The roles of the Opioid Growth Regulatory System and naltrexone in diabetes: One side make you taller and the other side makes you smaller
Main Article Content
Abstract
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 8th Annual Honored Alumni Lecture & Inaugural Alan M. Laties, M.D. Memorial Lecture, University of Pennsylvania, Scheie Institute, Philadelphia, PA, April 9, 2022.
Keywords:
Opioid, naltrexone, diabetes, review
Article Details
How to Cite
SASSANI, Joseph W.; ZAGON, Ian S.; MCLAUGHLIN, Patricia J..
The roles of the Opioid Growth Regulatory System and naltrexone in diabetes: One side make you taller and the other side makes you smaller.
Medical Research Archives, [S.l.], v. 12, n. 4, apr. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5260>. Date accessed: 27 july 2024.
doi: https://doi.org/10.18103/mra.v12i4.5260.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Carroll L. Alice's Adventures in Wonderland Alice in Wonderland Collection. Los Angeles, CA.: Enhanced Media Publishing; 2016:29.
3. Prevntion USCfDCa. By the Numbers: Diabetes in America: National Diabetes Statistics Report 2023. https://www.cdc.gov/diabetes/health-equity/diabetes-by-the-numbers.html. Accessed 2/18/2024, 2024.
4. Association AD. Statistics About Diabetes. https://www.cdc.gov/diabetes/data/statistics-report/index.html. Accessed 2/18/2024, 2024.
5. Parker ED, Lin J, Mahoney T, et al. Economic Costs of Diabetes in the U.S. in 2022. Diabetes Care. Jan 1 2024;47(1):26-43.
6. Wang H, Akbari-Alavijeh S, Parhar RS, Gaugler R, Hashmi S. Partners in diabetes epidemic: A global perspective. World J Diabetes. Oct 15 2023;14(10):1463-1477.
7. Namazi N, Moghaddam SS, Esmaeili S, et al. Burden of type 2 diabetes mellitus and its risk factors in North Africa and the Middle East, 1990-2019: findings from the Global Burden of Disease study 2019. BMC Public Health. Jan 5 2024;24(1):98.
8. Kanaya AM. Diabetes in South Asians: Uncovering Novel Risk Factors With Longitudinal Epidemiologic Data: Kelly West Award Lecture 2023. Diabetes Care. Jan 1 2024;47(1):7-16.
9. Fleifel M, Fleifel B, El Alam A. Diabetes Mellitus across the Arabo-Islamic World: A Revolution. Int J Endocrinol. 2023;2023:5541808.
10. Tang FY, Guo XT, Zhang L, et al. The prevalence of diabetes distress in Chinese patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Res Clin Pract. Dec 2023;206:110996.
11. Tampe I, Garfias C, Borzutzky A, Slaibe L, García H. Incidence of type 1 diabetes in Chilean children between 2006 and 2021: significant increase during the COVID-19 pandemic. Acta Diabetol. Jan 2024;61(1):29-34.
12. Bu Y, Shih KC, Tong L. The ocular surface and diabetes, the other 21st Century epidemic. Exp Eye Res. Jul 2022;220:109099.
13. Arshad MS, Alqahtani F, Rasool MF. A Systematic Review of the Economic Burden of Diabetes in Eastern Mediterranean Region Countries. Diabetes Metab Syndr Obes. 2024;17:479-487.
14. Hacker K. The Burden of Chronic Disease. Mayo Clin Proc Innov Qual Outcomes. Feb 2024;8(1):112-119.
15. Morya AK, Ramesh PV, Kaur K, et al. Diabetes more than retinopathy, it's effect on the anterior segment of eye. World J Clin Cases. Jun 6 2023;11(16):3736-3749.
16. Zhou Q, Yang L, Wang Q, Li Y, Wei C, Xie L. Mechanistic investigations of diabetic ocular surface diseases. Front Endocrinol (Lausanne). 2022;13:1079541.
17. Zhang X, Zhao L, Deng S, Sun X, Wang N. Dry Eye Syndrome in Patients with Diabetes Mellitus: Prevalence, Etiology, and Clinical Characteristics. J Ophthalmol. 2016;2016:8201053.
18. Zagon., I.S., McLaughlin., et al. Opioid receptors and endogenous opioids in diverse human and animal cancers. J Natl Cancer Inst. 1987 1987;79:1059-1065.
19. Zagon IS, Sassani JW, Allison G, McLaughlin PJ. Conserved expression of the opioid growth factor, [Met5]enkephalin, and the zeta (zeta) opioid receptor in vertebrate cornea. Brain Research. 2/6/1995 1995;671(1) :105-111.
