Topical fentanyl stimulates healing of ischemic wounds in diabetic rats 局部芬太尼麻醉可以促进糖尿病大鼠缺血性伤口的愈合

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth‐promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used <jats:styled-content style="fixed-case">Z</jats:styled-content>ucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the <jats:styled-content style="fixed-case">L</jats:styled-content>eptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho‐platelet derived growth factor receptor‐β (<jats:styled-content style="fixed-case">PDGFR</jats:styled-content>‐β) were visualized by <jats:styled-content style="fixed-case">CD</jats:styled-content>31‐, lymphatic vessel endothelium‐1, protein gene product 9.5‐ and anti‐phospho <jats:styled-content style="fixed-case">PDGFR</jats:styled-content>‐β‐immunoreactivity, respectively. Nitric oxide synthase (<jats:styled-content style="fixed-case">NOS</jats:styled-content>) and <jats:styled-content style="fixed-case">PDGFR</jats:styled-content>‐β signaling were analyzed using <jats:styled-content style="fixed-case">W</jats:styled-content>estern immunoblotting.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Fentanyl significantly promoted wound closure as compared to phosphate‐buffered saline (<jats:styled-content style="fixed-case">PBS</jats:styled-content>). Histology scores were significantly higher in fentanyl‐treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, <jats:styled-content style="fixed-case">NOS</jats:styled-content> and <jats:styled-content style="fixed-case">PDGFR</jats:styled-content>‐β signaling as compared to <jats:styled-content style="fixed-case">PBS</jats:styled-content>. Phospho‐<jats:styled-content style="fixed-case">PDGFR</jats:styled-content>‐β co‐localized with <jats:styled-content style="fixed-case">CD</jats:styled-content>31 co‐staining for vasculature.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, <jats:styled-content style="fixed-case">NO</jats:styled-content> and <jats:styled-content style="fixed-case">PDGFR</jats:styled-content>‐β signaling are associated with fentanyl‐induced tissue remodeling and wound healing.</jats:p></jats:sec>