Pharmacology of opioid actions in vivo

阿片类药物体内作用的药理学

基本信息

批准号：
10404669
负责人：
YING-XIAN PAN
金额：
$ 36.11万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-05-31
项目状态：
已结题

项目摘要

Opiates remain among the most useful and important class of drugs in medicine, but not without problems. This submission proposes to examine two clinically relevant issues in opioid use – safety and tolerance. Most opioids used clinically act through the mu opioid receptor. The mu opioid receptor gene Oprm1 undergoes alternative splicing to generate a family of opioid receptors that can be categorized into three classes based upon their structure, each of which contain a number of variants. Knockout mouse models that selectively remove different sets of Oprm1 variants suggest that morphine acts through only one of these sets of variants while drugs acting through different sets of mu receptors lack respiratory depression, physical dependence and reward while maintaining their analgesic activity, thus enhancing their safety. The focus of this application is to understand the role and significance of the sets of mu opioid receptor splice variants in opioid analgesia, side-effects and tolerance. The current application will explore this concept by generating a mouse model in which selected opioid receptor splice variants can be expressed under native control of the Oprm1 gene, thereby permitting the exploration of their actions in vivo. The second aspect of this application involves tolerance. Preclinicla models reveal that short-term opioid administration leads to progressive tolerance. Yet, cancer patients can be maintained on fixed opioid doses without dose escalation to relieve their pain for many months. In a recent study using an extended chronic administration paradigm we reconciled these observations, showing a progressively increasing tolerance to morphine for up to three weeks that then stabilized with no further increases for as long as 6 weeks. Furthermore, this stabilization was associated with changes of select Oprm1 splice variants in specific brain regions of as much as 400-fold. The second component of this application will explore the stabilization of opioid tolerance with extended administration and potential mechanisms.

阿片类药物仍然是医学中最有用，最重要的药物类别之一，但并非没有问题。该提交的建议旨在检查阿片类药物使用中两个临床相关问题 - 安全性和公差。大多数阿片类药物使用临床上的MU阿片类药物接收器作用。 MU OpioID受体基因OPRM1经历替代剪接以产生Opioid家族可以根据其结构分为三个类的接收器包含许多变体。敲除鼠标模型，有选择地删除不同的集合 OPRM1变体表明吗啡仅通过这些变体中的一组起作用，而通过不同的MU受体作用的药物缺乏呼吸抑制，身体依赖和奖励，同时保持其镇痛活动，从而提高其安全性。该应用的重点是了解MU阿片类药物集的作用和意义接收器剪接变体在阿片类镇痛，副作用和公差中。当前的应用程序将通过生成鼠标模型来探索这个概念变体可以在OPRM1基因的天然控制下表达，从而允许探索他们在体内行动。该应用程序的第二个方面涉及公差。临床前模型表明，短期阿片类药物给药会导致渐进耐受性。然而，癌症患者可以维持固定的阿片类药物剂量，而无需升级剂量升级他们的痛苦已经有好几个月了。在最近使用延长的慢性管理的研究中范式我们对这些观察结果进行了调和，显示了逐渐增加的公差吗啡最多三周，然后稳定而无需进一步增加，长达6周几周。此外，这种稳定与精选OPRM1剪接的变化有关特定大脑区域的变体高达400倍。第二个组成部分应用将探索通过扩展给药的稳定阿片类药物耐受性和潜在机制。