Pharmacology of Kappa Opioid Receptor

Kappa 阿片受体的药理学

基本信息

  • 批准号:
    10212993
  • 负责人:
  • 金额:
    $ 53.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-15 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

Opioid receptors (µ, d and k), are Gi/o-coupled, rhodopsin-like receptors. κ opioid receptor (KOPR) agonists may be useful as analgesics and antipruritic agents without abuse potential and respiratory depression associated with currently use µ opioid analgesics. However, prototypic selective KOPR agonists cause dysphoria or aversion, which limits their development. G protein-coupled receptors (GPCRs) signal via both G protein or arrestin to activate different downstream effectors. Biased agonists preferentially activate G protein- or arrestin-mediated signaling and thus may have advantages over balanced or unbiased agonists in that they may produce therapeutic effects with fewer side effects. However, translating in vitro ligand bias to in vivo pharmacology has been uncertain. Nalfurafine, the only selective KOPR agonist in clinical use, is prescribed in Japan for treatment of uremic pruritus, without causing dysphoria at therapeutic doses. In mice, we observed that nalfurafine caused conditioned place aversion (CPA) at doses higher than the effective doses for the antinociceptive and anti-scratch effects; however, the reverse was true for two other selective KOPR agonists, U50,488H and MOM-SalB. Similarly, U50,488H, but not nalfurafine, induced anhedonia. Thus, we established an animal model to understand the mechanisms underlying separation of anti-pruritic and analgesic effects from dysphoria / aversion of KOPR agonists. Importantly, we found in mouse brains U50,488H and MOM-SalB caused robust KOPR phosphorylation, but nalfurafine did not. Also,U50,488H, but not nalfurafine, enhanced phosphorylation of some proteins downstream of mTOR and the mTOR pathway may be involved in KOPR-mediated CPA. For Specific Aim 1, We will test the hypothesis that the ability of agonists to promote CPA is related to its ability cause KOPR phosphorylation by examining several structurally distinct KOPR agonists. KOPR phosphorylation will be detected with immunoblotting using our own antibodies that specifically recognize phosphorylated KOPR. For Specific Aim 2, we will examine the differences between U50,488H and nalfurafine in downstream phosphoproteomic changes in brain regions important in KOPR pharmacology. Furthermore, we will investigate the involvement of differentially regulated proteins / pathways in KOPR-mediated CPA and anhedonia. For Specific Aim 3, we will generate mutant mouse lines to examine the roles of agonist-promoted KOPR phosphorylation and GRK5 and GRK6 in KOPR pharmacology in vivo. KOPR-mediated antipruritic, antinociceptive, aversive and sedative effects and motor incoordination will be used as the in vivo pharmacological measures. Our “from bedside to bench” approach, distinctly different from the commonly used “from bench to bedside” strategy, allows us to circumvent the challenges of translating in vitro cell-based results to in vivo pharmacology. Taken together, the proposed studies will greatly advance our understanding of KOPR pharmacology at the molecular, cellular, and behavioral levels and signaling at a system level. Signaling pathways identified to be involved in KOPR-mediated aversion and anhedonia may shed light on mechanisms underlying aversion- and depression-like behaviors in general. In addition, it may lead to development of KOPR agonists that cause lower dysphoria and can be used as anti-itch medications and analgesics, which will contribute to solving the problems of the opioid abuse epidemic.
阿片受体(μ、d和k)是Gi/o偶联的视紫红质样受体。κ阿片受体(KOPR)激动剂可能是有用的 作为镇痛药和抗炎药,无滥用可能性和与当前使用相关的呼吸抑制 阿片类镇痛药然而,原型选择性KOPR激动剂引起烦躁不安或厌恶,这限制了它们的应用。 发展G蛋白偶联受体(GPCR)通过G蛋白或抑制蛋白两者发出信号以激活不同的下游受体。 效应器偏性激动剂优先激活G蛋白或抑制蛋白介导的信号传导,因此可能具有优势 相对于平衡或无偏激动剂,它们可以产生具有较少副作用的治疗效果。然而,在这方面, 将体外配体偏好转化为体内药理学还不确定。唯一选择性KOPR激动剂纳呋萘芬 在临床使用中,在日本被处方用于治疗尿毒症性瘙痒症,在治疗剂量下不会引起烦躁不安。在 在小鼠中,我们观察到纳呋拉芬在高于有效剂量的剂量下引起条件性位置厌恶(CPA)。 抗伤害感受和抗刮伤作用;然而,对于两种其它选择性KOPR激动剂, U 50、488 H和MOM-SalB。类似地,U 50,488 H,而不是纳呋拉芬,诱导快感缺乏。因此,我们创造了一种动物, 了解抗癫痫和镇痛作用与烦躁/厌恶分离的潜在机制的模型 KOPR激动剂。重要的是,我们在小鼠大脑中发现U 50、488 H和MOM-SalB引起了强有力的KOPR 磷酸化,但nalfurafine没有。此外,U 50,488 H,而不是纳呋拉芬,增强了一些蛋白质的磷酸化 在mTOR下游,mTOR通路可能参与KOPR介导的CPA。具体目标1: 检验激动剂促进CPA的能力与其引起KOPR磷酸化的能力有关的假设, 检查几种结构上不同的KOPR激动剂。KOPR磷酸化将用免疫印迹法检测 使用我们自己的抗体来识别磷酸化的KOPR。对于具体目标2,我们将研究 U 50,488 H和纳呋拉芬在脑区下游磷酸化蛋白质组学变化中的差异, KOPR药理学。此外,我们还将研究差异调节蛋白/途径在 KOPR介导的CPA和快感缺乏。对于特异性目标3,我们将产生突变小鼠系,以检查 激动剂促进体内KOPR药理学中的KOPR磷酸化和GRK 5和GRK 6。KOPR介导 抗过敏、抗伤害感受、厌恶和镇静作用以及运动不协调将用作体内 药理学措施。我们的“从床边到长凳”的方法,明显不同于通常使用的“从 从实验室到床边”的策略,使我们能够规避将体外细胞结果转化为体内结果的挑战 药理学总之,拟议的研究将大大促进我们对KOPR药理学的理解, 分子、细胞和行为水平以及系统水平的信号传导。确定参与的信号通路 在KOPR介导的厌恶和快感缺失中,可能揭示了厌恶和抑郁样的潜在机制, 一般的行为。此外,它可能导致KOPR激动剂的发展,其引起较低的烦躁不安,并且可以是 用作止痒药和止痛药,这将有助于解决阿片类药物滥用流行病的问题。

