Chronic Inflammatory Pain Alters Expression of Limbic MAPK Phosphatases.

Chronic pain activates specific MKP/DUSP genes in limbic brain regions, which may contribute to the development of depression. Male rats exposed to 21 days of inflammatory pain showed increased MKP-1 expression in the hippocampus, prefrontal cortex, and anterior cingulate cortex. Female rats also showed increased hippocampal MKP-1, but MKP-1 decreased in the anterior cingulate cortex and did not change in the prefrontal cortex. Similar region-specific changes occurred for MKP-2 and MKP-3. Low-dose ketamine (10 mg/kg) blocked pain-induced upregulation of limbic MKP-1. The findings suggest dysregulation of these genes may underlie mood disorders associated with chronic pain.

Study at a glance

Abstract

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.