Naltrexone, an Opioid Antagonist, Facilitates Reepithelialization of the Cornea in Diabetic Rat

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 10; pp. 3055 - 3062
• Main Authors: ZAGON, Ian S, JENKINS, Joe B, SASSANI, Joseph W, WYLIE, James D, RUTH, Torre B, FRY, Jamie L, LANG, C. Max, MCLAUGHLIN, Patricia J
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2002
• Subjects: Animals; Associated diseases and complications; Biological and medical sciences; Cornea; Corneal diseases; Corneal Ulcer - drug therapy; Corneal Ulcer - etiology; Diabetes; Diabetes Mellitus, Experimental - complications; Diabetes. Impaired glucose tolerance; DNA - biosynthesis; Drug therapy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enkephalin, Methionine - analysis; Epithelial Cells - ultrastructure; Epithelium, Corneal - chemistry; Epithelium, Corneal - cytology; Epithelium, Corneal - drug effects; Evaluation; Growth factors; Male; Medical sciences; Microscopy, Electron; Naltrexone; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics; Rats; Rats, Sprague-Dawley; Receptors, Opioid - analysis; Ulcers; Variance analysis; Wound healing; Wound Healing - drug effects; Endocrinopathy; Morphinan derivatives; Cornea; Rat; Diabetes mellitus; Rodentia; Epithelium; Naltrexone; Opioid peptide; Visual system; Eye disease; Vertebrata; Mammalia; Animal; Complication; Ulcer; Antagonist; Cicatrization
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.10.3055

Naltrexone, an Opioid Antagonist, Facilitates Reepithelialization of the Cornea in Diabetic Rat Ian S. Zagon 1 , Joe B. Jenkins 2 , Joseph W. Sassani 3 , James D. Wylie 1 , Torre B. Ruth 1 , Jamie L. Fry 1 , C. Max Lang 2 and Patricia J. McLaughlin 1 1 Department of Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 2 Department of Comparative Medicine, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 3 Department of Ophthalmology and Pathology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania Abstract Ulcers and erosions of the corneal epithelium, as well as delays in resurfacing of the cornea after wounding, are major causes of ocular morbidity and visual loss in diabetes. To study whether intervention by the opioid antagonist naltrexone (NTX; 30 mg/kg, twice daily) can restore reepithelialization in diabetic cornea, we induced diabetes in rats by intravenous injection of 65 mg/kg streptozotocin. After confirmation of diabetes, 5-mm-diameter epithelial defects that did not include the limbus were created by mechanical scraping of the cornea. At 4 and 8 weeks, corneal reepithelialization was markedly subnormal, with delays ranging from 11% to 17-fold in the diabetic animals compared with control counterparts. Rats that were diabetic for 8 weeks also had a significant decrease in the incidence of complete wound closure. At 4 and 8 weeks, diabetic animals that were receiving NTX had an acceleration in reepithelialization compared with diabetic animals that were receiving vehicle and even surpassed controls. DNA synthesis in the corneal epithelium of diabetic rats was decreased up to 90% of control levels, and NTX exposure of diabetic subjects elevated the labeling index by up to eightfold from diabetic animals that were receiving vehicle. Opioid growth factor and opioid growth factor receptor distribution were comparable in diabetic and control animals. These results indicate a delay in reepithelialization that is dependent on the duration of diabetes and that intervention of endogenous opioid-receptor interfacing with an opioid antagonist can facilitate the process of wound healing. Footnotes Address correspondence and reprint requests to Dr. Ian S. Zagon, Department of Neuroscience and Anatomy, H109, The Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033. E-mail: isz1{at}psu.edu . Received for publication 23 April 2002 and accepted in revised form 26 June 2002. ANOVA, analysis of variance; CCD, charged-coupled device; LI, labeling index; NTX, naltrexone; OGF, opioid growth factor; OGFr, opioid growth factor receptor; STZ, streptozotocin. DIABETES