OPIATE RECEPTOR PHARMACOLOGY

阿片受体药理学

• 批准号: 2458335
• 负责人: GAVRIL W PASTERNAK
• 金额: $ 10.21万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458335
• 关键词: analgesia; antisense nucleic acid; chemical binding; cyclic AMP; drug tolerance; glucuronides; laboratory mouse; laboratory rat; molecular site; morphine; narcotic antagonists; neuropharmacology; nitric oxide; opiate alkaloid; opioid receptor; pharmacogenetics; protein isoforms; protein structure function; receptor binding; receptor expression; tissue /cell culture

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.

这是一个研究科学家奖（KO 5）的请求。 尽管他们 虽然阿片类药物在疼痛管理中的重要性，但阿片类药物仍被滥用， 一个大问题。通过了解许多阿片受体的作用 在疼痛控制和成瘾行为的亚型，它可能是可能的， 开发无滥用潜力的镇痛药。阿片受体多样性 已经扩展到三种主要类型的受体（μ，δ和κ） 每个类中都有子类型。这些受体亚型已经被 与体内特定药理作用相关， 在传统的结合分析中研究。最近克隆的德尔塔，穆和 κ 1受体极大地促进了阿片受体的研究 异质性例如，我们已经证实了脊髓三角洲 使用反义寡脱氧核苷酸的脑啡肽镇痛中的受体 并基于DOR-1鉴定了一种新的推定κ 3受体克隆， 序列同源性一种基于此的反义寡脱氧核苷酸， 克隆通过kappa 3配体而不是吗啡阻止体内镇痛。 这些对阿片受体异质性的研究将继续进行， 重点是μ和κ 3受体。它们将包括约束力， 细胞中mu和kappa 3受体的调节和第二信使系统 线使用传统的生物化学和分子生物学方法， 以及我实验室合成的新型配体。与组织不同 在文化中，大脑是一个高度复杂的神经系统网络。的 描述了各种脑干核团之间的显著区域协同作用， 大脑和脊髓之间的联系强调了体内 问题研究我们对中枢神经系统内协同作用的研究将 继续，并将确定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 继续进行，同时进行更多的研究， 代谢物吗啡6 β-葡萄糖醛酸苷将被扩增。我们最近 在大脑中识别抗阿片类物质sigma 1系统可能有助于 解释了不同品系小鼠对阿片类药物反应的广泛差异 可能还有人探索这些sigma 1/阿片类药物的其他研究 互动是有计划的。虽然了解阿片类药物药理学是 重要的是，将这些知识传播给医学界， 社区和公众。这只会导致更有效的 控制疼痛的方法和减少这些药物的滥用 重要药物。