“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.

“压力引起的痛觉过敏（SIH）”是一种压力会导致疼痛敏感性增加的现象。众所周知，表观遗传机制在压力和疼痛中发挥着重要作用。组蛋白乙酰化是一种表观遗传特征，在许多与压力相关的疾病情况下都会发生变化。然而，SIH 的表观遗传机制尚不清楚。我们使用 SPS（单一延长应激）+ CFA（完全弗氏佐剂）模型研究了组蛋白乙酰化对疼痛超敏反应的影响。我们发现糖皮质激素受体 (GR)-pERK-pCREB-Fos 信号通路在应激性痛觉过敏中上调，与 SPS 或 CFA 组相比，SPS + CFA 组的缩爪阈值显着下降。与 CFA 暴露或 SPS 暴露组相比，SPS + CFA 暴露组中内侧前额叶皮层 (mPFC) 中表达组蛋白去乙酰化酶 4 (HDAC4) 的神经元增加。并且我们表明，应激诱导的痛觉过敏的影响通过 GR 的可逆乙酰化 (HDAC4) 受到严格调节。通过将丁酸钠微注射到 mPFC 中抑制 HDAC4 可以破坏糖皮质激素受体 (GR) 信号通路，从而降低 SPS + CFA 引起的机械性异常性疼痛并减轻焦虑样行为。总之，我们的研究表明 HDAC 抑制剂可能参与应激诱导的痛觉过敏过程。通过将丁酸钠微注射到 mPFC 中抑制 HDAC4 可以破坏糖皮质激素受体 (GR) 信号通路，从而降低 SPS + CFA 引起的机械性异常性疼痛并减轻焦虑样行为。总之，我们的研究表明 HDAC 抑制剂可能参与应激诱导的痛觉过敏过程。通过将丁酸钠微注射到 mPFC 中抑制 HDAC4 可以破坏糖皮质激素受体 (GR) 信号通路，从而降低 SPS + CFA 引起的机械性异常性疼痛并减轻焦虑样行为。总之，我们的研究表明 HDAC 抑制剂可能参与应激诱导的痛觉过敏过程。