Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression
Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression
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DOI：
10.1172/jci61884
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发表时间：
2012-08-01
影响因子：
15.9
通讯作者：
Mao, Jianren
中科院分区：
文献类型：
--
作者：
Kim, Hyangin;Chen, Lucy;Mao, Jianren
疼痛和抑郁症是常见的共病性疾病，但这种关联的机制尚不清楚。在这里，我们报告说，脑吲哚胺2，3-双加氧酶1（ID 01），色氨酸代谢的限速酶，在这种并发症中起着关键作用。我们发现，慢性疼痛大鼠抑郁行为和IDO 1在双侧海马上调。IDO 1的上调导致双侧海马中犬尿氨酸/色氨酸比率增加和5-羟色胺/色氨酸比率降低。我们观察到升高的血浆IDO活性的患者疼痛和抑郁症，以及在大鼠与快感缺乏引起的慢性社会压力。除了体外实验之外，在大鼠中海马内施用IL-6也证明IL-6通过JAK/STAT途径诱导IDO 1表达。此外，Ido 1基因敲除或海马IDO 1活性的药理学抑制减弱了伤害性和抑郁行为。这些结果揭示了ID 01介导的调节机制的基础上的并发症的疼痛和抑郁症，并建议一个新的策略，同时治疗这两种情况通过调制大脑IDO 1活性。
Pain and depression are frequently comorbicl disorders, but the mechanism underlying this association is unknown. Here, we report that brain indoleamine 2,3-dioxygenase 1 (ID01), a rate-limiting enzyme in tryptophan metabolism, plays a key role in this comorbidity. We found that chronic pain in rats induced depressive behavior and IDO1 upregulation in the bilateral hippocampus. Upregulation of IDO1 resulted in the increased kynurenine/tryptophan ratio and decreased serotonin/tryptophan ratio in the bilateral hippocampus. We observed elevated plasma IDO activity in patients with both pain and depression, as well as in rats with anhedonia induced by chronic social stress. Intra-hippocampal administration of IL-6 in rats, in addition to in vitro experiments, demonstrated that IL-6 induces IDO1 expression through the JAK/STAT pathway. Further, either Ido1 gene knockout or pharmacological inhibition of hippocampal IDO1 activity attenuated both nociceptive and depressive behavior. These results reveal an ID01-mediated regulatory mechanism underlying the comorbidity of pain and depression and suggest a new strategy for the concurrent treatment of both conditions via modulation of brain IDO1 activity.