and second messenger systems of mu and kappa3 receptors in cell lines using traditional biochemical and molecular biological approaches, as well as novel ligands synthesized by my laboratory. Unlike tissue culture, the brain is a highly complex network of neuronal systems. The descriptions of marked regional synergy among various brainstem nuclei and between the brain and the spinal cord underscore the need for in vivo studies. Our studies on synergy within the central nervous system will continue and the roles of the various receptor subtypes will be defined. Investigations into tolerance and the role of nitric oxide (NO) also will be continued while additional studies looking at an important morphine metabolite, morphine 6beta-glucuronide, will be expanded. Our recent identification of an antiopioid sigma1 system within the brain may help explain the wide variability of responses to opioids among strains of mice and possibly people. Additional studies exploring these sigma1/opioid interactions are planned. While understanding opioid pharmacology is crucial, it is important to disseminate this knowledge to the medical community and the general public. This can only lead to a more effective approach to the control of pain and a decrease in the abuse of these important drugs.