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

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 opioidreceptor interfacing with an opioid antagonist can facilitate the process of wound healing. Diabetes 51: 3055-3062, 2002

Insulin Treatment Ameliorates Impaired Corneal Reepithelialization in Diabetic Rats

“…The results showed that DNA synthesis was markedly subnormal in the basal epithelial cells of the peripheral cornea and the conjunctiva but not the limbus of rats with uncontrolled diabetes. These data supplement the results of our earlier study on homeostatic corneal epithelium (25) and demonstrate that poorly controlled diabetes depresses DNA synthesis in corneal epithelial cells that should be undergoing active proliferation. Because cell proliferation is an essential step in the corneal epithelial healing process (28), it could be postulated that compromising DNA synthesis under diabetic conditions contributes to the impaired corneal wound healing in diabetic individuals.…”

“…Specifically, are the delays in wound healing displayed by the DB group compared with controls and the DB-IN groups related to the reduced body weights in the DB group? However, examination of the data in this study and those performed earlier (20,25) with animals of less body weight showed no differences in the temporal course of wound healing or the rate of corneal reepithelialization of rats despite marked differences in body weights at the time of corneal abrasion. Therefore, body weight differences between the DB and control or DB-IN groups were not related to the changes in corneal reepithelialization.…”

“…Thus, in comparison to the marked delays in wound healing experienced by rats with uncontrolled hyperglycemia recorded in this and previous studies (25), animals that are diabetic but receiving insulin to maintain euglycemia had the size of the corneal defect, rate of repair, and incidence of complete reepithelialization comparable with levels recorded in control rats. These data support the thesis set forth in previous reports (1,13) regarding systemic complications of diabetes in humans, which demonstrated that intensive therapy with insulin delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in type 1 diabetic patients.…”

“…Cell proliferation has been reported to be decreased in the basal epithelial layer of the peripheral cornea, limbus, and conjunctiva in STZ-induced diabetic rats, which are not rendered normoglycemic with insulin (25), and monitored 8 weeks after induction of diabetes. In the present investigation, rats were examined 14 weeks after induction of diabetes.…”

Ocular safety of Topical Naltrexone

“…Accordingly, we produced standardized corneal abrasions in rats with four or eight weeks of streptozotocin-induced diabetes. 51 Utilizing immunocytologic techniques, such diabetic animals were shown to possess a similar distribution of OGF and its receptor as non-diabetic control rats. When diabetic rats were treated with NTX (30 mg/kg twice daily), depending upon the duration of the diabetic state, untreated animals displayed delays in epithelial wound healing from 11% to 1700% compared to non-diabetic control animals.…”