title: An epigenetic hypothesis for the genomic memory of pain.
abstract: 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.
authors: Department of Biology, Stanford University Palo Alto, CA, USA ; Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University Montréal, QC, Canada ; Sackler Program for Epigenetics and Developmental Psychobiology, McGill University Montréal, QC, Canada.
authors: Sebastian
authors: S
authors: Alvarado
authors: Department of Anesthesiology, Stanford University Palo Alto, CA, USA ; Integrated Program in Neuroscience, McGill University Montréal, QC, Canada ; Alan Edwards Centre for Research on Pain, McGill University Montréal, QC, Canada.
authors: Maral
authors: M
authors: Tajerian
authors: Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University Montréal, QC, Canada ; Sackler Program for Epigenetics and Developmental Psychobiology, McGill University Montréal, QC, Canada.
authors: Matthew
authors: M
authors: Suderman
authors: Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University Montréal, QC, Canada ; Sackler Program for Epigenetics and Developmental Psychobiology, McGill University Montréal, QC, Canada.
authors: Ziv
authors: Z
authors: Machnes
authors: Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University Montréal, QC, Canada ; Sackler Program for Epigenetics and Developmental Psychobiology, McGill University Montréal, QC, Canada.
authors: Stephanie
authors: S
authors: Pierfelice
authors: Alan Edwards Centre for Research on Pain, McGill University Montréal, QC, Canada ; Faculty of Dentistry, McGill University Montréal, QC, Canada.
authors: Magali
authors: M
authors: Millecamps
authors: Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University Montréal, QC, Canada ; Integrated Program in Neuroscience, McGill University Montréal, QC, Canada ; Alan Edwards Centre for Research on Pain, McGill University Montréal, QC, Canada ; Faculty of Dentistry, McGill University Montréal, QC, Canada ; Department of Anesthesiology, Anesthesia Research Unit, Faculty of Medicine, McGill University Montréal, QC, Canada.
authors: Laura S
authors: LS
authors: Stone
authors: Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University Montréal, QC, Canada ; Sackler Program for Epigenetics and Developmental Psychobiology, McGill University Montréal, QC, Canada ; Integrated Program in Neuroscience, McGill University Montréal, QC, Canada.
authors: Moshe
authors: M
authors: Szyf
keywords: DNA methylation; chronic pain; epigenetics; neuropathy; neuroplasticity; prefrontal cortex; synaptotagmin