The methyl donor S-adenosyl methionine reverses the DNA methylation signature of chronic neuropathic pain in mouse frontal cortex

Abstract

Introduction:. Chronic pain is associated with persistent but reversible structural and functional changes in the prefrontal cortex (PFC). This stable yet malleable plasticity implicates epigenetic mechanisms, including DNA methylation, as a potential mediator of chronic pain–induced cortical pathology. We previously demonstrated that chronic oral administration of the methyl donor S-adenosyl methionine (SAM) attenuates long-term peripheral neuropathic pain and alters global frontal cortical DNA methylation. However, the specific genes and pathways associated with the resolution of chronic pain by SAM remain unexplored. Objective:. To determine the effect of long-term therapeutic exposure to SAM on the DNA methylation of individual genes and pathways in a mouse neuropathic pain model. Methods:. Male CD-1 mice received spared nerve injury or sham surgery. Three months after injury, animals received SAM (20 mg/kg, oral, 3× a week) or vehicle for 16 weeks followed by epigenome-wide analysis of frontal cortex. Results:. Peripheral neuropathic pain was associated with 4000 differentially methylated genomic regions that were enriched in intracellular signaling, cell motility and migration, cytoskeletal structure, and cell adhesion pathways. A third of these differentially methylated regions were reversed by SAM treatment (1415 regions representing 1013 genes). More than 100 genes with known pain-related function were differentially methylated after nerve injury; 29 of these were reversed by SAM treatment including Scn10a, Trpa1, Ntrk1, and Gfap. Conclusion:. These results suggest a role for the epigenome in the maintenance of chronic pain and advance epigenetic modulators such as SAM as a novel approach to treat chronic pain.