Opioids Enhance CXCL1 Expression and Function After Incision in Mice

• Peripheral CXCL1/CXCR2 contributes to control nociceptive sensitization after incision.
• Chronic opioid pretreatment epigenetically activated CXCL1 gene expression after incision via histone acetylation.
• Epigenetic regulation of CXCL1 expression explains in part opioid-enhanced incisional allodynia in mice.

Chronic opioid consumption increases postoperative pain. Epigenetic changes related to chronic opioid use and surgical incision may be partially responsible for this enhancement. The CXCL1/CXCR2 signaling pathway, implicated in several pain models, is known to be epigenetically regulated via histone acetylation. The current study was designed to investigate the role of CXCL1/CXCR2 signaling in opioid-enhanced incisional sensitization and to elucidate the possible epigenetic mechanism underlying CXCL1/CXCR2 pathway–mediated regulation of nociceptive sensitization in mice. Chronic morphine treatment generated mechanical and thermal nociceptive sensitization and also significantly exacerbated incision-induced mechanical allodynia. Peripheral but not central messenger RNA levels of CXCL1 and CXCR2 were increased after incision. The source of peripheral CXCL1 appeared to be wound area neutrophils. Histone H3 subunit acetylated at the lysine 9 position (AcH3K9) was increased in infiltrating dermal neutrophils after incision and was further increased in mice with chronic morphine treatment. The association of AcH3K9 with the promoter region of CXCL1 was enhanced in mice after chronic morphine treatment. The increase in CXCL1 near wounds caused by chronic morphine pretreatment was mimicked by pharmacologic inhibition of histone deacetylation. Finally, local injection of CXCL1 induced mechanical sensitivity in naive mice, whereas blocking CXCR2 reversed mechanical hypersensitivity after hind paw incision.PerspectivePeripheral CXCL1/CXCR2 signaling helps to control nociceptive sensitization after incision, and epigenetic regulation of CXCL1 expression explains in part opioid-enhanced incisional allodynia in mice. These results suggest that targeting CXCL1/CXCR2 signaling may be useful in treating nociceptive sensitization, particularly for postoperative pain in chronic opioid-consuming patients.