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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >N-naphthoyl-p-naltrexamine (NNTA), a highly selective and potent activator of μ/κ-opioid heteromers
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N-naphthoyl-p-naltrexamine (NNTA), a highly selective and potent activator of μ/κ-opioid heteromers

机译:N-萘甲酰对纳曲胺(NNTA),μ/κ阿片类异构体的高度选择性和有效活化剂

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摘要

Numerous G protein-coupled receptors (GPCRs) have been shown to form heteromeric receptors in cell-based assays. Among the many heteromers reported in the opioid receptor family are μ/κ, κ/δ, and μ/δ. However, the in vivo physiological and behavioral relevance for the proposed heteromers have not yet been established. Here we report a unique example of a ligand, N-naphthoylp-naltrexamine (NNTA) that selectively activates heteromeric μ/κ-opioid receptors in HEK-293 cells and induces potent antinociception in mice. NNTA was an exceptionally potent agonist in cells expressing μ/κ-opioid receptors. Intriguingly, it was found to be a potent antagonist in cells expressing only n-receptors. In the mouse tail-flick assay, intrathecal (i.t.) NNTA produced antinociception that was ~ 100-fold greater than by intracerebroventricular (i.c.v,) administration. The κ-antagonist, norBNI, decreased the i.t. potency, and the activity was virtually abolished in |i-opioid receptor knockout mice. No tolerance was induced i.t., but marginal tolerance (3-fold) was observed via the i.c.v. route. Moreover, NNTA produced neither significant physical dependence nor place preference in the ED_(50) dose range. Taken together, this work provides an important pharmacologic tool for investigating the in vivo functional relevance of heteromeric μ/κ-opioid receptors and suggests an approach to potent analgesics with fewer deleterious side effects.
机译:在基于细胞的测定中,许多G蛋白偶联受体(GPCR)已显示形成异聚受体。在阿片受体家族中报道的许多异聚体中有μ/κ,κ/δ和μ/δ。但是,尚未建立所提出的异聚体的体内生理和行为相关性。在这里,我们报告了一个独特的配体实例,N-萘甲酰-纳曲胺(NNTA),可选择性激活HEK-293细胞中的异源μ/κ阿片受体并在小鼠中诱导有效的镇痛作用。在表达μ/κ阿片受体的细胞中,NNTA是一种非常有效的激动剂。有趣的是,发现它是仅表达n受体的细胞中的有效拮抗剂。在小鼠甩尾试验中,鞘内(i.t.)NNTA产生的抗伤害感受比脑室内(i.c.v)给予的伤害感受高约100倍。 κ拮抗剂norBNI降低了i.t.效价,而该活性实际上在| i阿片受体敲除小鼠中被废除了。在i.t.中未诱导出耐受性,但是通过i.c.v.观察到边缘耐受性(3倍)。路线。此外,NNTA在ED_(50)剂量范围内既不产生明显的身体依赖性,也不产生位置偏爱。两者合计,这项工作提供了一种重要的药理学工具,用于研究异聚μ/κ阿片受体的体内功能相关性,并提出了一种有效的镇痛药方法,具有较少的有害副作用。

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  • 作者单位

    Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455,Department of Pharmacology,University of Minnesota, Minneapolis, MN 55455;

    Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455;

    Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455;

    Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455;

    Department of Neuroscience, Medical School, University of Minnesota, Minneapolis, MN 55455;

    Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Science Center,Shreveport, LA 71115;

    Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455,Department of Pharmacology,University of Minnesota, Minneapolis, MN 55455,Department of Neuroscience, Medical School, University of Minnesota, Minneapolis, MN 55455;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    pain;

    机译:痛;

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