Opiate Receptor Pharmacology

描述（由申请人提供）： 阿片类药物对治疗疼痛很重要，但滥用阿片类药物会造成严重的健康问题。了解阿片类药物的作用对于临床合理使用和开发潜在的滥用治疗方法至关重要。阿片类药物和阿片肽通过一个受体家族发挥作用，其中一些已经被克隆。了解这些受体如何在分子水平和体内发挥作用，对于提高我们开发治疗疼痛的新药和避免滥用问题以及更好地利用现有药物的能力至关重要。该应用程序的重点是了解这些阿片受体的作用。临床经验表明，mu阿片类镇痛药不同的神经元，提高了多种mu受体亚型的可能性。详细的结合和药理学研究也表明了这种可能性。最近，我们已经在小鼠、大鼠和人中鉴定了莫尔-1受体的许多剪接变体。本申请的一个主要组成部分是基于这些变体的表征并理解其与阿片类药物药理学的相关性。受体异质性也可以通过二聚化来实现。我们将研究莫尔-1及其剪接变体与小鼠版本的FQ/痛敏受体（ORL 1）（称为KOR-3）的相互作用。最后，有一些调节系统涉及阿片类药物的作用。这些药物有可能增强阿片类药物的作用，而不会相应增加副作用。Sigma 1受体与阿片类镇痛的调节有关，但与胃肠转运无关。Sigma 1受体拮抗剂增强阿片类镇痛作用，并消除小鼠品系中对阿片类药物敏感性的许多差异。现在已经克隆了小鼠和大鼠版本的sigma 1受体，我们计划在分子和功能水平上探索其作用。最后，转运蛋白如P-糖蛋白在维持血脑屏障中起主要作用。然而，最近的研究表明，它们也负责将神经递质/调节剂从大脑运输到外周，包括各种阿片类药物。我们还将继续研究这些转运蛋白对阿片类药物的作用。通过检查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，并深入了解如何适当使用它们并最大限度地减少滥用。

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.