Epigenetic suppression of GAD65 expression mediates persistent pain

Nat Med. 2011 Oct 9;17(11):1448-55. doi: 10.1038/nm.2442.


Chronic pain is a common neurological disease involving lasting, multifaceted maladaptations ranging from gene modulation to synaptic dysfunction and emotional disorders. Sustained pathological stimuli in many diseases alter the output activities of certain genes through epigenetic modifications, but it is unclear how epigenetic mechanisms operate in the development of chronic pain. We show 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 Gad2 (encoding glutamic acid decarboxylase 65 (GAD65)) transcription through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in impaired γ-aminobutyric acid (GABA) synaptic inhibition. Gad2 knockout mice showed sensitized pain behavior and impaired GABA synaptic function in their brainstem neurons. In wild-type but not Gad2 knockout mice, HDAC inhibitors strongly increased GAD65 activity, restored GABA synaptic function and relieved sensitized pain behavior. These findings suggest GAD65 and HDACs as potential therapeutic targets in an epigenetic approach to the treatment of chronic pain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chronic Disease
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Enzymologic*
  • Glutamate Decarboxylase / genetics*
  • Glutamate Decarboxylase / metabolism*
  • Histone Deacetylase Inhibitors / therapeutic use
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Pain / drug therapy
  • Pain / physiopathology*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • Synapses / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • Histone Deacetylase Inhibitors
  • Histones
  • gamma-Aminobutyric Acid
  • Histone Deacetylases
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2