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:
  • 金额:
    $ 36.09万
  • 依托单位:
  • 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之一,但并非没有

项目成果

期刊论文数量(0)
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专利数量(0)

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YING-XIAN PAN其他文献

YING-XIAN PAN的其他文献

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{{ truncateString('YING-XIAN PAN', 18)}}的其他基金

Identifying novel molecular targets, signaling pathways and mechanisms underlying fentanyl overdose-induced severe respiratory depression and lethality in rats using TMT phosphoproteomics/proteomics
使用 TMT 磷酸蛋白质组学/蛋白质组学识别芬太尼过量引起大鼠严重呼吸抑制和致死的新分子靶标、信号通路和机制
  • 批准号:
    10831163
  • 财政年份:
    2023
  • 资助金额:
    $ 36.09万
  • 项目类别:
Pharmacology of opioid actions in vivo
阿片类药物体内作用的药理学
  • 批准号:
    10404669
  • 财政年份:
    2020
  • 资助金额:
    $ 36.09万
  • 项目类别:
Pharmacology of opioid actions in vivo
阿片类药物体内作用的药理学
  • 批准号:
    10258294
  • 财政年份:
    2020
  • 资助金额:
    $ 36.09万
  • 项目类别:
Arylepoxamides: A new class of potent, safer analgesics
芳基环酰胺:一类新型强效、更安全的镇痛药
  • 批准号:
    10291187
  • 财政年份:
    2020
  • 资助金额:
    $ 36.09万
  • 项目类别:
Alternative pre-mRNA splicing of mu opioid receptor gene and mu opioid actions
mu阿片受体基因的选择性前mRNA剪接和mu阿片作用
  • 批准号:
    10166814
  • 财政年份:
    2020
  • 资助金额:
    $ 36.09万
  • 项目类别:
Alternative pre-mRNA splicing of mu opioid receptor gene and mu opioid actions
mu阿片受体基因的选择性前mRNA剪接和mu阿片作用
  • 批准号:
    10257279
  • 财政年份:
    2020
  • 资助金额:
    $ 36.09万
  • 项目类别:
Mapping mu agonist-induced receptor-protein interactions for OPRM1 7TM variants
绘制 OPRM1 7TM 变体 mu 激动剂诱导的受体-蛋白质相互作用图谱
  • 批准号:
    9788403
  • 财政年份:
    2018
  • 资助金额:
    $ 36.09万
  • 项目类别:
Alternative pre-mRNA splicing of mu opioid receptor gene and mu opioid actions
mu阿片受体基因的选择性前mRNA剪接和mu阿片作用
  • 批准号:
    9383212
  • 财政年份:
    2017
  • 资助金额:
    $ 36.09万
  • 项目类别:
Alternative pre-mRNA splicing of mu opioid receptor gene and mu opioid actions
mu阿片受体基因的选择性前mRNA剪接和mu阿片作用
  • 批准号:
    9550957
  • 财政年份:
    2017
  • 资助金额:
    $ 36.09万
  • 项目类别:
Exploring function of mu opioid receptor splice variants in rat by gene targeting
通过基因打靶探索大鼠μ阿片受体剪接变体的功能
  • 批准号:
    9312277
  • 财政年份:
    2016
  • 资助金额:
    $ 36.09万
  • 项目类别:

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Alternative splicing of Grin1 controls NMDA receptor function in physiological and disease processes
Grin1 的选择性剪接控制生理和疾病过程中的 NMDA 受体功能
  • 批准号:
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长非编码 RNA H19 介导 ALD 发病机制中的选择性剪接
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  • 财政年份:
    2023
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使用蛋白质基因组学评估选择性剪接事件对胶质母细胞瘤的功能影响
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    10577186
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心脏中 CLTC 的选择性剪接调节
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CAREER: Mechanotransduction, transcription, and alternative splicing in cell biology
职业:细胞生物学中的机械转导、转录和选择性剪接
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