Epigenetic suppression of GAD65 expression mediates persistent pain

Chronic pain is a common neurological disease involving lasting, multifaceted maladaptations from gene modulations to synaptic malfunctions and to emotional disorders. Sustained pathological stimuli in many diseases alter output activities of certain genes through epigenetic modifications, but it is unclear how epigenetic mechanisms operate in the development of chronic pain. We demonstrate here that, in the rat brainstem nucleus raphe magnus, which is important for central mechanisms of chronic pain, persistent inflammatory and neuropathic pain epigenetically suppresses gad65 activities through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in impaired GABA synaptic inhibition. gad65 knockout mice display similar sensitized pain behavior and impaired GABA synaptic function in the brainstem neurons. HDAC inhibitors overwhelmingly increase gad65 activities, restore GABA synaptic function and relieve the sensitized pain behavior, but not in gad65 knockout mice. These findings suggest GAD65 and HDACs as potential therapeutic targets in an epigenetic approach to the treatment of chronic pain.