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.

这是获得研究科学家奖（KO5）的要求。 尽管他们 在疼痛管理中的重要性，阿片类药物被滥用，这仍然存在 一个主要问题。通过了解许多阿片类药物受体的作用 疼痛控制和成瘾行为中的亚型，可能有可能 开发镇痛药，而不会滥用电位。鸦片受体的多样性 已经扩展到三个主要的受体（MU，Delta和Kappa） 每个类都具有亚型。这些受体亚型已经 与体内特定的药理作用相关，并且已经 在传统的约束测定中进行了研究。 Delta，MU和 KAPPA1受体大大促进了阿片受体的研究 异质性。例如，我们已经确认了脊柱三角洲的作用 使用反义寡脱氧核苷酸中脑镇痛的受体 dor-l并根据 序列同源性。基于此的反义寡脱氧核苷酸 克隆通过kappa3配体阻止体内镇痛，但不是吗啡。 这些对阿片受体异质性的调查将继续 专注于MU和KAPPA3受体。他们将包括绑定， 细胞中MU和KAPPA3受体的调节和第二个允许系统 使用传统的生化和分子生物学方法的线条， 以及我的实验室合成的新型配体。与组织不同 培养，大脑是一个高度复杂的神经元系统网络。这 各种脑干核之间明显区域协同作用的描述 在大脑和脊髓之间强调了体内的需求 研究。我们对中枢神经系统中协同作用的研究将 继续定义各种受体亚型的角色。 对耐受性和一氧化氮（NO）的作用的研究也将 继续研究重要的吗啡的其他研究 代谢产物，吗啡6Beta-葡萄糖苷将扩展。我们最近 识别大脑内抗白皮细胞SigMA1系统可能有助于 解释小鼠菌株中对阿片类药物反应的广泛差异 还有人。探索这些Sigma1/阿片类药物的其他研究 计划进行互动。同时了解阿片类药理学是 至关重要的是，将这些知识传播给医学很重要 社区和公众。这只会导致更有效 控制疼痛的方法和滥用的减少 重要药物。