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

Lucas Topham; Stephanie Gregoire; HyungMo Kang; Mali Salmon-Divon; Elad Lax; Magali Millecamps; Moshe Szyf; Laura Stone

doi:10.1097/PR9.0000000000000944

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

Pain Rep. 2021 Jul 13;6(2):e944. doi: 10.1097/PR9.0000000000000944. eCollection 2021 Jul-Aug.

Authors

Lucas Topham^{1

2}, Stephanie Gregoire^{1

2}, HyungMo Kang^{1

2}, Mali Salmon-Divon^{3

4

5}, Elad Lax^{3

4}, Magali Millecamps^{1

2}, Moshe Szyf^{4

6}, Laura Stone^{1

2

4

7

8

9}

Affiliations

¹ Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
² Faculty of Dentistry, McGill University, Montreal, QC, Canada.
³ Department of Molecular Biology, Ariel University, Ariel, Israel.
⁴ Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
⁵ Adelson School of Medicine, Ariel University, Ariel, Israel.
⁶ Sackler Program for Epigenetics and Psychobiology, McGill University, Montreal, QC, Canada.
⁷ Department of Anesthesiology, McGill University, Montreal, QC, Canada.
⁸ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
⁹ Department of Anesthesiology, Faculty of Medicine, University of Minnesota, Minneapolis, MN, USA.

Abstract

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.