Opioids and opioid receptors orchestrate wound repair #MMPMID28554003
Wang Y; Gupta M; Poonawala T; Farooqui M; Li Y; Peng F; Rao S; Ansonoff M; Pintar JE; Gupta K
Transl Res 2017[Jul]; 185 (ä): 13-23 PMID28554003show ga
We have previously shown that topical opioids including morphine and its congeners promote healing of full thickness ischemic wounds in rats. We examined the contribution of mu opioid receptor (MOPr)-mediated healing of full thickness ischemic wounds using MOPr and delta or kappa opioid receptor (DOPr or KOPr) knockout (KO) mice. Wound closure in the early (day 5) as well as later phases was delayed in topical morphine or PBS treated MOPr-KO mice compared to reciprocal treatments of wounds in wild-type (WT) mice. MOPr expression was significantly upregulated at 30 min in the wound margins and colocalized with wound margins and vasculature in the epidermal and dermal layers of the skin. We next examined whether neuropeptide expression was involved in the mechanism of MOPr-mediated wound closure. Substance P (SP) and calcitonin gene related peptide (CGRP) immunoreactivity (ir) was significantly increased in the skin of MOPr-KO mice as compared to WT mice. Neuropeptide-ir was increased significantly in PBS-treated wounds of MOPr and WT mice, but morphine treatment reduced neuropeptide immunoreactivity in both as compared to PBS. Wounding of keratinocytes led to the release of opioid peptide beta-endorphin (?-END) in conditioned medium, which stimulated the proliferation of endothelial cells. MOPr-selective (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, CTOP) and non-selective OPr antagonist naloxone inhibited endothelial proliferation induced by wounded keratinocyte conditioned medium. Additionally, accelerated wound area closure in vitro by morphine was suppressed by methylnaltrexone, a non-selective OPr antagonist with high affinity for MOPr. Morphine and its congeners stimulated the proliferation of endothelial cells from WT mice but not those from MOPr-KO mice. Furthermore, morphine-induced mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) phosphorylation in endothelial cells was significantly decreased in MOPr-KO mice as compared to WT mice. Collectively, these data suggest that MOPr plays a critical role in the proliferation phase with the formation of granulation tissue during wound healing.
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Transl+Res 2017 ; 185 (ä): 13-23
