Peripheral indoleamine 2,3-dioxygenase 1 is required for comorbid depression-like behavior but does not contribute to neuropathic pain in mice.
Peripheral indoleamine 2,3-dioxygenase 1 is required for comorbid depression-like behavior but does not contribute to neuropathic pain in mice.
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DOI：
10.1016/j.bbi.2015.01.013
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发表时间：
2015-05
影响因子：
15.1
通讯作者：
Kavelaars, Annemieke
中科院分区：
文献类型：
--
作者：
Zhou, Wenjun;Dantzer, Robert;Budac, David P.;Walker, Adam K.;Mao-Ying, Qi-Liang;Lee, Anna W.;Heijnen, Cobi J.;Kavelaars, Annemieke
慢性疼痛经常与重度抑郁症同时发生，但其机制尚不清楚。我们研究了吲哚胺-2，3-双加氧酶-1（IDO 1）的贡献，IDO 1是色氨酸转化为神经毒性代谢产物的限速酶，使用小鼠神经病理性疼痛的备用神经损伤（SNI）模型对此并发症的贡献。SNI导致单侧机械性异常性疼痛，减少社会互动，并增加不动性在强迫游泳试验中没有改变自发活动。这些发现表明SNI诱导的疼痛和共病抑郁样行为。这些行为反应伴随着血浆犬尿氨酸/色氨酸比值的增加和肝脏中Ido 1和Il 1b mRNA表达的增加。有趣的是，SNI后脊髓或脑Ido 1 mRNA水平没有引起可检测的变化。SNI与脊髓炎性活动相关，这一点通过Il 1b mRNA表达的增加来证明。鞘内注射IL-1抑制剂IL-1 RA可抑制SNI诱导的肝Ido 1和Il 1b mRNA表达的增加。鞘内IL-1 RA也抑制机械异常性疼痛和抑郁样行为。我们还表明，Ido 1是抑郁样行为的发展所必需的，因为Ido 1-/-小鼠在强迫游泳测试中没有增加不动性，也没有减少对SNI的社会探索。WT和Ido 1-/-小鼠的机械性异常性疼痛相似。总之，我们的研究结果首次表明，神经性疼痛与脊髓IL-1β信号下游肝脏而非大脑中Ido 1的增加相关，并且Ido 1介导了共病抑郁症。此外，共病的神经性疼痛和抑郁症，只有部分介导的共同机制，因为机械痛觉过敏的发展独立于Ido 1。
Chronic pain frequently co-occurs with major depressive disorder but the mechanisms are poorly understood. We investigated the contribution of indoleamine-2,3-dioxygenase-1 (IDO1), a rate-limiting enzyme in the conversion of tryptophan to neurotoxic metabolites to this comorbidity using the spared nerve injury (SNI) model of neuropathic pain in mice. SNI resulted in unilateral mechanical allodynia, reduced social interaction, and increased immobility in the forced swim test without changes in locomotor activity. These findings indicate SNI-induced pain and comorbid depression-like behavior. These behavioral responses were accompanied by increases in plasma kynurenine/tryptophan ratios and increased expression of Ido1 and Il1b mRNA in the liver. Interestingly, SNI did not induce detectable changes in spinal cord or brain Ido1 mRNA levels after SNI. SNI was associated with spinal cord inflammatory activity as evidenced by increased Il1b mRNA expression. The SNI-induced increase of liver Ido1and Il1b mRNA was abrogated by intrathecal administration of the IL-1 inhibitor IL-1RA. Intrathecal IL-1RA also inhibited both mechanical allodynia and depression-like behavior. We also show that Ido1 is required for the development of depression-like behavior because Ido1-/- mice do not develop increased immobility in the forced swim test or decreased social exploration in response to SNI. Mechanical allodynia was similar in WT and Ido1-/- mice. In conclusion, our findings show for the first time that neuropathic pain is associated with an increase of Ido1 in liver, but not brain, downstream of spinal cord IL-1β signaling and that Ido1 mediates co-morbid depression. Moreover, comorbidity of neuropathic pain and depression are only partially mediated by a common mechanism because mechanical hyperalgesia develops independently of Ido1.
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DOI：
10.1523/jneurosci.3295-09.2010
发表时间：
2010-01-13
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Clark AK;Staniland AA;Marchand F;Kaan TK;McMahon SB;Malcangio M
通讯作者：
Malcangio M
影响因子：
9.3
作者：
Lawson MA;Parrott JM;McCusker RH;Dantzer R;Kelley KW;O'Connor JC
通讯作者：
O'Connor JC
影响因子：
7.4
作者：
MAGNI, G;MARCHETTI, M;LUCHINI, SR
通讯作者：
LUCHINI, SR
影响因子：
15.9
作者：
Kim, Hyangin;Chen, Lucy;Mao, Jianren
通讯作者：
Mao, Jianren
影响因子：
11
作者：
O'Connor, J. C.;Lawson, M. A.;Dantzer, R.
通讯作者：
Dantzer, R.