GSE162016
DNA Methylation in the PFC in response to peripheral neuropathic pain and therapeutic treatment with s-adenosylmethionine
Chronic pain is associated with persistent but reversible structural and functional changes in prefrontal cortex (PFC). This stable yet malleable plasticity implicates epigenetic mechanisms, including DNA methylation, as a potential mediator of chronic pain-induced changes. We have previously demonstrated that chronic oral administration of the methyl donor S-adenosyl methionine (SAM) is capable of attenuating long-term peripheral neuropathic pain and affecting global PFC DNA methylation. However, there was no evidence as of yet that alterations in DNA methylation underlie SAM-mediated pain attenuation. To elucidate these mechanisms, we performed epigenome-wide analysis of mouse PFC after 4 months of SAM treatment initiated 3 months following induction of peripheral nerve injury. Over injury triggered chronic pain was associated with 4000 differentially methylated genomic regions which were enriched in intracellular signaling, cell locomotion and migration, cytoskeletal structure, and cell adhesion pathways. A third of the regions that were differentially methylated in chronic pain mice (1415 regions representing 1030 genes) were reversed by SAM treatment. 100 genes with known pain-related function were differentially methylated following nerve injury; several of which were reversed by SAM treatment. These results demonstrate that DNA methylation alterations in the PFC caused by chronic pain and reversed by SAM treatment providing at least partially a mechanism of action.  These data point to the possibility of epigenetic modulators such as SAM as novel approach to treat chronic pain. Overall design: Comparison of DNA Methylation between Sham-Vehicle, Sham-SAM Treated, Injury-vehicle, and injury-SAM treated animals