title: Therapeutic benefits of the methyl donor S-adenosylmethionine on nerve injury-induced mechanical hypersensitivity and cognitive impairment in mice.
abstract: Despite considerable advances in understanding mechanisms involved in chronic pain, effective treatment remains elusive. Comorbid conditions including anxiety, depression, and cognitive impairment further impact quality of life. Chronic pain is associated with reversible changes in brain anatomy and function and with long-term changes in gene expression. Epigenetic mechanisms, including DNA methylation, contribute to wide-spread and long-lasting reprogramming of gene expression. We previously reported decreases in global DNA methylation in the mouse frontal cortex 6 months after induction of neuropathic pain using the spared nerve injury (SNI) model. Here, we examined the therapeutic effect of increasing DNA methylation using the methyl donor S-adenosylmethionine (SAM). S-adenosylmethionine is marketed as a nutritional supplement for a range of conditions including liver disease, depression, osteoarthritis, fibromyalgia, and dementia. Three months after SNI or sham surgery, animals were treated with SAM (20 mg/kg, 3×/week) or saline orally for 4 months, and the impact on sensory, motor, motivational, and cognitive indices was measured. S-adenosylmethionine attenuated SNI-induced mechanical hypersensitivity and reduced active avoidance of mechanical stimuli but had no effect on cold sensitivity or motor capacity. S-adenosylmethionine completely blocked nerve injury-induced cognitive impairment and attenuated SNI-induced decreases in global DNA methylation in the frontal cortex. In summary, chronic oral administration of the methyl donor, SAM, attenuated sensory and cognitive symptoms associated with nerve injury in mice. These effects may be mediated, in part, through modulation of DNA methylation in the central nervous system by systemic administration of the methyl donor SAM.
authors.affiliation: Alan Edwards Centre for Research on Pain, Montreal, QC, Canada.|Faculty of Dentistry, McGill University, Montreal, QC, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Grégoire
authors.affiliation: Alan Edwards Centre for Research on Pain, Montreal, QC, Canada.|Faculty of Dentistry, McGill University, Montreal, QC, Canada.
authors.forename: Magali
authors.initials: M
authors.lastname: Millecamps
authors.affiliation: Alan Edwards Centre for Research on Pain, Montreal, QC, Canada.|Faculty of Dentistry, McGill University, Montreal, QC, Canada.
authors.forename: Lina
authors.initials: L
authors.lastname: Naso
authors.affiliation: Faculty of Medicine, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Do Carmo
authors.affiliation: Alan Edwards Centre for Research on Pain, Montreal, QC, Canada.|Faculty of Medicine, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: A Claudio
authors.initials: AC
authors.lastname: Cuello
authors.affiliation: Faculty of Medicine, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
authors.affiliation: Alan Edwards Centre for Research on Pain, Montreal, QC, Canada.|Faculty of Dentistry, McGill University, Montreal, QC, Canada.|Faculty of Medicine, Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Stone
mesh_terms: D000818:Animals; D019540:Area Under Curve; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D019175:DNA Methylation / Q000187:drug effects; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000187:drug effects; D006967:Hypersensitivity / Q000188:drug therapy* / Q000209:etiology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D059348:Peripheral Nerve Injuries / Q000150:complications* / Q000473:pathology; D010812:Physical Stimulation / Q000009:adverse effects; D021641:Recognition, Psychology / Q000187:drug effects; D012436:S-Adenosylmethionine / Q000627:therapeutic use*
chemical_list: D012436:S-Adenosylmethionine