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

Brain Behav Immun. 2017 Nov;66:94-102. doi: 10.1016/j.bbi.2017.07.008. Epub 2017 Jul 11.


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.

Keywords: Comorbidity; Depression; Hippocampus; Interleukin-1; Kynurenine 3-monooxygenase; Kynurenine pathway; Pain; Psychoneuroimmunology; Quinolinic acid.

MeSH terms

  • Animals
  • Depression / complications
  • Depression / enzymology*
  • Disease Models, Animal
  • Hippocampus / enzymology
  • Hyperalgesia / complications
  • Hyperalgesia / enzymology
  • Interleukin-1 / metabolism
  • Kynurenine 3-Monooxygenase / genetics
  • Kynurenine 3-Monooxygenase / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Microglia / enzymology
  • Neuralgia / complications
  • Neuralgia / enzymology*
  • Neurons / enzymology*
  • Peripheral Nerve Injuries / complications
  • Peripheral Nerve Injuries / enzymology
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Up-Regulation


  • Interleukin-1
  • RNA, Messenger
  • Kynurenine 3-Monooxygenase