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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Research Article Neuroscience

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 9

Role of IL-6 signaling in hippocampal IDO expression and behavioral changes.

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Role of IL-6 signaling in hippocampal IDO expression and behavioral chan...
(A–D) Microinjection of an IL-6 antiserum (IL-6 Ab; 0.5 μg/d; once daily for 7 days) into the hippocampus contralateral to the hind paw with CFA-induced arthritis attenuated mechanical allodynia (A) and thermal hyperalgesia (B) on the ipsilateral hind paw, without a change in nociceptive threshold in sham rats (data not shown). The same IL-6 antiserum microinjection regimen concurrently improved depressive behavior in FST (C) and prevented the hippocampal IDO1 upregulation (D) in these same rats. Day 0, baseline (naive rats); Ab-1 and Ab-7, samples taken on day 1 and day 7 from Wistar rats treated with IL-6 antiserum; V-1 and V-7, samples taken on day 1 and day 7 from Wistar rats treated with control serum. β-Actin was used as loading control. Mean ± SEM, n = 6, *P < 0.05 compared with vehicle (control serum). (E–H) Microinjection of exogenous IL-6 (0.1 μg/0.5 μl; once daily for 7 days) into the left hippocampus of naive rats (without CFA injection) induced mechanical allodynia (E) and thermal hyperalgesia (F) on the right hind paw. The same IL-6 microinjection regimen concurrently induced depressive behavior in FST (G) and upregulated hippocampal Ido1 mRNA expression (H) in these same rats. The effects from the intra-hippocampal microinjection of IL-6 were blocked when IL-6 was co-administered with AG490 (a JAK/STAT inhibitor; 5 μg/0.5 μl) for 7 days. Mean ± SEM, n = 4–5, *P < 0.05 compared with vehicle control.