Yin and yang of opioid growth regulatory system focuses on diabetes

Take-home message: Research supports the hypothesis that manipulation of the opioid growth regulatory system can restore function and normalize corneal epithelial wound healing, corneal sensitivity, and tear production in models of both type 1 and type 2 diabetes.

By Nancy Groves; Reviewed by Joseph W. Sassani, MD, MHA

Hershey, PA-The opioid growth regulatory system (OGRS) is inadequately recognized for its implications in the pathobiology and treatment of the complications of diabetes, said Joseph W. Sassani, MD.

The OGRS appears to be disordered in diabetic animals, said Dr. Sassani, professor of ophthalmology and pathology, Penn State’s Hershey Medical Center (HMC), Hershey, PA.

Study have shown, however, that function can be restored to normalize corneal epithelial wound healing, corneal sensitivity, and tear production in models of both type 1 and type 2 diabetes through treatment with naltrexone, the pharmacologic antagonist of naturally occurring opioid growth factor (OGF, [MET⁵]-Enkephalin).

Dr. Sassani described OGF and naltrexone as the “yin and yang” of the OGRS, whose main components are OGF and its specific receptor, OGFr.

OGF is a naturally occurring opioid that suppresses cell division when bound to OGFr. It is tonically produced, and its level in tissue is usually neither maximized nor minimized. As a result of this characteristic, manipulation of the OGRS can decrease or increase cell division.

“These ‘yin and yang’ characteristics make it uniquely suitable for therapeutic manipulation,” Dr. Sassani said.

The OGF-OGFr axis can be manipulated in several ways to regulate cell division. OGF is a negative or inhibitory growth factor, while naltrexone, which blocks OGFr, stimulates growth.

The addition of exogenous OGF or an increase in the number of its receptors downregulates cell division, while cell division could be accelerated by decreasing the interaction of OGF with its receptor, either by decreasing the production of OGF or its receptor or by utilizing a blocking agent like naltrexone to directly block OGF-OGFr interaction, Dr. Sassani said.

Two decades of research

Over past 25 years, the research team-including Ian S. Zagon, PhD, and Patricia J. McLaughlin, PhD, of the HMC Department of Neural and Behavioral Science-has delineated the role of the OGF-OGFr system in the homeostasis and healing of ocular tissues and demonstrated its role in the pathobiology of diabetic ocular complications.

The researchers initially demonstrated that the OGRS modulates outgrowth of the corneal epithelium in organ culture, then demonstrated the ability of OGF treatment to suppress DNA synthesis in the cornea of the living rat and that of naltrexone to increase it.

Building on these findings, the researchers conducted a series of investigations determining that treatment with either systemic or topical naltrexone resulted in an increased rate of rat corneal epithelial wound healing. Treatment with topical naltrexone also led to more rapid healing in rabbit corneas.

The team also studied regulation of wound healing by using a gene gun to deliver sense and antisense OGFr cDNA into corneal epithelial cells in rat eyes. Sense caused overexpression of OGFr and delayed wound healing, while antisense diminished the expression and accelerated wound healing.

Next, a series of studies showed that naltrexone accelerated re-epithelialization while OGF suppressed epithelial wound healing. The results also showed that naltrexone increased DNA synthesis and OGF decreased the process.

Connecting these laboratory findings to patient care, Dr. Sassani explained that keratopathy and neuropathy are common complications of this disease, and both type 1 and type 2 diabetes are associated with delayed corneal epithelial wound healing, abnormal corneal sensitivity, and dry eye.

The link between endogenous opioids and diabetes is that elevated levels of OGF have been found in the plasma of diabetic humans, as well as in genetically obese diabetic mice, and both OGF and OGFr have been found in the epithelium of diabetic animals.

“We postulated that abnormalities of opioid regulation could contribute to the complications of diabetes and that blockade of the OGRS by naltrexone might reverse or ameliorate these complications,” Dr. Sassani said.

Summarizing a series of studies, he explained that in diabetic animals, topical naltrexone restores corneal epithelial wound healing to levels comparable to systemically or topically insulin-treated animals without apparent epithelial toxicity.

He also referred to results indicating that combined insulin and naltrexone were no more effective than either one used independently.

“The possibility exists that insulin and naltrexone have their effect through similar mechanisms in diabetic animals or that each has the potential to maximize epithelial wound healing in these animals, leaving no opportunity for further increase by the complementary modality,” Dr. Sassani said.

“Insulin has no effect on wound healing in normal animals, and naltrexone has no impact on blood glucose levels in diabetic animals,” he added.

Data from various studies also suggest that the route of administration could be a factor and that systemic insulin may be unable to reach the tear film in a concentration equivalent to that of topical administration.

Broader implications

Turning to diabetic corneal neuropathy, Dr. Sassani noted that several studies suggest that it can be reversible with naltrexone therapy.

The team has also studied dry eye and compiled data that support the concept of OGRS modulation of tear production even in nondiabetic rats. Naltrexone treatment of diabetic dry eye has restored tear production to normal levels for up to 3 days following discontinuation of the naltrexone therapy in type 1 or type 2 diabetic rats.

Proposing broader implications for the OGRS, Dr. Sassani suggested that it is important in the pathobiology of diabetic ocular surface disease and that blockade of the OGFr may have systemic implications for OGRS and diabetes.

Dr. Sassani and his colleagues have extended their research to non-ocular diabetic complications, such as delayed skin wound healing. A 2011 study showed that topical treatment with naltrexone facilitates closure of full-thickness wounds in diabetic rats.

Further research suggests that naltrexone accelerates wound closure in part by stimulating the expression of angiogenic factors within healing tissue in diabetic animals.

“Obviously, there is the potential for a significant impact on facilitating the initial closure of such wounds,” Dr. Sassani said.

He also observed that naltrexone has a more pervasive impact on the overall process of wound healing beyond wound closure. For example, research showed that diminished collagen formation and maturation in healing granulation tissue were restored to normal by topical treatment with the opioid antagonist.

In another study, inadequate healing at 60 days after wounding in type 1 diabetic rats, reflected in reduced tensile strength, was reversed by naltrexone.

Joseph W. Sassani, MD, MHA

P: 717/531-5690

E: jsassani@psu.edu

This article was adapted from Dr. Sassani’s presentation of the Zimmerman Lecture at the 2014 meeting of the American Academy of Ophthalmology. Dr. Sassani has patent interests through Pennsylvania State University in the clinical applications of opioid growth regulatory system.