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

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

Author information

1
Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: GOLaumet@mdanderson.org.
2
Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: Wenjun.Zhou@bcm.edu.
3
Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: RDantzer@mdanderson.org.
4
Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: JDEdralin@mdanderson.org.
5
Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: XHuo@mdanderson.org.
6
Bioanalysis and Physiology, Lundbeck Research, Paramus, NJ, USA. Electronic address: dbudac@yahoo.com.
7
Department of Pharmacology, The University of Texas Health Science Center and Audie L. Murphy VA Hospital, South Texas Veteran's Heath Care System, San Antonio, TX, USA. Electronic address: oconnorj@uthscsa.edu.
8
Neuroinflammation Disease Biology Unit, Lundbeck Research USA, Paramus, NJ, USA(3). Electronic address: anna.newyork@gmail.com.
9
Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: CJHeijnen@mdanderson.org.
10
Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: AKavelaars@mdanderson.org.

Abstract

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

PMID:
28709913
PMCID:
PMC5650931
DOI:
10.1016/j.bbi.2017.07.008
[Indexed for MEDLINE]
Free PMC Article

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