Activation of Extracellular Signal-Regulated Kinase1/2 in the Medial Prefrontal Cortex Contributes to Stress-Induced Hyperalgesia

Stressful stimuli can exacerbate persistent pain disorder. However, the underlying mechanism is still unknown. Here, to reveal the underlying mechanism for stressful stimuli-induced hyperalgesia in chronic pain, we investigated the effect of extracellular signal-regulated kinase1/2 (ERK1/2) activation on pain hypersensitivity using single-prolonged stress (SPS) model, complete Freund's adjuvant (CFA) model and SPS+CFA model. The experimental results revealed significantly reduced paw withdrawal threshold in the SPS, CFA, and SPS+CFA group compared with the control group. However, the increased phosphorylation of ERK1/2 in the medial prefrontal cortex (mPFC) was observed in the SPS- or SPS+CFA-exposed group but not the CFA group compared with control group. There was also a significant increase in mPFC ERK1/2 phosphorylation and mechanical allodynia after SPS+CFA treatment compared to SPS or CFA treatment alone. Furthermore, inhibiting ERK1/2 phosphorylation by microinjection of U0126, a MAPK kinase (MEK) inhibitor, into the mPFC attenuated SPS+CFA- and SPS-but not CFA-induced mechanical allodynia, anxiety-like behavior, and cognitive impairments. These results suggest that the activation of ERK1/2 in the mPFC may contribute to the process of stress-induced cognitive and emotional disorders, leading to an increase in pain sensitivity.