Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: Role of mGluR1/5 and mTOR
Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: Role of mGluR1/5 and mTOR
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DOI：
10.1523/jneurosci.4383-07.2007
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发表时间：
2007-12-19
影响因子：
5.3
通讯作者：
Cervero, Fernando
中科院分区：
文献类型：
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作者：
Price, Theodore J.;Rashid, Md Harunor;Cervero, Fernando
脆性 X 型智力障碍是由编码影响神经元翻译的 RNA 结合蛋白 (FMRP) 的基因 (FMR1) 沉默引起的。人类疾病的一个显着特征是自残行为，这表明疼痛处理存在异常。此外，FMRP 调节 I 类代谢型谷氨酸受体 (mGluR1/5) 依赖性可塑性，已知这有助于伤害性敏化。我们在这里使用 Fmr1 敲除 (KO) 小鼠证明 FMRP 在疼痛处理中发挥重要作用，因为 Fmr1 KO 小鼠表现出 (1) 对持续伤害感受的反应减少（接近 50%）（第 2 期，福尔马林测试），(2) 周围神经损伤引起的异常性疼痛的发展延迟 3 周，以及 (3) 上行感觉几乎没有结束反应 重复 C 纤维刺激后的纤维。我们提供的证据表明，行为缺陷与 mGluR1/5 和哺乳动物雷帕霉素靶点 (mTOR) 介导的机制有关，因为 (1) 脊髓 mGluR5 拮抗作用未能抑制福尔马林测试的第二阶段，并且我们观察到鞘内注射 mGluR1/5 激动剂的伤害性反应显着减少 Fmr1 KO 小鼠中的 (RS)-3,5-二羟基苯基甘氨酸 (DHPG)； (2) 外周注射 DHPG 对 KO 小鼠没有影响，但在野生型小鼠中引起热痛觉过敏； (3) mTOR 抑制剂雷帕霉素抑制福尔马林和 DHPG 诱导的野生型伤害感受，但不能抑制 Fmr1 KO 小鼠。这些实验表明，通过 FMRP 和 mTOR 进行翻译调节是伤害感受可塑性的一个重要特征。这些观察结果还支持这样的假设：在脆性 X 智力低下患者中观察到的持续自伤行为可能与伤害性敏感度缺陷有关。
Fragile X mental retardation is caused by silencing of the gene (FMR1) that encodes the RNA-binding protein (FMRP) that influences translation in neurons. A prominent feature of the human disorder is self-injurious behavior, suggesting an abnormality in pain processing. Moreover, FMRP regulates group I metabotropic glutamate receptor (mGluR1/5)-dependent plasticity, which is known to contribute to nociceptive sensitization. We demonstrate here, using the Fmr1 knock-out (KO) mouse, that FMRP plays an important role in pain processing because Fmr1 KO mice showed (1) decreased (similar to 50%) responses to ongoing nociception (phase 2, formalin test), (2) a 3 week delay in the development of peripheral nerve injury-induced allodynia, and (3) a near absence of wind-up responses in ascending sensory fibers after repetitive C-fiber stimulation. We provide evidence that the behavioral deficits are related to a mGluR1/5- and mammalian target of rapamycin (mTOR)-mediated mechanism because (1) spinal mGluR5 antagonism failed to inhibit the second phase of the formalin test, and we observed a marked reduction in nociceptive response to an intrathecal injection of an mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice; (2) peripheral DHPG injection had no effect in KO mice yet evoked thermal hyperalgesia in wild types; and (3) the mTOR inhibitor rapamycin inhibited formalin- and DHPG-induced nociception in wild-type but not Fmr1 KO mice. These experiments show that translation regulation via FMRP and mTOR is an important feature of nociceptive plasticity. These observations also support the hypothesis that the persistence of self-injurious behavior observed in fragile X mental retardation patients could be related to deficits in nociceptive sensitization.