Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression
Hyangin Kim, … , Yinghong Tian, Jianren Mao
Hyangin Kim, … , Yinghong Tian, Jianren Mao
Published July 2, 2012
Citation Information: J Clin Invest. 2012;122(8):2940-2954. https://doi.org/10.1172/JCI61884.
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Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression

Abstract

Pain and depression are frequently comorbid disorders, but the mechanism underlying this association is unknown. Here, we report that brain indoleamine 2,3-dioxygenase 1 (IDO1), 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 IDO1-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.

Authors

Hyangin Kim, Lucy Chen, Grewo Lim, Backil Sung, Shuxing Wang, Michael F. McCabe, Gabriel Rusanescu, Liling Yang, Yinghong Tian, Jianren Mao

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Figure 6

Effect of IDO-knockout on behavioral changes.

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Effect of IDO-knockout on behavioral changes. (A) IDO-knockout mice had ...
(A) IDO-knockout mice had no Ido1 mRNA expression (real-time PCR) in the hippocampus. Ido1 mRNA expression in wild-type mice was increased in the hippocampus after the CFA injection. Mean ± SEM, n = 6, *P < 0.05 compared with sham control. (B and C) Mechanical allodynia (B) and thermal hyperalgesia (C) on the ipsilateral hind paw were attenuated in IDO-knockout mice. (D and E) IDO-knockout also reduced the immobility time in FST (D) and the decreased frequency in OFT (E) in the same mice with CFA-induced arthritis. Mean ± SEM, n = 6, *P < 0.05 compared with wild-type mice. (F and G) Intraperitoneal injection of acetaminophen (APAP; 100 mg/kg), given once on day 14, attenuated ipsilateral mechanical allodynia (F) and thermal hyperalgesia (G) when mice were examined at 1 hour after the injection. Mean ± SEM, n = 6, *P < 0.05 compared with vehicle control. (H) The same APAP treatment did not change the immobility time in FST in the same rats. (I) Contralateral hippocampal Ido1 mRNA expression was increased after the CFA injection, which was not reversed by a single APAP treatment. Data in H and I are mean ± SEM, n = 6, *P < 0.05 compared with vehicle control.