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Epigenetic suppression of GAD65 expression mediates persistent pain

Abstract

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.

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Figure 1: Persistent inflammatory pain induces time-dependent hyperacetylation of histones H3 and H4.
Figure 2: Persistent pain decreases GABAergic synaptic function by inhibiting presynaptic GABA release.
Figure 3: Persistent pain induces histone hypoacetylation at the Gad2 promoter.
Figure 4: Persistent inflammatory and neuropathic pain reduces GAD65 expression.
Figure 5: Histone hyperacetylation overcomes pain-induced reduction in GABA synaptic function through GAD65.
Figure 6: HDAC inhibitors relieve pain through GAD65.

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Acknowledgements

This work was supported by US National Institutes of Health National Institute on Drug Abuse grants DA023069 and DA027541. We thank L. Gao of Baylor College of Medicine for his generous gifts of GAD67 primers.

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Z.Z. designed the studies, performed most of the experiments and wrote a draft manuscript. Y.-Q.C., F.Z. and B.B. conducted some of the molecular and behavioral experiments. Z.Z.P. was involved in the overall designs of the project and individual experiments, the data analyses and the writing of the final manuscript.

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Correspondence to Zhizhong Z Pan.

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The authors declare no competing financial interests.

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Zhang, Z., Cai, YQ., Zou, F. et al. Epigenetic suppression of GAD65 expression mediates persistent pain. Nat Med 17, 1448–1455 (2011). https://doi.org/10.1038/nm.2442

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