ensembl.org, http://www.genome.ucsc.edu), and efforts are underway to sequence the epigenome to create DNA methylation and histone modification Onalespib manufacturer maps for as many different cell types as possible (Nature, 2010). There has

also been a surge in research investigating epigenetic mechanisms in the nervous system with a significant literature on memory and synaptic plasticity (for review, see Guan et al., 2009, Peleg et al., 2010 and Day and Sweatt, 2011) and the emergence of a whole new field dubbed “behavioral epigenetics” (Szyf and Meaney, 2008 and Weaver et al., 2004). In chronic pain, three main areas of epigenetic control can be identified based on the work to date and will be discussed below. As explained previously, the importance of inflammatory mediators in the establishment of many pain conditions is well recognized. Equally, there is quite a thorough literature on epigenetic influences in the inflammatory process (for review, see Selvi et al., 2010). Histone deacetylase (HDAC) inhibitors—compounds that prevent the removal of acetyl groups from histones—can ameliorate symptoms in a number of animal models of inflammatory diseases, such as arthritis, colitis, and hepatitis (Chung

et al., 2003, Glauben et al., 2006 and Leoni et al., 2005). Moreover, significant clinical benefits of an HDAC inhibitor have been observed against both arthritic and painful components of juvenile idiopathic arthritis, albeit in an open-label trial (Vojinovic et al., 2011). The effects of these compounds HDAC inhibitor drugs are believed to be mediated in part through suppression of cytokines, with their administration having been shown to reduce expression of many crucial proinflammatory mediators,

including IL-1β and TNFα (Leoni et al., 2002). In turn, binding of these same proinflammatory factors to their receptors can also harness epigenetic processes. Thus, interleukin and TNFα receptor activation results in H4 hyperacetylation of many other inflammatory Resminostat promoters through the action of the transcription factor NF-κB and its subunits p50 and p65 (Ito et al., 2000 and Rahman et al., 2002). Similarly, H3k4 methylation via methyltransferase SET7/9 can affect recruitment of NF-κB to proinflammatory genes (Li et al., 2008). The peripheral mechanisms underpinning chronic inflammatory pain states are controlled by these same mediators (Marchand et al., 2005) and involve action of both glial and neuronal NF-κB (Fu et al., 2010 and Niederberger and Geisslinger, 2008), making it likely that similar epigenetic processes are at play. Three epigenetic factors have so far been uncovered that can influence expression of nociceptive genes in chronic pain states. These are histone acetylation, DNA methylation, and REST. Pharmacological interference with the process of histone acetylation can affect pain behavior, with both systemic and intrathecal administration of HDAC inhibitors having analgesic effects in models of inflammatory pain (Chiechio et al.