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This article provides an overview of the inhibitory role of the Opioid Growth Regulatory System, which is characterized by its mediator, Opioid Growth Factor, [Met⁵]-enkephalin, and its specific receptor, Opioid Growth Factor receptor, in the pathobiology of diabetic complications involving the ocular surface. Additionally, involvement of the Opioid Growth Regulatory System in systemic diabetic complications is illustrated by its role in poor diabetic cutaneous wound healing. An overarching theme is the ability of naltrexone to restore normal homeostasis.

The title of this paper is derived from Lewis Carroll’s Alice’s Adventures in Wonderland in which Alice is invited by the caterpillar to eat either side of a mushroom with powerful growth inducing characteristics. In the context of this review, this metaphor highlights the antagonistic relationship between the Opioid Growth Regulatory System and naltrexone, which blocks the binding of Opioid Growth Factor to the Opioid Growth Factor receptor thereby preventing or reversing the deleterious effects of the Opioid Growth Regulatory System in the pathobiology of diabetic complications including dry eye, keratopathy (delayed corneal epithelial wound healing and decreased corneal sensitivity) and delayed cutaneous wound healing in animal models of type 1 and type 2 diabetes.

The article proceeds in a stepwise fashion to introduce the reader to the components of the Opioid Growth Regulatory System, their relationships, and the impact of naltrexone on the functioning of that system. The roles of the Opioid Growth Regulatory System on normal cellular homeostasis and its dysfunction in diabetic complications are discussed as is the ability of naltrexone to reverse or prevent these complications. The main focus of the review is on the ocular surface complications of diabetes; however, the impact of the Opioid Growth Regulatory System on cutaneous wound healing in diabetes is included to demonstrate the potential systemic implications of the system in the pathogenesis of diabetic complications. Early phase human studies are discussed.

We believe these data support further clinical trials of naltrexone in the treatment of diabetic ocular surface disease and delayed cutaneous wound healing and may have implications for the significance of the Opioid Growth Regulatory System in the pathobiology of other diabetic complications.

^aPresented, in part, as the 8^th Annual Honored Alumni Lecture & Inaugural Alan M. Laties, M.D. Memorial Lecture, University of Pennsylvania, Scheie Institute, Philadelphia, PA, April 9, 2022.