The epigenetic signature of chronic pain in the mouse brain
© Tajerian et al; licensee BioMed Central Ltd. 2014
Published: 15 December 2014
Peripheral nerve injury can be accompanied by long-term pain-related manifestations, such as affective and cognitive disturbances, suggesting the involvement of supraspinal mechanisms. One particular region of interest is the prefrontal cortex (PFC), an area implicated in depression, anxiety and cognitive impairment, all of which are frequently associated with chronic pain [1–4]. Clinically, pathological pain-related changes in the PFC in individuals with chronic low back pain can be reversed following effective pain management . However, the mechanisms behind pain-induced brain plasticity remain poorly understood.
Epigenetics is a term used to describe modifications to genomic DNA that alter gene expression. DNA methylation is an epigenetic mechanism that is involved in gene regulation mainly by silencing promoter activity. We propose that long-term alterations in DNA methylation could provide a molecular substrate for chronic pain-related changes in the CNS, forming a ‘‘memory trace’’ for pain in the brain.
Materials and methods
Spared nerve injury or sham surgery was performed in male CD1 mice at three months of age. Six months after injury, mechanical hypersensitivity was confirmed, brains were collected and DNA and RNA were extracted. Global DNA methylation was measured by the luminometric methylation assay in various brain regions, including the PFC. Promoter methylation of individual genes was assessed by sodium bisulfite sequencing and functionally validated using an in vitro promoter assay. Finally, mRNA levels of the target genes were measured by RT-PCR.
Six months following peripheral nerve injury, abnormal sensory thresholds and increased anxiety were accompanied by significant genomic DNA hypomethylation  and transcriptional reprogramming . This was linked to the hypomethylation of individual genes, including (synaptotagmin 2) syt2, a known regulator of synaptic function. Furthermore, transcription of syt2 was regulated by differential methylation of its promoter in vitro and syt2 mRNA was upregulated in the PFC of injured animals. Thus chronic pain-induced changes in the PFC are detected long after the original injury, at a long distance from the site of injury.
We show that peripheral injury produces long-term changes in the PFC methylome and propose that DNA methylation mediates the changes in brain structure and cortical function that are associated with chronic pain.
The authors declare no competing interests.
The authors would like to thank Dr. Ziv Machnes and Ms. Stephanie Pierrefelice for technical assistance.
- Schweinhardt P, Bushnell MC: Neuroimaging of pain: Insights into normal and pathological pain mechanisms. Neuroscience letters 2012, 520: 129–130. 10.1016/j.neulet.2012.06.014PubMedView ArticleGoogle Scholar
- Apkarian AV, Bushnell MC, Treede RD, Zubieta JK: Human brain mechanisms of pain perception and regulation in health and disease. European Journal of Pain 2005, 9: 463–484. 10.1016/j.ejpain.2004.11.001PubMedView ArticleGoogle Scholar
- Apkarian AV, Baliki MN, Geha PY: Towards a theory of chronic pain. Progress in neurobiology 2009, 87: 81–97. 10.1016/j.pneurobio.2008.09.018PubMed CentralPubMedView ArticleGoogle Scholar
- Neugebauer V, Galhardo V, Maione S, Mackey SC: Forebrain pain mechanisms. Brain research reviews 2009, 60: 226–242. 10.1016/j.brainresrev.2008.12.014PubMed CentralPubMedView ArticleGoogle Scholar
- Seminowicz DA, Wideman TH, Naso L, Hatami-Khoroushahi Z, Fallatah S, Ware MA, Jarzem P, Bushnell MC, Shir Y, Ouellet JA, Stone LS: Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. The Journal of neuroscience: the official journal of the Society for Neuroscience 2011, 31: 7540–7550. 10.1523/JNEUROSCI.5280-10.2011View ArticleGoogle Scholar
- Tajerian M, Alvarado S, Millecamps M, Vachon P, Crosby C, Bushnell MC, Szyf M, Stone LS: Peripheral nerve injury is associated with chronic, reversible changes in global DNA methylation in the mouse prefrontal cortex. PloS one 2013, 8: e55259. 10.1371/journal.pone.0055259PubMed CentralPubMedView ArticleGoogle Scholar
- Alvarado S, Tajerian M, Millecamps M, Suderman M, Stone LS, Szyf M: Peripheral nerve injury is accompanied by chronic transcriptome-wide changes in the mouse prefrontal cortex. Molecular pain 2013, 9: 21. 10.1186/1744-8069-9-21PubMed CentralPubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.