118. Indoleamine 2,3 dioxygenase (IDO1) is a key regulator of depressive-like behavior but not of mechanical hyperalgesia in the spared nerve injury model of neuropathic pain

Abstract

Chronic pain and depression frequently co-occur. We used the spared nerve injury (SNI) model of neuropathic pain in mice to explore the neuroimmune mechanism of the comorbidity of neuropathic pain and depressive-like behaviors. SNI induces both mechanical hyperalgesia and depressive-like behavior assessed as reduced social interaction and increased immobility in the forced swim test. These behavioral responses were associated with increased IL-1beta mRNA in the contralateral frontal cortex, ipsilateral lumbar dorsal horn and liver. Daily intrathecal injection of IL-1RA inhibited mechanical hyperalgesia and depressive-like behavior. IL-1RA also abrogated SNI-induced increases IL-1beta and in microglial activation. Peripheral inflammation-induced depressive-like behavior is mediated via increased expression of the indoleamine 2,3-dioxygenase1(IDO1), which catalyzes the conversion of tryptophan to kynurenine. SNI surgery increases the kynurenine/tryptophan ratio in plasma. Concomitantly, IDO1 mRNA expression was increased in liver but not in brain or spinal cord. Intrathecal IL-1RA prevented the increase in liver IDO1mRNA in SNI mice. Importantly, genetic deletion of IDO1 prevented the SNI-induced depressive like behaviors without affecting the pain response. Spinal cord IL-1β signaling is key for both SNI-induced pain and depressive-like behaviors. In contrast, IDO1 activity only contributes to SNI-induced depressive behaviors. Our finding that SNI induces an increase in IDO1 in the liver and not in the brain indicates that IDO controls SNI-induced depressive-like behavior through a peripheral-to-brain pathway. Supported by NIH grants NS083939 and NS074999.