Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain.
Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain.
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DOI：
10.1016/j.bbi.2017.07.008
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Kavelaars A
中科院分区：
文献类型：
--
作者：
Laumet G;Zhou W;Dantzer R;Edralin JD;Huo X;Budac DP;O'Connor JC;Lee AW;Heijnen CJ;Kavelaars A
疼痛和抑郁经常同时发生，但潜在的机制尚未阐明。在这里，我们使用小鼠的备用神经损伤(SNI)模型来诱导神经病理性疼痛和抑郁样行为。我们研究了脑内IL-1信号和犬尿氨酸3-单加氧酶(KMO)的活性是否对神经病理性疼痛和抑郁样行为是必需的，KMO是犬尿氨酸代谢成神经毒性NMDA受体激动剂喹啉酸的关键酶。SNI组小鼠对侧大脑IL1b和KMO mRNA表达水平升高。SNI诱导的KMO基因表达增加与对侧海马区KMO蛋白表达增加、喹啉酸增加、犬尿酸减少有关。SNI后KMO蛋白的增加主要发生在海马神经元阳性神经元中，而不是小胶质细胞。SNI后侧脑室注射IL-1RA抑制脑内IL-1信号转导，可阻止强迫游泳实验中KMO基因表达的增加和抑郁样行为。然而，抑制脑内IL-1信号转导对机械性痛觉异常没有影响。此外，脑室内注射KMO抑制剂Ro 61-8048可消除SNI后的抑郁样行为，而不影响机械性痛觉异常。我们首次证明在SNI模型中抑郁样行为的发展需要脑内IL-1信号和神经元KMO的激活，而疼痛不依赖于这一途径。抑制KMO可能是治疗抑郁症的一个有希望的靶点。
Pain and depression often co-occur, but the underlying mechanisms have not been elucidated. Here, we used the spared nerve injury (SNI) model in mice to induce both neuropathic pain and depression-like behavior. We investigated whether brain IL-1 signaling and activity of kynurenine 3-monoxygenase (KMO), a key enzyme for metabolism of kynurenine into the neurotoxic NMDA receptor agonist quinolinic acid, are necessary for comorbid neuropathic pain and depression-like behavior. SNI mice showed increased expression levels of Il1b and Kmo mRNA in the contralateral side of the brain. The SNI-induced increase of Kmo mRNA was associated with increased KMO protein and elevated quinolinic acid and reduced kynurenic acid in the contralateral hippocampus. The increase in KMO-protein in response to SNI mostly took place in hippocampal NeuN-positive neurons rather than microglia. Inhibition of brain IL-1 signaling by intracerebroventricular administration of IL-1RA after SNI prevented the increase in Kmo mRNA and depression-like behavior measured by forced swim test. However, inhibition of brain IL-1 signaling has no effect on mechanical allodynia. In addition, intracerebroventricular administration of the KMO inhibitor Ro 61-8048 abrogated depression-like behavior without affecting mechanical allodynia after SNI. We show for the first time that the development of depression-like behavior in the SNI model requires brain IL-1 signaling and activation of neuronal KMO, while pain is independent of this pathway. Inhibition of KMO may represent a promising target for treating depression.
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影响因子：
3.1
作者：
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