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I.S. Zagon, J.W. Sassani, M.S. Klocek, P.J. McLaughlin; Naltrexone as a Novel Treatment for Diabetic Keratopathy: Toxicity Studies . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2762.
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© ARVO (1962-2015); The Authors (2016-present)
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. To establish the safety and efficacy of NTX as a putative clinical therapy for diabetic keratopathy, the toxicity of topical application of NTX needs to be established.
In this study, 10–3 to 10–7 M NTX was administered topically to one eye of Type 1 diabetic rats (glucose levels <400 mg/dl), as well as a diabetic group that were rendered normoglycemic with insulin implants; normal (non–diabetic) rats acted as controls. Eight weeks after establishment of diabetes with streptozotocin, rats were subjected to 7 days of topical administration of NTX or vehicle (4 times daily). Prior to NTX treatment and 7 days after NTX treatment, rats were examined for ocular toxicity with a series of non–invasive measurements including corneal thickness (pachymetry), endothelial cell count (specular microscopy), intraocular pressure (tonometry), and pain perception (aesthesiometer). Some animals in each group were euthanized and tissues collected to assess corneal structure (biomicroscopy, histology), and DNA synthesis (BrdU) and cytotoxicity (apoptosis, necrosis) in the central and peripheral cornea, limbus, conjunctiva, stroma, and endothelium.
There were no differences in intraocular pressures or pachymetry across groups or dosages. The corneas of all diabetic rats combined had heightened sensitivity to pain in comparison to either normoglycemic diabetic rats or non–diabetic rats. Only a dosage of 10–3 M NTX rendered eyes more sensitive to pain perception relative to non–treated eyes of the same animal. Endothelial cell counts were comparable among all groups. Apoptosis and/or necrosis were negligible in all areas of the cornea for all groups. DNA synthesis was not markedly altered by treatment with NTX 7 days earlier in the cornea, limbus, or conjunctiva in any group.
These data reveal that NTX over a 10,000–fold range of dosage had no overt toxicity on corneal epithelium as measured by both non–invasive and invasive criteria. Thus, studies on the efficacy of NTX as a therapy for diabetic keratopathy should be pursued. Acknowledgement: Alcon Laboratories, Inc. (Ft. Worth, TX) for donation of Vigamox.
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