Highlights
- •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.
Abstract
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.
Perspective
Peripheral 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.
Key words
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Article info
Publication history
Published online: May 30, 2014
Accepted:
May 20,
2014
Received in revised form:
April 29,
2014
Received:
March 14,
2014
Footnotes
The work was supported by National Institutes of Health award GM079126 (Bethesda, MD) and VA Merit Review award 5I01BX000881 (Washington, DC).
The authors declare no conflict of interests.
Identification
Copyright
Published by Elsevier Inc.