项目成果

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LEE-YUAN LIU-CHEN其他文献

LEE-YUAN LIU-CHEN的其他文献

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{{ truncateString('LEE-YUAN LIU-CHEN', 18)}}的其他基金

Kappa Opioid Receptor in Paraventricular Nucleus of Thalamus
丘脑室旁核中的 Kappa 阿片受体
  • 批准号:
    10659960
  • 财政年份:
    2023
  • 资助金额:
    $ 53.9万
  • 项目类别:
Pharmacology of Kappa Opioid Receptor
Kappa 阿片受体的药理学
  • 批准号:
    10400320
  • 财政年份:
    2017
  • 资助金额:
    $ 53.9万
  • 项目类别:
Pharmacology of Kappa Opioid Receptor
Kappa 阿片受体的药理学
  • 批准号:
    9383834
  • 财政年份:
    2017
  • 资助金额:
    $ 53.9万
  • 项目类别:
Generation of knockin mice expressing KOPR conjugated with a fluorescent protein
表达与荧光蛋白缀合的 KOPR 的敲入小鼠的产生
  • 批准号:
    8623020
  • 财政年份:
    2014
  • 资助金额:
    $ 53.9万
  • 项目类别:
Generation of knockin mice expressing KOPR conjugated with a fluorescent protein
表达与荧光蛋白缀合的 KOPR 的敲入小鼠的产生
  • 批准号:
    8836513
  • 财政年份:
    2014
  • 资助金额:
    $ 53.9万
  • 项目类别:
Biochemical Pharmacology Core
生化药理学核心
  • 批准号:
    7849838
  • 财政年份:
    2010
  • 资助金额:
    $ 53.9万
  • 项目类别:
BIOCHEMICAL PHARMACOLOGY CORE
生化药理学核心
  • 批准号:
    7646202
  • 财政年份:
    2008
  • 资助金额:
    $ 53.9万
  • 项目类别:
BIOCHEMICAL PHARMACOLOGY CORE
生化药理学核心
  • 批准号:
    6933612
  • 财政年份:
    2005
  • 资助金额:
    $ 53.9万
  • 项目类别:
Cellular Pharmacology of Kappa Opioid Receptor
Kappa 阿片受体的细胞药理学
  • 批准号:
    7232651
  • 财政年份:
    2004
  • 资助金额:
    $ 53.9万
  • 项目类别:
Cellular Pharmacology of Kappa Opioid Receptor
Kappa 阿片受体的细胞药理学
  • 批准号:
    7064864
  • 财政年份:
    2004
  • 资助金额:
    $ 53.9万
  • 项目类别:

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临床记录中缩写词的实时消歧
  • 批准号:
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  • 财政年份:
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  • 批准号:
    8589822
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  • 资助金额:
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Real-time Disambiguation of Abbreviations in Clinical Notes
临床记录中缩写词的实时消歧
  • 批准号:
    8305149
  • 财政年份:
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