title: Peripheral indoleamine 2,3-dioxygenase 1 is required for comorbid depression-like behavior but does not contribute to neuropathic pain in mice.
abstract: Chronic pain frequently co-occurs with major depressive disorder but the mechanisms are poorly understood. We investigated the contribution of indoleamine 2,3-dioxygenase-1 (IDO1), a rate-limiting enzyme in the conversion of tryptophan to neurotoxic metabolites, to this comorbidity using the spared nerve injury (SNI) model of neuropathic pain in mice. SNI resulted in unilateral mechanical allodynia, reduced social interaction, and increased immobility in the forced swim test without changes in locomotor activity. These findings indicate SNI-induced pain and comorbid depression-like behavior. These behavioral responses were accompanied by increases in plasma kynurenine/tryptophan ratios and increased expression of Ido1 and Il1b mRNA in the liver. Interestingly, SNI did not induce detectable changes in spinal cord or brain Ido1 mRNA levels. SNI was associated with spinal cord inflammatory activity as evidenced by increased Il1b mRNA expression. The SNI-induced increase of liver Ido1and Il1b mRNA was abrogated by intrathecal administration of the IL-1 inhibitor IL-1RA. Intrathecal IL-1RA also inhibited both mechanical allodynia and depression-like behavior. We also show that Ido1 is required for the development of depression-like behavior because Ido1(-/-) mice do not develop increased immobility in the forced swim test or decreased social exploration in response to SNI. Mechanical allodynia was similar in WT and Ido1(-/-) mice. In conclusion, our findings show for the first time that neuropathic pain is associated with an increase of Ido1 in liver, but not brain, downstream of spinal cord IL-1β signaling and that Ido1 mediates comorbid depression. Moreover, comorbidity of neuropathic pain and depression are only partially mediated by a common mechanism because mechanical hyperalgesia develops independently of Ido1.
authors: Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Wenjun
authors: W
authors: Zhou
authors: Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Robert
authors: R
authors: Dantzer
authors: Bioanalysis and Physiology, Lundbeck Research, Paramus, NJ 07652, USA.
authors: David P
authors: DP
authors: Budac
authors: Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Adam K
authors: AK
authors: Walker
authors: Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institute of Acupuncture Research, Fudan University, Shanghai 200032, China.
authors: Qi-Liang
authors: QL
authors: Mao-Ying
authors: Neuroinflammation Disease Biology Unit, Lundbeck Research USA, Paramus, NJ 07652, USA.
authors: Anna W
authors: AW
authors: Lee
authors: Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Cobi J
authors: CJ
authors: Heijnen
authors: Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: AKavelaars@mdanderson.org.
authors: Annemieke
authors: A
authors: Kavelaars
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D003863:Depression / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009437:Neuralgia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase
keywords: Brain; Depression; Indoleamine 2,3-dioxygenase 1; Interleukin-1; Liver; Neuropathic pain
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