title: Topical fentanyl stimulates healing of ischemic wounds in diabetic rats.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin 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 (PDGFR-β) were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting.
  
  
  RESULTS
  Fentanyl significantly promoted wound closure as compared to phosphate-buffered saline (PBS). 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, NOS and PDGFR-β signaling as compared to PBS. Phospho-PDGFR-β co-localized with CD31 co-staining for vasculature.
  
  
  CONCLUSIONS
  Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing.
authors.affiliation: Stanford University School of Medicine, Stanford, CA, 94305.
authors.forename: Mihir
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Department of Medicine, Minneapolis, MN 55455.
authors.forename: Tasneem
authors.initials: T
authors.lastname: Poonawala
authors.affiliation: Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Department of Medicine, Minneapolis, MN 55455.
authors.forename: Mariya
authors.initials: M
authors.lastname: Farooqui
authors.affiliation: Department of Dermatology, University of Minnesota Medical School, Minneapolis, MN 55455.
authors.forename: Marna E
authors.initials: ME
authors.lastname: Ericson
authors.affiliation: Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Department of Medicine, Minneapolis, MN 55455.
authors.forename: Kalpna
authors.initials: K
authors.lastname: Gupta
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005283:Fentanyl / Q000494:pharmacology*; D007511:Ischemia / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D005283:Fentanyl
keywords: angiogenesis; diabetes; fentanyl; lymphangiogenesis; opioid; pain; wound; 关键词：血管生成，芬太尼，淋巴管生成，伤口，糖尿病，疼痛，芬太尼，罂粟碱