Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain.
Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain.
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DOI：
10.1523/jneurosci.1473-12.2012
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发表时间：
2012-10-10
期刊：
影响因子：
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通讯作者：
Gereau RW 4th
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文献类型：
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作者：
Crock LW;Kolber BJ;Morgan CD;Sadler KE;Vogt SK;Bruchas MR;Gereau RW 4th
膀胱疼痛综合征是一种使人衰弱的疾病，在美国影响着3 - 6%的女性。多方面的证据表明，中枢神经系统处理过程的改变是慢性膀胱疼痛疾病发展的关键，但对于潜在的细胞、分子和神经元机制知之甚少。利用一种扩张诱导的膀胱疼痛小鼠模型，我们发现杏仁核中央核（CeA）是处理膀胱伤害性感受的神经调节的关键部位。此外，我们证明杏仁核中央核中的代谢型谷氨酸受体5（mGluR5）激活通过增加杏仁核中央核的输出诱导膀胱疼痛敏化。因此，杏仁核中央核中mGluR5的药理激活足以增加对膀胱扩张的反应。另外，杏仁核中央核中mGluR5的药理阻断或病毒介导的条件性缺失减少了对膀胱扩张的反应，这表明杏仁核中央核中的mGluR5对这些反应也是必需的。最后，我们利用杏仁核中央核的光遗传学激活，证明这会导致内脏疼痛反应显著增加。杏仁核中央核对膀胱扩张反应的局部影响与脊髓中细胞外信号调节激酶1/2磷酸化的变化有关。总体而言，这些数据表明mGluR5激活导致杏仁核中央核输出增加，从而驱动膀胱疼痛敏化。
Painful bladder syndrome is a debilitating condition that affects 3–6% of women in the United States. Multiple lines of evidence suggest that changes in central nervous system processing are key to the development of chronic bladder pain conditions, but little is known regarding the underlying cellular, molecular, and neuronal mechanisms. Using a mouse model of distension-induced bladder pain, we found that the central nucleus of the amygdala (CeA) is a critical site of neuromodulation for processing of bladder nociception. Furthermore, we demonstrate that metabotropic glutamate receptor 5 (mGluR5) activation in the CeA induces bladder pain sensitization by increasing CeA output. Thus, pharmacological activation of mGluR5 in the CeA is sufficient to increase the response to bladder distension. Additionally, pharmacological blockade or virally-mediated conditional deletion of mGluR5 in the CeA reduced responses to bladder distention suggesting that mGluR5 in the CeA is also necessary for these responses. Finally, we used optogenetic activation of the CeA and demonstrated that this caused a robust increase in the visceral pain response. The CeA localized effects on responses to bladder distention are associated with changes in extracellular signal regulated kinases 1/2 phosphorylation in the spinal cord. Overall, these data demonstrate that mGluR5 activation leads to increased CeA output that drives bladder pain sensitization.