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: 21 dec. 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.
References
1. Organization WH. Diabetes: Overview. https://www.who.int/health-topics/diabetes#tab=tab_1.
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.
40. Zagon., I.S., Sassani., J.W., McLaughlin., P.J. Re-epithelialization of the rat cornea is accelerated by blockade of opioid receptors. Brain Research. 1998 1998;798:254-260.
41. Zagon IS, Sassani JW, Verderame MF, McLaughlin PJ. Particle-mediated gene transfer of opioid growth factor receptor cDNA regulates cell proliferation of the corneal epithelium. Cornea. 7/2005 2005;24 (5):614-619.
42. Zagon IS, Sassani JW, Malefyt KJ, McLaughlin PJ. Regulation of corneal repair by particle-mediated gene transfer of opioid growth factor receptor complementary DNA. Arch. Ophthalmol. 11/2006 2006;124(11):162 0-1624.
43. Zagon IS, Sassani JW, McLaughlin PJ. Reepithelialization of the human cornea is regulated by endogenous opioids. Investigative. Ophthalmology & Visual Science. 1/2000 2000;41(1):73-81.
44. Zagon IS, Jenkins JB, Sassani JW, et al. Naltrexone, an opioid antagonist, facilitates reepithelialization of the cornea in diabetic rat. Diabetes. 2002 2002;51:3055-3062.
45. Negri M, Tonnarini G, D'Alessandro M, Fallucca F. Plasma met-enkephalin in type I diabetes. Metabolism. 5/1992 1992;41(5):460-461.
46. Negri M, Fallucca F, Tonnarini G, Mariani P, D'Alessandro M, Pachi A. High levels of circulating met-enkephalin in pregnant and menstruating type 1 diabetic women. Gynecol. Endocrinol. 3/1990 1990;4(1):25-31.
47. Fallucca F, Tonnarini G, Di Biase N, D'Allessandro M, Negri M. Plasma met-enkephalin levels in diabetic patients: influence of autonomic neuropathy. Metabolism. 9/1996 1996;45(9):1065-1068.
48. Greenberg J, Ellyin F, Pullen G, Ehrenpreis S, Singh SP, Cheng J. Methionine-enkephalin and beta-endorphin levels in brain, pancreas, and adrenals of db/db mice. Endocrinology. 1/1985 1985;116(1):328-331.
49. Zagon IS, Sassani JW, McLaughlin PJ. Insulin treatment ameliorates impaired corneal reepithelialization in diabetic rats. Diabetes. 4/2006 2006;55(4):1141-1147.
50. Zagon IS, Klocek MS, Sassani JW, McLaughlin PJ. Use of topical insulin to normalize corneal epithelial healing in diabetes mellitus. Arch Ophthalmol. 8/2007 2007;125(8):1082-1088.
51. Klocek MS, Sassani JW, McLaughlin PJ, Zagon IS. Naltrexone and insulin are independently effective but not additive in accelerating corneal epithelial healing in type I diabetic rats. Exp. Eye Res. 11/2009 2009;89(5):686-692.
52. Purushothaman I, Zagon IS, Sassani JW, McLaughlin PJ. Ocular surface complications in diabetes: The interrelationship between insulin and enkephalin. Biochem Pharmacol. Oct 2021;192:114712.
53. Zagon IS, Klocek MS, Sassani JW, Mauger DT, McLaughlin PJ. Corneal safety of topically applied naltrexone. J. Ocul. Pharmacol. Ther. 10/2006 2006;22(5):377-387.
54. Zagon IS, Sassani JW, Myers RL, McLaughlin PJ. Naltrexone accelerates healing without compromise of adhesion complexes in normal and diabetic corneal epithelium. Brain Res. Bull. 4/2/2007 2007;72( 1):18-24.
55. Petropoulos IN, Alam U, Fadavi H, et al. Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy. Invest Ophthalmol. Vis. Sci. 4/3/2014 2014;55(4):2071-2078.
56. Tavakoli M, Quattrini C, Abbott C, et al. Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Diabetes Care. 8/2010 2010;33(8):1792-1797.
57. Tavakoli M, Kallinikos P, Iqbal A, et al. Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet. Med. 10/2011 2011;28(10):1261-1267.
58. Tavakoli M, Boulton AJ, Efron N, Malik RA. Increased Langerhan cell density and corneal nerve damage in diabetic patients: role of immune mechanisms in human diabetic neuropathy. Cont. Lens Anterior. Eye. 2/2011 2011;34(1):7-11.
59. Tavakoli M, Petropoulos IN, Malik RA. Assessing corneal nerve structure and function in diabetic neuropathy. Clin. Exp. Optom. 5/2012 2012;95(3):338-347.
