Topical application of naltrexone facilitates reepithelialization of the cornea in diabetic rabbits.
Delayed corneal reepithelialization is a complication of diabetes, and may lead to ulcers and erosions, which cause ocular morbidity and visual loss. This study examined the efficacy of naltrexone (NTX), a long-acting, potent opioid antagonist, applied topically, to facilitate the repair of standardized corneal abrasions in diabetic (alloxan-induced) New Zealand White rabbits (glucose levels>450 mg/dL). NTX at a concentration of 10(-4)M, or sterile vehicle (SV), was administered topically 4 times per day for 7 days to the abraded eye of uncontrolled Type 1 diabetic (DB), insulin-controlled Type 1 diabetic (DB-IN), or non-diabetic (Normal) rabbits. Wound healing was monitored, and non-invasive (tonopen, pachymeter, hand-held slit lamp, and retinal camera) and invasive (histopathology) measurements evaluated. Corneal reepithelialization in the uncontrolled DB rabbits was significantly enhanced (up to a 47% reduction in wound area) following treatment with NTX relative to both Normal SV and DB SV rabbits at 24, 48, and 56 h following surgery. At 72 h, DB NTX rabbits had residual defects that were 64-82% smaller than Normal and DB SV animals. NTX treated DB-IN rabbits had residual defects that were 9-37% smaller than DB-IN rabbits receiving SV, and 6-40% smaller than Normal rabbits. No signs of toxicity from topical applications were noted. These data confirm and extend those documented in rats that demonstrated a lack of toxicity of NTX at a wide range of dosages, as well as efficacy for enhanced corneal epithelialization. These studies set the stage for clinical trials using NTX as a therapy for diabetic keratopathy.
Department of Neural & Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. isz1@psu.edu
I S
IS
Zagon
Joseph W
JW
Sassani
Melissa A
MA
Carroll
Patricia J
PJ
McLaughlin
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003316:Corneal Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D048909:Diabetes Complications / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004744:Enkephalin, Methionine / Q000097:blood; D019573:Epithelium, Corneal / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D009271:Naltrexone / Q000494:pharmacology* / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D012038:Regeneration / Q000187:drug effects*; D013997:Time Factors
D001786:Blood Glucose; D009292:Narcotic Antagonists; D004744:Enkephalin, Methionine; D009271:Naltrexone