Activation of HDAC4 and GR signaling contributes to stress-induced hyperalgesia in the medial prefrontal cortex of rats.

"Stress-induced hyperalgesia (SIH)" is a phenomenon that stress can lead to an increase in pain sensitivity. Epigenetic mechanisms have been known to play fundamental roles in stress and pain. Histone acetylation is an epigenetic feature that is changed in numerous stress-related disease situations. However, epigenetic mechanism for SIH is not well known. We investigated the effect of histone acetylation on pain hypersensitivity using SPS (single-prolonged stress) + CFA (complete Freund's adjuvant) model. We showed that the glucocorticoid receptor (GR)-pERK-pCREB-Fos signaling pathway was upregulated on stress-induced hyperalgesia and the paw withdrawal threshold in the SPS + CFA group dropped significantly compared with the SPS or CFA group. Histone deacetylases 4 (HDAC4)-expressing neurons in the medial prefrontal cortex (mPFC) were increased in the SPS + CFA-exposed group compared with CFA-exposed or SPS-exposed group. And we showed that the effects of stress-induced hyperalgesia were critically regulated via reversible acetylation (HDAC4) of the GR. Inhibiting HDAC4 by microinjection of sodium butyrate into the mPFC could disrupt glucocorticoid receptor (GR) signaling pathway, which lowered SPS + CFA-caused mechanical allodynia and alleviated anxiety-like behavior. Together, our studies suggest that HDAC inhibitors might involve in the process of stress-induced hyperalgesia.