New Study Examines How Topical Naltrexone Restores Tear Production in Diabetic Dry Eye

New Study Examines How Topical Naltrexone Restores Tear Production in Diabetic Dry Eye

WASHINGTON, DC / ACCESSWIRE / June 18, 2024 / A recently published article in Experimental Biology and Medicine (249:3, 2024) entitled “Topical naltrexone increases aquaporin 5 production in the lacrimal gland and restores tear production in diabetic rats” highlights factors underlying sustained dry eye in diabetes. The study, led by Dr. Pat McLaughlin and Dr. Ian Zagon, and their graduate student David Diaz, at Pennsylvania State University College of Medicine in Hershey, along with Dr. Joseph W. Sassani, an ophthalmologist at the Pennsylvania State Hershey Medical Center, reports that blockade of the Opioid Growth Factor – Opioid Growth Factor Receptor pathway using formulations of naltrexone is effective at reversing dry eye and stabilizing corneal surface sensitivity in preclinical diabetic animal models.

Diabetes and pre-diabetes are a global epidemic and are accompanied by complications of the visual system. In addition to retinopathy and keratopathy, diabetes is often associated with low tear production (i.e., dry eye) and corneal surface irregularities. Due to the multiple causes of dry eye, how these symptoms occur is not well understood. Chronic dry eye has been described as a dysfunction in the lacrimal functional unit that includes the cornea, lacrimal glands, conjunctiva, and eyelids; tissues that function to create, maintain, and clear tears from the eyes. Previous studies by these researchers have shown that animal models of diabetes develop dry eye within weeks of becoming hyperglycemic. Simultaneously an innate pathway, the Opioid Growth Factor (OGF) – OGF Receptor (OGFr) axis, that regulates cellular homeostasis becomes dysregulated and there is an overproduction of OGF, an inhibitory peptide that reduces cellular proliferation. Blockade of the interaction between peptide and receptor using topical applications of the FDA-approved opioid antagonist naltrexone reverses dry eye symptoms in 5 days and restores tear fluid volumes to normal baseline.

The mechanism related to this relatively fast reversal of dry eye following OGFr blockade is the focus of the current paper and continues their pioneering studies of the dysregulation of the OGF-OGFr axis and corneal surface complications. Hyperglycemic male and female rats showing characteristic type 1 diabetic ocular surface complications including dry eye and decreased corneal sensitivity received topical naltrexone treatment in one eye for 10 days. Within 5 days, normal tear volume was measured, dry eye was reversed, and corneal sensitivity was restored. Treatment with naltrexone resulted in no significant morphological changes in the lacrimal or meibomian glands, however, there was an increase in conjunctiva goblet cells that produce beneficial mucin. Topical naltrexone treatment also increased the presence of aquaporin-5, an aqueous protein marker for secretory function in the lacrimal gland.

The results in this paper extend knowledge about the role of receptor blockade of the OGF-OGFr pathway by naltrexone, demonstrating that the mechanism behind short-term topical application to reverse dry eye is not related to direct morphological changes in the lacrimal glands. Rather it is due to the amounts of aqueous protein and mucin secretions which in turn are related to sensory fibers that reside on the surface of the cornea. Dr. McLaughlin stated that “these data are provocative and direct our research toward sensory nerve density and function in the cornea in order to better understand the mechanisms of dry eye and its relationship to the OGF-OGFr pathway.”

Dr. Goodman, Editor-in-Chief for Experimental Biology and Medicine, said: “McLaughlin and Zagon initially identified and characterized the OGF-OGFr axis. With clinical colleagues, they have studied its dysregulation in diabetes and have patented treatments for treatment of dry eye and delayed skin repair. Their important findings warrant clinical studies to determine the efficacy of receptor blockade by naltrexone for treatment of dry eye in persons with diabetes.”

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Benjamin Zimmer

SOURCE: Experimental Biology and Medicine


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