Pharmacology of opioid actions in vivo

阿片类药物体内作用的药理学

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10304208
• 关键词: Address; Alternative Splicing; Analgesics; Animal Model; Brain region; C-terminal; Cancer Patient; Chronic; Clinical; Cloning; Coupled; Dose; Family; Generations; Genes; Genetic; In Situ Hybridization; Individual; Knockout Mice; Lentivirus; Medicine; Messenger RNA; Modeling; Molecular; Morphine; Mus; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Patients; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Proteins; RNA Splicing; Receptor Activation; Receptor Gene; Rewards; Role; Safety; Series; Structure; Time; Up-Regulation; Variant; Ventilatory Depression; base; behavioral study; cancer pain; clinically relevant; gene product; in vivo; morphine tolerance; mouse model; mu opioid receptors; mu receptors; opiate tolerance; opioid therapy; opioid use; pre-clinical; promoter; receptor; receptor expression; selective expression; side effect

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 问题本文件建议审查阿片类药物使用中的两个临床相关问题- 安全和宽容。临床上使用的大多数阿片类药物通过μ阿片受体起作用。慕 阿片受体基因Oprm 1经过选择性剪接产生一个阿片受体家族， 根据其结构，可将受体分为三类，每一类 包含许多变体。敲除小鼠模型，选择性地去除不同组的 oprm 1变体表明吗啡仅通过这些变体中的一种起作用， 通过不同的μ受体组起作用的药物缺乏呼吸抑制、物理抑制、 依赖性和奖励，同时保持其镇痛活性，从而提高其安全性。 本申请的重点是了解μ阿片类药物的作用和意义 受体剪接变体在阿片类镇痛、副作用和耐受性中的作用。当前应用程序 我将通过建立一个小鼠模型来探索这一概念，在这个模型中， 变体可以在Oprm 1基因的天然控制下表达，从而允许 探索它们在体内的作用。本申请的第二个方面涉及宽容。 临床前模型表明，短期阿片类药物给药导致渐进性耐受。 然而，癌症患者可以维持固定的阿片类药物剂量，而无需剂量递增来缓解。 痛苦了好几个月。在最近的一项研究中， 我们调和了这些观察结果，显示出逐渐增加的宽容， 吗啡长达三周，然后稳定下来，没有进一步增加长达6周 周此外，这种稳定性与选择的Oprm 1拼接的变化相关 大脑特定区域的变异高达400倍。第二个组成部分 本申请将探索延长给药的阿片耐受性的稳定， 潜在机制。