Effective pharmacological management of pain associated with tissue pathology is an unmet medical need. Transcriptional modifications in nociceptive pathways are pivotal for the development and the maintenance of pain associated with tissue damage. Accumulating evidence has shown the importance of the epigenetic control of transcription in nociceptive pathways via histone post-translational modifications (PTMs). Hence, histone PTMs could be targets for novel effective analgesics. Here, we discuss the current understanding of histone PTMs in the modulation of gene expression affecting nociception and pain phenotypes following tissue injury. We also provide a critical view of the translational implications of preclinical models and discuss opportunities and challenges of targeting histone PTMs to relieve pain in clinically relevant tissue injuries.

The activity of the transient receptor potential vanilloid type 1 ion channel (TRPV1) that is expressed by the great majority of polymodal nociceptors is pivotal for the development of inflammatory heat hyperalgesia. The responsiveness of TRPV1 is regulated by a series of intracellular signalling molecules including the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA); increased or decreased PKA activity results in TRPV1 sensitisation or desensitisation, respectively. Activation of the cannabinoid 1 (CB1) receptor that is expressed by the majority of the TRPV1-expressing primary sensory neurons reduces PKA activity. Therefore, here we studied whether activation of the CB1 receptor resulted in reduced TRPV1-mediated responses in cultured rat primary sensory neurons. We found that TRPV1-mediated whole-cell currents were significantly reduced respectively, by 50% and 25% by 10 nM and 30 nM of the endogenous CB1 receptor agonist, anandamide. The PKA inhibitor, H89 (10 microM) also had a significant inhibitory effect on TRPV1-mediated currents ( approximately 70%). These findings suggest that activation of the CB1 receptor can reduce the activity of TRPV1 in primary sensory neurons, and that this inhibitory effect could be mediated through the reduction of PKA-mediated phosphorylation of TRPV1.