title: Peripheral nerve injury is associated with chronic, reversible changes in global DNA methylation in the mouse prefrontal cortex.
abstract: Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with abnormal behavior and pathological gene expression in the central nervous system. DNA methylation might also be involved in mediating the pathologies associated with chronic pain in the brain. We therefore tested a) whether alterations in DNA methylation are found in the brain long after chronic neuropathic pain is induced in the periphery using the spared nerve injury modal and b) whether these injury-associated changes are reversible by interventions that reverse the pathologies associated with chronic pain. Six months following peripheral nerve injury, abnormal sensory thresholds and increased anxiety were accompanied by decreased global methylation in the PFC and the amygdala but not in the visual cortex or the thalamus. Environmental enrichment attenuated nerve injury-induced hypersensitivity and reversed the changes in global PFC methylation. Furthermore, global PFC methylation correlated with mechanical and thermal sensitivity in neuropathic mice. In summary, induction of chronic pain by peripheral nerve injury is associated with epigenetic changes in the brain. These changes are detected long after the original injury, at a long distance from the site of injury and are reversible with environmental manipulation. Changes in brain structure and cortical function that are associated with chronic pain conditions may therefore be mediated by epigenetic mechanisms.
authors: Alan Edwards Centre for Research on Pain, Faculty of Medicine, McGill University, Montreal, Canada.
authors: Maral
authors: M
authors: Tajerian
authors: Sebastian
authors: S
authors: Alvarado
authors: Magali
authors: M
authors: Millecamps
authors: Pascal
authors: P
authors: Vachon
authors: Cecilia
authors: C
authors: Crosby
authors: M Catherine
authors: MC
authors: Bushnell
authors: Moshe
authors: M
authors: Szyf
authors: Laura S
authors: LS
authors: Stone
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000503:physiopathology; D059350:Chronic Pain / Q000209:etiology / Q000473:pathology*; D019175:DNA Methylation / Q000502:physiology*; D004777:Environment; D044127:Epigenesis, Genetic / Q000502:physiology*; D008297:Male; D051379:Mice; D059348:Peripheral Nerve Injuries / Q000150:complications*; D017397:Prefrontal Cortex / Q000473:pathology*; D045442:Rotarod Performance Test; D012684:Sensory Thresholds / Q000502:physiology
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