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.

No abstract

Amyloid-induced microglial activation and neuroinflammation impair central synapses and memory function, although the mechanism remains unclear. Neuroligin 1 (NLGN1), a postsynaptic protein found in central excitatory synapses, governs excitatory synaptic efficacy and plasticity in the brain. Here we found, in rodents, that amyloid fibril-induced neuroinflammation enhanced the interaction between histone deacetylase 2 and methyl-CpG-binding protein 2, leading to suppressed histone H3 acetylation and enhanced cytosine methylation in the Nlgn1 promoter region and decreased NLGN1 expression, underlying amyloid-induced memory deficiency. Manipulation of microglia-associated neuroinflammation modulated the epigenetic modification of the Nlgn1 promoter, hippocampal glutamatergic transmission and memory function. These findings link neuroinflammation, synaptic efficacy and memory, thus providing insight into the pathogenesis of amyloid-associated diseases.

No abstract

The functional involvement of CB2 receptor in neuropathic pain and other neuroinflammatory diseases highlights the potential therapeutic role of drugs acting at the CB2 receptor.