The emerging field of pain epigenetics.

Covalent modification of DNA by methylation is a critical epigenetic mechanism regulating gene expression; increased methylation inhibits and decreased methylation increases gene expression. In this issue of PAIN, twomanuscripts provide evidence for a significant contribution of DNA methylation to chronic pain [3,4]. During gestation, different tissues acquire specific patterns of DNA methylation. These patterns confer cell type identity by regulating genome function [6]. Until recently, these tissue-specific DNA methylation patterns were believed to be fixed in differentiated tissues, particularly since it was assumed that DNA could not lose methyl groups by an active process of demethylation. Because neurons are generally non-dividing, this assumption excluded any possible role for DNA methylation in neuronal plasticity in response to external triggers. However, it is now becoming clear that DNA methylation is, in fact, a reversible biological signal [5]. In addition to innate developmental processes that sculpt the DNA methylation pattern during gestation, DNA methylation patterns can also be altered in response to external signals, such as social exposures early in life [10]. This idea has led to the emergence of the field of ‘‘behavioural’’ epigenetics. There are fundamental and important differences between genetics and epigenetics that have critical diagnostic and therapeutic implications. In contrast to the genetic code, DNA methylation is influenced by experience and is potentially reversible by pharmacological or therapeutic interventions. DNA methylation is therefore an excellent candidate for both the modulation of chronic pain in response to transient experiential exposures as well as a mechanism underlying inter-individual differences in the susceptibility for developing chronic pain. In support of this hypothesis, Wang et al. recently demonstrated a role for DNA methylation in the spinal cord following nerve injury in rats [9] and Tajerian et al. reported that methylation of the SPARC promoter in intervertebral discs is associated with chronic back pain in both preclinical models and in human patients [8]. The two papers in this issue of PAIN provide further examples of changes in DNA methylation in response to two different external exposures that are associated with pain. Doehring et al. [3] examined the effect of chronic opioid use on DNA methylation in two interesting and complementary human cohorts: drug addicts on methadone replacement therapy and opioid-treated vs. non-opioid-treated chronic pain patients. By using these two cohorts the authors attempt to dissociate the effects of pain from the consequences of exposure to opioids. In their study, the authors examined methylation of the gene encoding the muopioid receptor, OPRM1, as well as the repetitive sequence, LINE1, which is used as a marker of global methylation. Although they found increased methylation of the OPRM1 gene in the opioidexposed populations, this did not correlate with doses used.