HDAC4 regulates GR signaling Contributes to Stress-Induced Hyperalgesia in the Medial Prefrontal Cortex

“Stress-induced hyperalgesia (SIH)” is a phenomenon that stress can lead to an increase in pain sensitivity. Recent findings showed that epigenetic mechanisms have been known to play fundamental roles in stress and pain. Histone acetylation is an outstanding epigenetic feature that is changed in numerous stress-related disease situations. However, epigenetic mechanism for the control of SIH is not well known. We investigated the effect of histone acetylationon pain hypersensitivity on SPS (single-prolonged stress) + CFA (complete Freund’s adjuvant) model. Here, we show that the glucocorticoid receptor (GR) is regulated by histone deacetylases 4 (HDAC4) on stress-induced hyperalgesia and the paw withdrawal threshold in the SPS+CFA group dropped significantly compared with the control group. HDAC4-expressing neurons in the medial prefrontal cortex (mPFC) were increased in the SPS+CFA-exposed group compared with CFA-exposed group. Inhibiting HDAC4 by microinjection of sodium butyrate into the mPFC could disrupting glucocorticoid receptor (GR) signaling pathway, lowered SPS+CFA-caused mechanical allodynia and alleviated anxiety-like behavior. Together, our studies suggest that HDAC inhibitors may involve in the process of stress-induced anxiety-like behavior, amplifying the sensitivity to pain.