Editors' Choicechronic Pain

Epigenetic Modulation of CNS Pathways: What a Pain!

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Science Translational Medicine  07 Dec 2011:
Vol. 3, Issue 112, pp. 112ec198
DOI: 10.1126/scitranslmed.3003537

Chronic pain affects nearly 10% of the world’s population, and symptoms are only marginally responsive to traditional analgesics. This unmet clinical need stems in large part from a poor understanding of the pathways that underlie chronic pain, limiting the development of targeted therapies. Now, Zhang and colleagues have investigated whether chronic pain modulates epigenetic architecture and gene expression in the nucleus raphe magnus—a key brain region for the integration and maintenance of pain signals.

In order to pack nearly 2 meters of DNA into cells less than 100 micrometers in diameter, DNA is tightly wound around histone proteins. Covalent modification of these histone proteins can alter gene expression: Acetylation loosens the interaction between positively charged histone proteins and negatively charged DNA, allowing transcription. Using a rat model of hyperalgesia, Zhang et al. found that chronic but not acute pain led to global histone hyperacetylation in the nucleus raphe magnus and an associated loss of inhibitory GABAergic synaptic function. The neurotransmitter γ-aminobutyric acid (GABA) is synthesized in presynaptic terminals by the enzyme GAD65, so the authors were particularly interested in the fact that chronic pain was associated with decreased acetylation of histone 3 and increased recruitment of histone deacetylase enzymes at the GAD65 promoter. Moreover, compounds that nonspecifically inhibited histone deacetylase activity reversed these changes and effectively treated the rats’ chronic pain.

Taken together, Zhang and colleagues suggest that GAD65 transcription is silenced after loss of histone acetylation at its promoter. Decreased GAD65 results in decreased GABAergic action to dampen pain signals. Although further study is needed in humans, these findings reveal an epigenetic component to chronic pain and offer hope of better therapies for the nearly 60 million individuals worldwide who suffer from this disorder.

Z. Zhang et al., Epigenetic suppression of GAD65 expression mediates persistent pain. Nat. Med. 17, 1448–1456 (2011). [Abstract]

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