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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mas-related G-protein-coupled receptors inhibit pathological pain in mice
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Mas-related G-protein-coupled receptors inhibit pathological pain in mice

机译:Mas相关的G蛋白偶联受体抑制小鼠的病理性疼痛

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摘要

An important objective of pain research is to identify novel drug targets for the treatment of pathological persistent pain states, such as inflammatory and neuropathic pain. Mas-related G-protein-coupled receptors (Mrgprs) represent a large family of orphan receptors specifically expressed in small-diameter nociceptive primary sensory neurons. To determine the roles of Mrgprs in persistent pathological pain states, we exploited a mouse line in which a chromosomal locus spanning 12 Mrgpr genes was deleted (KO). Initial studies indicated that .these KO mice show prolonged mechanical- and thermal-pain hypersensitivity after hind-paw inflammation compared with wild-type littermates. Here, we show that this mutation also enhances the windup response of dorsal-horn wide dynamic-range neurons, ah electrophysiological model for the triggering of central pain sensi-tization. Deletion of the Mrgpr cluster also blocked the analgesic effect of intrathecally applied bovine adrenal medulla peptide 8-22 (BAM 8-22), an MrgprC11 agonist on both inflammatory heat hyperalgesia and neuropathic mechanical allodynia. Spinal application of bovine adrenal medulla peptide 8-22 also significantly attenuated windup in wild-type mice, an effect eliminated in KO mice. These data suggest that members of the Mrgpr family, in particular MrgprCH, may constitute an endogenous inhibitory mechanism for regulating persistent pain in mice. Agonists for these receptors may, therefore, represent a class of antihyperalgesics for treating persistent pain with minimal side effects because of the highly specif ic expression of their targets.
机译:疼痛研究的一个重要目标是确定用于治疗诸如炎症性和神经性疼痛等病理性持续性疼痛状态的新型药物靶标。与Mas相关的G蛋白偶联受体(Mrgprs)代表了一大批孤儿受体,这些受体在小直径伤害性原代感觉神经元中特别表达。为了确定Mrgprs在持续的病理性疼痛状态中的作用,我们利用了一种小鼠谱系,其中删除了跨越12个Mrgpr基因的染色体基因座(KO)。最初的研究表明,与野生型同窝仔相比,这些KO小鼠在后爪发炎后表现出较长的机械和热痛超敏反应。在这里,我们表明该突变还增强了背角宽动态范围神经元的缠绕反应,这是触发中枢痛敏化的电生理模型。 Mrgpr簇的删除也阻断了鞘内施用的牛肾上腺髓质肽8-22(BAM 8-22)的镇痛作用,MrgprC11激动剂对炎性热痛觉过敏和神经性机械性异常性疼痛都有作用。牛肾上腺髓质肽8-22的脊柱应用也显着减弱了野生型小鼠的缠绕,在KO小鼠中消除了这种作用。这些数据表明,Mrgpr家族的成员,尤其是MrgprCH,可能构成调节小鼠持续性疼痛的内源性抑制机制。因此,这些受体的激动剂可能代表了一类用于治疗持续性疼痛且副作用最小的抗痛觉镇痛药,这是由于其靶标的高度特异性表达。

著录项

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  • 作者单位

    Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;

    rnThe Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;

    rnThe Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;

    rnDepartment of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;

    rnDivision of Biology, California Institute of Technology, Pasadena, CA 91125 Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125;

    rnThe Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205 Howard Hughes Medical Institute, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;

  • 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

    inflammation; neuropeptides; sensory neurons; mrgpr;

    机译:炎;神经肽感觉神经元r;

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