, 2008, Li et al., 2009 and Wu et al., 2005). Most recently, cortical epigenetic processes have been hypothesized to be modulators of chronic back pain to account for shifts in event-related EEG peaks over relevant brain regions (Vossen et al., 2010). In summary, direct evidence that epigenetic mechanisms could be involved in the development and/or maintenance of chronic pain conditions is only just beginning

to surface, and the field is in its infancy. Yet the current research already indicates that this new direction has promise and presents an opportunity to identify new treatments for chronic pain. There are also a number of questions that arise from this new knowledge and will be discussed in the following section. The first and most obvious PLX4032 ic50 question is whether epigenetic marks contribute to the altered transcriptional control observed in chronic pain states. For instance, histone modifications and consequent changes in chromatin structure and recruitment of transcription factor complexes could be hypothesized to be possible mechanisms through which

widespread gene expression BMN673 changes are implemented and coordinated (see Figure 4). In particular, the three-dimensional aspect of chromatin conformation and evidence for extensive histone cross-talk (for review, see Bannister and Kouzarides, 2011) could explain how seemingly varied sets of genes are regulated in tandem. In individual cases, there is already evidence that changes in transcription are correlated with changes in L-NAME HCl acetylation (mGluR2 and GAD65; Chiechio et al., 2009 and Zhang et al., 2011), but evidence for clear causal directionality is still lacking. Hence, rigorous animal studies will be required to move beyond correlational data and establish a timeline of events. Moreover, it is likely that expression changes at multiple genes will be the cause of most complex chronic pain syndromes. Hence, patterns of modifications across loci will have to be determined with genome-wide techniques such as ChIP-seq and MeDIP-seq (Figure 3). Another issue is whether epigenetic mechanisms

are equally important in the different cell types involved in the nociceptive pathway. It is well known that DNA methylation and histone modification patterns are very cell type specific, which not only has implications for scientific hypotheses, but also raises several methodological issues. Genome-wide methylation studies examining complex neurological phenotypes in human are currently conducted using blood samples, and information on how the data obtained in this way correlate with more disease-relevant tissues is only just beginning to be addressed (Dempster et al., 2011). In the case of chronic pain, where prominent transcriptional changes are occurring in spinal cord and DRG, assaying relevant human tissue will be problematic.