20. Zagon IS, Wu Y, McLaughlin PJ. Opioid growth factor and organ development in rat and human embryos. Brain Research. 8/28/ 1999 1999;839(2):313-322.
21. Zagon., I.S., McLaughlin., P.J. Naltrexone modulates growth in infant rats. Life Sci. 1983 1983;33:2449-2454.
22. Zagon., I.S., McLaughlin., P.J. Naloxone modulates body and organ growth of rats: dependency on the duration of opioid receptor blockade and stereospecificity. Pharmacol Biochem Behav. 1989 1989;33:325-328.
23. Zagon., I.S., McLaughlin., P.J. Naltrexone modulates body and brain development in rats: a role for endogenous opioid systems in growth. Life Sci. 1984 1984;35:2057-2064.
24. Zagon., I.S., Sassani., et al. The autocrine derivation of the opioid growth factor, [Met5]-enkephalin, in ocular surface epithelium. Brain Research. 1998 1998;792:72-78.
25. Zagon IS, Verderame MF, Allen SS, McLaughlin PJ. Cloning, sequencing, expression and function of a cDNA encoding a receptor for the opioid growth factor, [Met(5)]enkephalin. Brain Research. 12/4/199 9 1999;849(1-2):147-154.
26. Zagon IS, Verderame MF, Allen SS, McLaughlin PJ. Cloning, sequencing, chromosomal location, and function of cDNAs encoding an opioid growth factor receptor (OGFr) in humans. Brain Research. 2/21/2000 2000;856(1-2):75-83.
27. Coffa D, Snyder H. Opioid Use Disorder: Medical Treatment Options. Am Fam Physician. Oct 1 2019;100(7):416-425.
28. Townsend EA, Negus SS, Banks ML. Medications Development for Treatment of Opioid Use Disorder. Cold Spring Harb Perspect Med. Jan 4 2021;11(1).
29. Konakanchi JS, Sethi R. The Growing Epidemic of Opioid Use Disorder in the Elderly and Its Treatment: A Review of the Literature. Prim Care Companion CNS Disord. Jan 10 2023;25(1).
30. Marin MCD, Pedro MOP, Perrotte G, et al. Pharmacological Treatment of Alcohol Cravings. Brain Sci. Aug 15 2023;13(8).
31. Stokłosa I, Więckiewicz G, Stokłosa M, Piegza M, Pudlo R, Gorczyca P. Medications for the Treatment of Alcohol Dependence-Current State of Knowledge and Future Perspectives from a Public Health Perspective. Int J Environ Res Public Health. Jan 19 2023;20(3).
32. Isayama T, McLaughlin PJ, Zagon IS. Ontogeny of preproenkephalin mRNA expression in the rat retina. Visual Neuroscience. 7/1996 1996;13(4):695-704.
33. Isayama T, Hurst WJ, McLaughlin PJ, Zagon IS. Ontogeny of the opioid growth factor, [Met5]-enkephalin, and its binding activity in the rat retina. Visual Neuroscience. 9/1995 1995;12(5):939-950.
34. Patten DK, Schultz BG, Berlau DJ. The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders. Pharmacotherapy. Mar 2018;38(3):382-389.
35. Turel AP, Oh KH, Zagon IS, McLaughlin PJ. Low Dose Naltrexone for Treatment of Multiple Sclerosis: A Retrospective Chart Review of Safety and Tolerability. J Clin Psychopharmacol. Oct 2015;35(5):609-611.
36. Zagon IS, Ruth TB, Leure-duPree AE, Sassani JW, McLaughlin PJ. Immunoelectron microscopic localization of the opioid growth factor receptor (OGFr) and OGF in the cornea. Brain Res. 3/28/2003 2003;967(1-2):37-47.
37. Zagon., I.S., Sassani., et al. Conserved expression of the opioid growth factor, [Met5]enkephalin, and the zeta (z) opioid receptor in vertebrate cornea. Brain Res. 1995 1995;671:105-111.
38. Zagon., I.S., Sassani., J.W., McLaughlin., P.J. Opioid growth factor modulates corneal epithelial outgrowth in tissue culture. Am J Physiol. 1995 1995;286:R942-R950.
39. Zagon IS, Sassani JW, McLaughlin PJ. Re-epithelialization of the rabbit cornea is regulated by opioid growth factor. Brain Research. 8/24/1998 1998;803(1-2):61-68.
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