Chronic Inflammatory Pain Alters Expression of Limbic MAPK Phosphatases.

Brain mechanisms involved in comorbidity between chronic pain conditions and clinical depression are still largely unknown. Our previous studies demonstrated that expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) is both necessary and sufficient for the development of enhanced behavioral emotionality (i.e., depressive- like behaviors) in rodents. Here, we investigated the role of the dual specificity phosphatase (DUSP) gene family, specifically MKP-1, MKP-2 and MKP-3, in limbic brain areas involved in affective pain processing and stress responses. Male rats exposed to 21 days of peripheral inflammatory pain exhibited a robust increase in MKP-1 gene expression within the hippocampus, prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Similar upregulation of hippocampal MKP-1 was also observed in female animals exposed to the same 21-day paradigm. However, the overall pattern of MKP-1 expression across various limbic areas differed in females exposed to chronic pain, as significant downregulation of MKP-1 was observed in the ACC, while no changes were detected within the PFC. Furthermore, similar limbic region-specific variances in pain-related dysregulation were also observed for MKP-2 and MKP-3. Finally, pain-induced upregulation of limbic MKP-1 was blocked by low-dose ketamine treatment (10 mg/kg) previously shown to produce rapid antidepressant effects in rodents. Overall, the results of this study suggest that chronic pain activates specific MKPs/DUSPs within limbic brain regions, which may underlie previously reported pain-related decreases in MAPK signaling. Thus, dysregulation of MKP-1 and other DUSP genes may play an important role in the development of mood disorders associated with chronic pain state.