Peripheral Nerve Injury Is Associated with Chronic, Reversible Changes in Global DNA Methylation in the Mouse Prefrontal Cortex

Maral Tajerian, Sebastian Alvarado, Magali Millecamps, Pascal Vachon, Cecilia Crosby, M. Catherine Bushnell, Moshe Szyf, Laura S. Stone

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with abnormal behavior and pathological gene expression in the central nervous system. DNA methylation might also be involved in mediating the pathologies associated with chronic pain in the brain. We therefore tested a) whether alterations in DNA methylation are found in the brain long after chronic neuropathic pain is induced in the periphery using the spared nerve injury modal and b) whether these injury-associated changes are reversible by interventions that reverse the pathologies associated with chronic pain. Six months following peripheral nerve injury, abnormal sensory thresholds and increased anxiety were accompanied by decreased global methylation in the PFC and the amygdala but not in the visual cortex or the thalamus. Environmental enrichment attenuated nerve injury-induced hypersensitivity and reversed the changes in global PFC methylation. Furthermore, global PFC methylation correlated with mechanical and thermal sensitivity in neuropathic mice. In summary, induction of chronic pain by peripheral nerve injury is associated with epigenetic changes in the brain. These changes are detected long after the original injury, at a long distance from the site of injury and are reversible with environmental manipulation. Changes in brain structure and cortical function that are associated with chronic pain conditions may therefore be mediated by epigenetic mechanisms.

Original languageEnglish (US)
Article numbere55259
JournalPloS one
Issue number1
StatePublished - Jan 28 2013
Externally publishedYes

Bibliographical note

Funding Information:
The authors wish to declare that this study was funded, in part, from a commercial funder (Eli Lilly Canada Inc). The funding was in the form of an unrestricted research grant and the funder has no influence on the content. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. The authors have declared that no competing interests exist.


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