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：
10304208
负责人：
YING-XIAN PAN
金额：
$ 36.09万
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上最有用和最重要的一类药物，但并非没有该意见建议研究阿片类药物使用中的两个临床相关问题 - 临床上使用的大多数阿片类药物通过 mu 阿片受体发挥作用。阿片受体基因 Oprm1 经过选择性剪接产生阿片类药物家族受体根据其结构可分为三类，每一类包含许多选择性去除不同组的基因敲除小鼠模型。 Oprm1 变体表明吗啡仅通过这些变体组中的一组起作用，而通过不同组的 mu 药物受体发挥作用，缺乏呼吸抑制、身体依赖性和奖励，同时保持其镇痛活性，从而提高其安全性。本应用的重点是了解 mu 阿片类药物组的作用和意义阿片类药物镇痛、副作用和耐受性中的受体剪接变异体的当前应用。将通过生成一个小鼠模型来探索这个概念，其中选定的阿片受体剪接变体可以在 Oprm1 基因的天然控制下表达，从而允许探索它们在体内的作用。该应用的第二个方面涉及耐受性。临床前模型表明，短期阿片类药物给药会导致逐渐耐受。然而，癌症患者可以维持固定的阿片类药物剂量，无需增加剂量来缓解症状在最近的一项研究中，他们的疼痛持续了好几个月。我们协调了这些观察的范式，显示出对吗啡长达三周，然后稳定下来，长达 6 周不再进一步增加再过几周，这种稳定与选择 Oprm1 剪接的变化有关特定大脑区域的变异高达 400 倍。该应用将探索通过延长给药来稳定阿片类药物耐受性和潜在的机制。