Opiate Receptor Pharmacology

阿片受体药理学

• 批准号: 7106618
• 负责人: GAVRIL W PASTERNAK
• 金额: $ 12.18万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7106618
• 关键词: P glycoprotein; analgesia; blood brain barrier; chemical binding; drug receptors; drug tolerance; laboratory mouse; laboratory rat; molecular cloning; molecular site; neuropharmacology; neurotransmitter transport; nociceptin; opiate alkaloid; opioid receptor; pharmacogenetics; posttranscriptional RNA processing; protein isoforms; protein protein interaction; protein structure function; receptor binding; receptor coupling; receptor expression; second messengers; tissue /cell culture

DESCRIPTION (provided by applicant): Opiates are important for the treatment of pain, but their abuse presents a major health problem. Understanding opioid actions is crucial to their rational use clinically and the development of potential treatments for abuse. Opiates and the opioid peptides act through a family of receptors, of which a number have been cloned. Understanding how these receptors work at the molecular level and in vivo is crucial to enhance our ability to develop new agents to treat pain and to avoid the problems of abuse, as well as to better utilize the drugs currently available. This application is focused upon understanding the actions of these opioid receptors. Clinical experiences suggest that mu opiate analgesics differ pharmacologically, raising the possibility of multiple mu receptor subtypes. This possibility has also been suggested from detailed binding and pharmacological studies. More recently, we have identified a number of splice variants of the MOR-1 receptor in mouse, rat and humans. A major component of this application is based upon the characterization of these variants and understanding their relevance to opioid pharmacology. Receptor heterogeneity can also be achieved by dimerization. We will examine the interactions of MOR-1 and its splice variants with the mouse version of the orphanin FQ/nociceptin receptor (ORL1), termed KOR-3. Finally, there are a number of modulatory systems involved with opioid actions. These have the potential of enhancing the actions of opioids without a corresponding increase in side effects. Sigma1 receptors have been implicated in the modulation of opioid analgesia, but not gastrointestinal transit. Sigma1 receptor antagonists potentiate opioid analgesia and eliminate many of the differences in sensitivity towards opioids seen among strains of mice. Having now cloned the mouse and rat versions of the sigma1 receptor, we plan to explore its actions at the molecular and functional level. Finally, transporters such as P-glycoprotein play a major role in maintaining the blood-brain barrier. However, recent work suggests that they also are responsible for transporting neurotransmitters/modulators from the brain into the periphery, including a variety of opioids. We also will continue our investigations of these transporters on opioid action. By examining both the receptors themselves and modulatory systems, we hope to extend our understanding of opioid analgesics and gain insights into how to use them appropriately and minimize their abuse.

描述（由申请人提供）： 阿片类药物对于治疗疼痛很重要，但他们的虐待提出了一个主要的健康问题。了解阿片类药物的作用对于在临床上的合理使用以及对滥用的潜在治疗方法的发展至关重要。阿片类药物和阿片类肽通过一个受体家族作用，其中许多受体被克隆。了解这些受体在分子水平和体内的工作方式对于增强我们发展新药物治疗疼痛和避免滥用问题的能力至关重要，并更好地利用当前可用的药物。该应用集中在理解这些阿片类药物受体的作用上。临床经验表明，MU阿片类镇痛药在药理学上有所不同，从而增加了多种MU受体亚型的可能性。从详细的结合和药理研究中也提出了这种可能性。最近，我们已经确定了小鼠，大鼠和人类中MOR-1受体的许多剪接变体。该应用程序的一个主要组成部分是基于这些变体的表征，并了解它们与阿片类药物的相关性。受体异质性也可以通过二聚化来实现。我们将研究MOR-1及其剪接变体与孤立蛋白FQ/NociTeptin受体（ORL1）的相互作用，称为KOR-3。最后，有许多与阿片类药物作用有关的调节系统。这些潜力可以增强阿片类药物的作用，而没有相应的副作用增加。 SIGMA1受体与阿片类镇痛的调节有关，但不参与胃肠道转移。 Sigma1受体拮抗剂增强了阿片类镇痛，并消除了小鼠菌株中对阿片类药物的敏感性的许多差异。现在，我们计划在Sigma1受体的小鼠和大鼠版本中克隆，我们计划在分子和功能水平上探索其作用。最后，诸如P-糖蛋白等转运蛋白在维持血脑屏障中起着重要作用。但是，最近的工作表明，它们还负责将神经递质/调节剂从大脑传输到外围，包括各种阿片类药物。我们还将继续对这些转运蛋白的阿片类药物作用进行调查。通过检查两个受体本身和调节系统，我们希望扩展我们对阿片类镇痛药的理解，并了解如何适当使用它们并最大程度地减少其滥用。