title: 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: MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Hyangin
authors: H
authors: Kim
authors: Lucy
authors: L
authors: Chen
authors: Grewo
authors: G
authors: Lim
authors: Backil
authors: B
authors: Sung
authors: Shuxing
authors: S
authors: Wang
authors: Michael F
authors: MF
authors: McCabe
authors: Gabriel
authors: G
authors: Rusanescu
authors: Liling
authors: L
authors: Yang
authors: Yinghong
authors: Y
authors: Tian
authors: Jianren
authors: J
authors: Mao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology*; D059350:Chronic Pain / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology*; D015897:Comorbidity; D003863:Depression / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology*; D005260:Female; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6