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Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression

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Science Signaling  21 Mar 2017:
Vol. 10, Issue 471, eaaj1549
DOI: 10.1126/scisignal.aaj1549

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Molecular links between pain, stress, and depression

Chronic stress or pain is associated with the development of depression. Mouse models suggest that chronic pain from nerve injury leads to the onset of depression-like behaviors. Descalzi et al. examined gene expression changes in the brain in mouse models of nerve injury– or chronic stress–induced depression. They found some common changes in the expression of genes encoding signaling pathway components (including those involved in inflammatory signaling) that also occur in patients with depression, anxiety, and pain. Analysis of knockout mice suggested that the molecular changes may be the result of global changes in chromatin acetylation. The findings not only identify molecular links between pain, stress, and depression but also provide a resource for further investigation and potential therapeutic development.


Neuropathic pain is a complex chronic condition characterized by various sensory, cognitive, and affective symptoms. A large percentage of patients with neuropathic pain are also afflicted with depression and anxiety disorders, a pattern that is also seen in animal models. Furthermore, clinical and preclinical studies indicate that chronic pain corresponds with adaptations in several brain networks involved in mood, motivation, and reward. Chronic stress is also a major risk factor for depression. We investigated whether chronic pain and stress affect similar molecular mechanisms and whether chronic pain can affect gene expression patterns that are involved in depression. Using two mouse models of neuropathic pain and depression [spared nerve injury (SNI) and chronic unpredictable stress (CUS)], we performed next-generation RNA sequencing and pathway analysis to monitor changes in gene expression in the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC), and the periaqueductal gray (PAG). In addition to finding unique transcriptome profiles across these regions, we identified a substantial number of signaling pathway–associated genes with similar changes in expression in both SNI and CUS mice. Many of these genes have been implicated in depression, anxiety, and chronic pain in patients. Our study provides a resource of the changes in gene expression induced by long-term neuropathic pain in three distinct brain regions and reveals molecular connections between pain and chronic stress.

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