Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain

• Published in: Brain, behavior, and immunity Vol. 66; pp. 94 - 102
• Main Authors: Laumet, Geoffroy, Zhou, Wenjun, Dantzer, Robert, Edralin, Jules D., Huo, XiaoJiao, Budac, David P., O'Connor, Jason C., Lee, Anna W., Heijnen, Cobi J., Kavelaars, Annemieke
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.11.2017
• Subjects: Animals; Comorbidity; Depression; Depression - complications; Depression - enzymology; Disease Models, Animal; Hippocampus; Hippocampus - enzymology; Hyperalgesia - complications; Hyperalgesia - enzymology; Interleukin-1; Interleukin-1 - metabolism; Kynurenine 3-monooxygenase; Kynurenine 3-Monooxygenase - genetics; Kynurenine 3-Monooxygenase - metabolism; Kynurenine pathway; Male; Mice, Inbred C57BL; Microglia - enzymology; Neuralgia - complications; Neuralgia - enzymology; Neurons - enzymology; Pain; Peripheral Nerve Injuries - complications; Peripheral Nerve Injuries - enzymology; Psychoneuroimmunology; Quinolinic acid; RNA, Messenger - metabolism; Signal Transduction; Up-Regulation; KYN; KYNA; Interleukin-1; IL; Comorbidity; FST; HAAO; Depression; 3-HK; Psychoneuroimmunology; KMO; SNI; RA; QA; Pain; IDO; KYNU; i.c.v; NMDA; Kynurenine 3-monooxygenase; Quinolinic acid; Hippocampus; Kynurenine pathway
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2017.07.008

•Nerve injury induces depression and upregulates kynurenine 3-monoxygenase (KMO) expression and activity.•KMO is upregulated in neurons in the contralateral hippocampus and not in microglia.•Upregulation of KMO is downstream of cerebral interleukin-1 signaling.•Inhibition of brain KMO reverses depression but not allodynia after nerve injury. Pain and depression often co-occur, but the underlying mechanisms have not been elucidated. Here, we used the spared nerve injury (SNI) model in mice to induce both neuropathic pain and depression-like behavior. We investigated whether brain interleukin (IL)-1 signaling and activity of kynurenine 3-monoxygenase (KMO), a key enzyme for metabolism of kynurenine into the neurotoxic NMDA receptor agonist quinolinic acid, are necessary for comorbid neuropathic pain and depression-like behavior. SNI mice showed increased expression levels of Il1b and Kmo mRNA in the contralateral side of the brain. The SNI-induced increase of Kmo mRNA was associated with increased KMO protein and elevated quinolinic acid and reduced kynurenic acid in the contralateral hippocampus. The increase in KMO-protein in response to SNI mostly took place in hippocampal NeuN-positive neurons rather than microglia. Inhibition of brain IL-1 signaling by intracerebroventricular administration of IL-1 receptor antagonist after SNI prevented the increase in Kmo mRNA and depression-like behavior measured by forced swim test. However, inhibition of brain IL-1 signaling has no effect on mechanical allodynia. In addition, intracerebroventricular administration of the KMO inhibitor Ro 61-8048 abrogated depression-like behavior without affecting mechanical allodynia after SNI. We show for the first time that the development of depression-like behavior in the SNI model requires brain IL-1 signaling and activation of neuronal KMO, while pain is independent of this pathway. Inhibition of KMO may represent a promising target for treating depression.