Opiate Receptor Pharmacology

描述(由申请人提供)： 鸦片类药物对于治疗疼痛很重要，但它们的滥用构成了一个主要的健康问题。了解阿片类药物的作用对于临床合理使用阿片类药物和开发潜在的滥用治疗方法至关重要。阿片剂和阿片肽通过一系列受体发挥作用，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物、避免滥用问题以及更好地利用现有药物的能力至关重要。这一应用的重点是了解这些阿片受体的作用。临床经验表明，Mu阿片类止痛药在药理上不同，增加了Mu受体亚型多种多样的可能性。从详细的结合和药理学研究中也提出了这种可能性。最近，我们在小鼠、大鼠和人类中发现了一些MOR-1受体的剪接变体。这一应用的一个主要组成部分是基于对这些变体的表征和对它们与阿片类药物药理学的相关性的了解。受体的异质性也可以通过二聚化来实现。我们将研究MOR-1及其剪接变体与小鼠版本的孤儿FQ/伤害素受体(ORL1)的相互作用，称为KOR-3。最后，还有一些与阿片类药物作用有关的调节系统。这些药物有可能在不相应增加副作用的情况下增强阿片类药物的作用。Sigma1受体参与了阿片类药物镇痛的调节，但与胃肠转运无关。Sigma1受体拮抗剂增强阿片类药物的止痛作用，并消除不同品系小鼠之间对阿片类药物敏感性的许多差异。现在我们已经克隆了Sigma1受体的小鼠和大鼠版本，我们计划在分子和功能水平上探索它的作用。最后，P-糖蛋白等转运蛋白在维持血脑屏障方面发挥着重要作用。然而，最近的研究表明，它们还负责将神经递质/调节剂从大脑输送到外周，包括各种阿片类药物。我们还将继续调查这些转运体的阿片类药物作用。通过研究受体本身和调节系统，我们希望扩大我们对阿片类止痛药的理解，并对如何正确使用它们和最大限度地减少它们的滥用获得洞察力。

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.