An epigenetic hypothesis for the genomic memory of pain

Sebastian Alvarado, Maral Tajerian, Matthew Suderman, Ziv Machnes, Stephanie Pierfelice, Magali Millecamps, Laura S. Stone, Moshe Szyf

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Chronic pain is accompanied with long-term sensory, affective and cognitive disturbances. What are the mechanisms that mediate the long-term consequences of painful experiences and embed them in the genome? We hypothesize that alterations in DNA methylation, an enzymatic covalent modification of cytosine bases in DNA, serve as a “genomic” memory of pain in the adult cortex. DNA methylation is an epigenetic mechanism for long-term regulation of gene expression. Neuronal plasticity at the neuroanatomical, functional, morphological, physiological and molecular levels has been demonstrated throughout the neuroaxis in response to persistent pain, including in the adult prefrontal cortex (PFC). We have previously reported widespread changes in gene expression and DNA methylation in the PFC many months following peripheral nerve injury. In support of this hypothesis, we show here that up-regulation of a gene involved with synaptic function, Synaptotagmin II (syt2), in the PFC in a chronic pain model is associated with long-term changes in DNA methylation. The challenges of understanding the contributions of epigenetic mechanisms such as DNA methylation within the PFC to pain chronicity and their therapeutic implications are discussed.

Original languageEnglish (US)
Article number88
JournalFrontiers in Cellular Neuroscience
StatePublished - Mar 24 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 Alvarado, Tajerian, Suderman, Machnes, Pierfelice, Millecamps, Stone and Szyf.


  • Chronic pain
  • DNA methylation
  • Epigenetics
  • Neuropathy
  • Neuroplasticity
  • Prefrontal cortex
  • Synaptotagmin


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