Abstract
Purpose: :
The opioid growth factor (OGF) interacts with the OGF receptor (OGFr) to regulate cell proliferation by a tonic inhibitory action. Disruption of the OGF–OGFr axis by the opioid antagonist, naltrexone (NTX), results in acceleration of corneal re–epithelialization in rat, rabbit, and human. NTX (10–6 M) also has been shown to accelerate corneal wound healing in rats with Type 1 diabetes.
Methods: :
To determine the optimal dose for efficacy of NTX as a clinical therapy for diabetic keratopathy, the effect of topical exposure to NTX on re–epithelialization of central cornea wounds was evaluated in 3 groups of male Sprague–Dawley rats. Type 1 diabetes (glucose levels <400 mg/dl) was induced with streptozotocin, and one group of diabetic rats was rendered normoglycemic using insulin implants. Eight weeks after induction of diabetes, a 5 mm central corneal wound was created in the right eye of each rat. Eye drops (0.05 ml) of 10–4, 10–5, or 10–6 M NTX or vehicle given 4 times daily for 7 days were administered topically. Wound healing was monitored by fluorescein dye and images recorded with a CCD camera. Areal measurements were made using Optimas software, and the percentage of epithelial defect remaining over a 40 hr period was calculated.
Results: :
Non–diabetic animals treated with 10–4 or 10–5 M NTX had residual wounds of 1–3% after 40 hr in comparison to an 11% wound for untreated corneas. Diabetic animals receiving 10–4 or 10–5 M NTX had significantly smaller wounds of 9% and 6%, respectively, in comparison to a 33% wound in vehicle–treated diabetic rats. For insulin–maintained diabetic rats, 10–4 or 10–5 M NTX treatment reduced wound size to 2–4% in comparison to a 21% residual wound in the untreated animals. Dosages of 10–6 M NTX reduced wound size, but this was reduction was not of the magnitude with 10–4 and 10–5 M NTX. In general, diabetic rats with or without insulin had corneal abrasions that healed more slowly than non–diabetic animals, and normoglycemic diabetic animals had healing rates that were more accelerated than diabetic animals. Administration of NTX to all 3 conditions accelerated corneal wound re–epithelialization. Wound healing in diabetic rats was often accelerated compared to that of normal animals receiving only vehicle; in some cases, healing rates in insulin rats receiving NTX were significantly faster than vehicle–treated non–diabetic animals.
Conclusions: :
NTX at these dosages was not toxic and significantly improved re–epithelialization of corneal abrasions. Acknowledgement: Alcon Laboratories, Inc. (Ft. Worth, TX) for donation of Vigamox.
Keywords: cornea: epithelium • wound healing • growth factors/growth factor receptors