Lanterna Rally

Author: Lucas Topham

Publisher:

Published: 2021

Total Pages:

ISBN-13:

"Chronic pain is one of the leading causes of disability and reduced quality of life worldwide. As a result of chronic pain, the prefrontal cortex (PFC) undergoes significant structural and functional remodeling, resulting in the loss of grey matter, altered synapse formation, and changes in neurotransmitter and ion channel signalling. These changes are accompanied by widespread alterations in gene expression and can be reversed if pain is attenuated by therapeutic intervention. The combination of widespread changes in gene expression with a reversible phenotype implicates epigenetics as a potential regulatory mechanism underlying chronic pain development and maintenance. Previous research has demonstrated the involvement of DNA methylation, an epigenetic mechanism, in mediating chronic pain. However, its response across the chronic pain time course and to interventions is poorly understood. Increased understanding of PFC DNA methylation in response to chronic pain and therapeutic interventions will reveal mechanisms of chronic pain development and identify possible novel therapeutic targets.We found that spared nerve injury (SNI) resulted in rapid and persistent changes in DNA methylation, with robust differential methylation observed at one day post-injury and up to 12 months post-injury. We identified hundreds of differentially methylated genes, including those with known functions in pain, affecting domains related to stimulus response at early time points, immune function at later time points and actin and cytoskeletal regulation throughout the time course (Manuscript I). This study confirmed the involvement of PFC DNA methylation throughout the chronic pain time course, and identified time point specific changes in DNA methylation across pain-related genes and domains. To explore the response of DNA methylation to intervention, SAM and voluntary exercise were provided after SNI in two separate experiments. Chronic administration of SAM beginning 3 months after injury resulted in attenuation of neuropathic pain and differential methylation of over 4000 genomic regions. These regions were related to functional domains of intracellular signaling, cell locomotion and migration, cytoskeletal structure, and cell adhesion (Manuscript II). Providing access to voluntary exercise after injury also resulted in the attenuation of neuropathic pain and the differential methylation of over 5000 genomic regions. These regions were related to functional domains of ion transport and homeostasis, cell adhesion and locomotion, and immune functioning and morphogenesis (Manuscript III). In each experiment, providing therapeutic intervention resulted in the reversal of pain-related DNA methylation changes in over 1000 genomic regions. These studies confirmed the responsiveness of PFC DNA methylation to intervention after chronic pain, and that therapeutic intervention reverses the methylation status of a subset of chronic pain affected genes"--