Mas-related G-protein-coupled receptors inhibit pathological pain in mice
Mas-related G-protein-coupled receptors inhibit pathological pain in mice
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DOI：
10.1073/pnas.1011221107
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发表时间：
2010-09-07
影响因子：
11.1
通讯作者：
Dong, Xinzhong
中科院分区：
文献类型：
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作者：
Guan, Yun;Liu, Qin;Dong, Xinzhong
疼痛研究的一个重要目标是确定治疗病理性持续性疼痛状态（例如炎症性疼痛和神经性疼痛）的新药物靶点。 Mas 相关的 G 蛋白偶联受体 (Mrgprs) 代表了一大类孤儿受体，在小直径伤害性初级感觉神经元中特异性表达。为了确定 Mrgprs 在持续病理性疼痛状态中的作用，我们利用了一个小鼠品系，其中跨越 12 个 Mrgpr 基因的染色体位点被删除 (KO)。初步研究表明，与野生型同窝小鼠相比，这些 KO 小鼠在后爪炎症后表现出长时间的机械和热痛过敏。在这里，我们表明这种突变还增强了背角宽动态范围神经元的饱和反应，这是触发中枢疼痛敏化的电生理学模型。 Mrgpr簇的缺失也阻断了鞘内应用的牛肾上腺髓质肽8-22 (BAM 8-22)（一种MrgprC11激动剂）对炎性热痛觉过敏和神经性机械异常性疼痛的镇痛作用。脊髓应用牛肾上腺髓质肽 8-22 也显着减弱了野生型小鼠的饱和度，而这种效应在 KO 小鼠中被消除。这些数据表明，Mrgpr 家族的成员，特别是 MrgprC11，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一类用于治疗持续性疼痛且副作用最小的抗痛觉过敏药，因为它们的靶标具有高度特异性的表达。
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 wildtype littermates. Here, we show that this mutation also enhances the windup response of dorsal-horn wide dynamic-range neurons, an electrophysiological model for the triggering of central pain sensitization. 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 MrgprC11, 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 specific expression of their targets.