Study examines how topical naltrexone restores tear production in diabetic dry eye

(Image Credit: AdobeStock/Chris Tefme)

A team of researchers has found 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.

The study, titled Topical naltrexone increases aquaporin 5 production in the lacrimal gland and restores tear production in diabetic rats, was published recently in Experimental Biology and Medicine.¹

The research was conducted by Patricia J. McLaughlin, PhD, Ian Zagon, PhD, MS, and their graduate student David Diaz, at Pennsylvania State University College of Medicine in Hershey, along with Joseph W. Sassani, MD, MHA, an ophthalmologist at the Pennsylvania State Hershey Medical Center.²

The researchers noted that diabetes and pre-diabetes are a global epidemic that can lead to visual issues, including retinopathy and keratopathy. Diabetes also can be associated with low tear production and corneal surface irregularities.

There are a number of causes of dry eye, and exactly how each of these symptoms occur remains unknown. 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.

According to a news release, previous studies by the research team 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 R=receptor (OGFr) axis, that regulates cellular homeostasis becomes dysregulated and there is an overproduction of OGF, an inhibitory peptide that reduces cellular proliferation.²

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.¹

The mechanism connected to this reversal of dry eye following OGFr blockade is the focus of the research team’s current paper and continues their pioneering studies of the dysregulation of the OGF-OGFr axis and corneal surface complications. According to the study, 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.¹

The researchers found that within 5 days, normal tear volume was measured, dry eye was reversed, and corneal sensitivity was restored. They found that treatment with naltrexone led to no meaningful morphological changes in the lacrimal or meibomian glands. However, they did note an increase in conjunctiva goblet cells that produce beneficial mucin. The topical naltrexone treatment also increased the presence of aquaporin-5, an aqueous protein marker for secretory function in the lacrimal gland.¹

“In this study, our experiments confirmed that type 1 diabetes results in decreased tear fluid and decreased corneal sensitivity, with dysregulation in the lacrimal functional unit (ie, decreases in lacrimal gland number and aquaporin 5 receptors, and number of conjunctival goblet cells),” the researchers wrote. “Topical NXT application restores tear production and corneal sensitivity, and increases the amount of aquaporin-5 expression in lacrimal gland acinar cells, but does not alter the defective morphology of the lacrimal functional unit, suggesting that the rapid reversal of dry eye is related to corneal nerve sensitivity.”

The researchers further noted that the results of their study extend what is known 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.²

The researchers noted that by studying neurotrophic abundance or corneal nerve density, they hope to elucidate the mechanism of naltrexone in dry eye.

“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,” McLaughlin concluded in the news release.

References:

1. Diaz David , Sassani Joseph P. , Zagon Ian S. , McLaughlin Patricia J. Topical naltrexone increases aquaporin 5 production in the lacrimal gland and restores tear production in diabetic rats. Experimental Biology and Medicine. Vol. 249. Published May 2024. Accessed June 18, 2024. DOI=10.3389/ebm.2024.10175. ISSN=1535-3699

2. New Study Examines How Topical Naltrexone Restores Tear Production in Diabetic Dry Eye. www.newswire.com. Accessed June 19, 2024. https://www.newswire.com/news/new-study-examines-how-topical-naltrexone-restores-tear-production-in-22355195