An epigenetic hypothesis for the genomic memory of pain.

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

doi:10.3389/fncel.2015.00088

Sebastian Alvarado, Magali Millecamps + Show 6 more

Open Access

https://doi.org/10.3389/fncel.2015.00088

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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.

Highlights

An epigenetic hypothesis for the genomic memory of painSebastian Alvarado 1,2,3†, Maral Tajerian 4,5,6†, Matthew Suderman 2,3, Ziv Machnes 2,3, Stephanie Pierfelice 2,3, Magali Millecamps 6,7, Laura S
Chronic pain is accompanied with long-term sensory, affective and cognitive disturbances
In support of this hypothesis, we show here that up-regulation of a gene involved with synaptic function, Synaptotagmin II, in the prefrontal cortex (PFC) in a chronic pain model is associated with long-term changes in DNA methylation

Summary

An epigenetic hypothesis for the genomic memory of pain

Sebastian Alvarado 1,2,3†, Maral Tajerian 4,5,6†, Matthew Suderman 2,3, Ziv Machnes 2,3, Stephanie Pierfelice 2,3, Magali Millecamps 6,7, Laura S. Studies in rodent models of chronic pain have demonstrated pain-related modifications in areas including the hippocampus, amygdala, perirhinal cortex, and prefrontal cortex (PFC; Seminowicz et al, 2009; Mutso et al, 2012; Alvarado et al, 2013; Tajerian et al, 2013, 2014) These findings extend to humans---multiple studies have reported decreased gray matter, reduced cortical thickness, Hypothesis of a genomic memory of pain abnormal cortical function, and altered connectivity in various brain regions in a wide range of chronic pain conditions including low back pain (Giesecke et al, 2004; Apkarian et al, 2005; Schmidt-Wilcke et al, 2006; Tagliazucchi et al, 2010; Berger et al, 2014), headache (Schmidt-Wilcke et al, 2005), fibromyalgia (Kuchinad et al, 2007; Schmidt-Wilcke et al, 2007), post-stroke pain (Krause et al, 2014), complex regional pain syndrome (Pleger et al, 2014), burning mouth syndrome (Khan et al, 2014), and irritable bowel syndrome (Davis et al, 2008). Increased physical activity resulted in improved memory and increased local gray matter

Housekeeping Weak promoter Narrow promoter Broad promoter Bivalent

Epigenetic Mechanisms and Function in the Prefrontal Cortex

Findings

Concluding Remarks