Abstract
DNA methylation is a key epigenetic mechanism controlling DNA accessibility and gene expression. Blockade of DNA methylation can significantly affect pain behaviors implicated in neuropathic and inflammatory pain. However, the role of DNA methylation with regard to postoperative pain has not yet been explored. In this study we sought to investigate the role of DNA methylation in modulating incisional pain and identify possible targets under DNA methylation and contributing to incisional pain. DNA methyltranferase (DNMT) inhibitor 5-Aza-2′-deoxycytidine significantly reduced incision-induced mechanical allodynia and thermal sensitivity. Aza-2′-deoxycytidine also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. Global DNA methylation and DNMT3b expression were increased in skin after incision, but none of DNMT1, DNMT3a or DNMT3b was altered in spinal cord or DRG. The expression of proopiomelanocortin Pomc encoding β-endorphin and Oprm1 encoding the mu-opioid receptor were upregulated peripherally after incision; moreover, Oprm1 expression was further increased under DNMT inhibitor treatment. Finally, local peripheral injection of the opioid receptor antagonist naloxone significantly exacerbated incision-induced mechanical hypersensitivity. These results suggest that DNA methylation is functionally relevant to incisional nociceptive sensitization, and that mu-opioid receptor signaling might be one methylation regulated pathway controlling sensitization after incision.
Highlights
Postoperative pain of moderate to severe intensity is experienced by 30–40% of patients after surgeries [1, 2]
Global DNA methylation and DNMT3b expression were increased in skin after incision, but none of DNMT1, DNMT3a or DNMT3b was altered in spinal cord or Dorsal root ganglia (DRG)
DNMT1 is described as the maintenance methyltransferase, while DNMT3a and DNMT3b are methyltransferases often expressed de novo [29, 30]
Summary
Postoperative pain of moderate to severe intensity is experienced by 30–40% of patients after surgeries [1, 2]. Unrelieved postoperative pain is a common cause for unplanned hospital admission and contributes to suboptimal functional outcomes. Current therapeutic approaches to postoperative pain are limited by our narrow understanding of the underlying biological mechanisms. Examining the mechanisms involved in supporting pain after surgical incision would have significant value in addressing these problems.
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