60. Tavakoli M, Petropoulos IN, Malik RA. Corneal confocal microscopy to assess diabetic neuropathy: an eye on the foot. J. Diabetes Sci. Technol. 9/1/2013 2013;7(5):11 79-1189.
61. Cousen P, Cackett P, Bennett H, Swa K, Dhillon B. Tear production and corneal sensitivity in diabetes. J. Diabetes Complications. 11/2007 2007;21(6):371-373.
62. Pritchard N, Edwards K, Vagenas D, Russell AW, Malik RA, Efron N. Corneal sensitivity is related to established measures of diabetic peripheral neuropathy. Clin. Exp. Optom. 5/2012 2012;95(3):355-361.
63. Pritchard N, Edwards K, Shahidi AM, et al. Corneal markers of diabetic neuropathy. Ocul. Surf. 1/2011 2011;9(1):17-28.
64. Wang F, Gao N, Yin J, Yu FS. Reduced innervation and delayed re-innervation after epithelial wounding in type 2 diabetic Goto-Kakizaki rats. Am. J. Pathol. 12/2012 2012;181 (6):2058-2066.
65. Davidson EP, Coppey LJ, Kardon RH, Yorek MA. Differences and similarities in development of corneal nerve damage and peripheral neuropathy and in diet-induced obesity and type 2 diabetic rats. Invest Ophthalmol. Vis. Sci. 3/3/2014 2014;55(3):1222-1230.
66. Tavakoli M, Mitu-Pretorian M, Petropoulos IN, et al. Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes. 1/2013 2013;62(1):254-260.
67. Davidson EP, Coppey LJ, Yorek MA. Early loss of innervation of cornea epithelium in streptozotocin-induced type 1 diabetic rats: improvement with ilepatril treatment. Invest Ophthalmol. Vis. Sci. 12/7/2012 2012;53(13):8 067-8074.
68. Zagon IS, Sassani JW, Immonen JA, McLaughlin PJ. Ocular surface abnormalities related to type 2 diabetes are reversed by the opioid antagonist naltrexone. Clin. Experiment. Ophthalmol. 6/18/2013 2013:10.
69. Zagon IS, Campbell AM, Sassani JW, McLaughlin PJ. Spontaneous episodic decreased tear secretion in rats is related to opioidergic signaling pathways. Invest Ophthalmol. Vis. Sci. 5/31/2012 2012;53(6):32 34-3240.
70. Zagon IS, Klocek MS, Sassani JW, McLaughlin PJ. Dry eye reversal and corneal sensation restoration with topical naltrexone in diabetes mellitus. Arch. Ophthalmol. 11/20 09 2009;127(11):1468-1473.
71. McLaughlin PJ, Sassani JW, Titunick MB, Zagon IS. Efficacy and safety of a novel naltrexone treatment for dry eye in type 1 diabetes. BMC Ophthalmol. Jan 28 2019;19(1):35.
72. Zagon IS. Sex Differences in Diabetic Ocular Surface Complications and Dysregulation of the OGF-OGFr Pathway. Int Immunopharmacol. 2022;4(1):20-24.
73. Purushothaman I, Zagon IS, Sassani JW, Zhou S, McLaughlin PJ. Sex differences in the magnitude of diabetic ocular surface complications: Role of serum OGF. Physiol Behav. Aug 1 2021;237:113436.
74. Purushothaman I, Zagon IS, Sassani JW, McLaughlin PJ. Ocular surface complications result from dysregulation of the OGF-OGFr signaling pathway in female diabetic rats. Exp Ther Med. Jul 2021;22(1):687.
75. Zagon IS, Sassani JW, Purushothaman I, McLaughlin PJ. Blockade of OGFr delays the onset and reduces the severity of diabetic ocular surface complications. Exp Biol Med (Maywood). Mar 2021;246(5):629-636.
76. Liang D, Sassani JW, McLaughlin PJ, Zagon IS. Topical Application of Naltrexone to the Ocular Surface of Healthy Volunteers: A Tolerability Study. J Ocul Pharmacol Ther. Mar 2016;32(2):127-132.
77. Maldonado-Valer T, Pareja-Mujica LF, Corcuera-Ciudad R, et al. Prevalence of diabetic foot at risk of ulcer development and its components stratification according to the international working group on the diabetic foot (IWGDF): A systematic review with metanalysis. PLoS One. 2023;18(11):e0284054.
78. Armstrong DG, Tan TW, Boulton AJM, Bus SA. Diabetic Foot Ulcers: A Review. Jama. Jul 3 2023;330(1):62-75.
79. Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. Jun 15 2017;376(24):2367-2375.
80. Hicks CW, Canner JK, Mathioudakis N, et al. The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification independently predicts wound healing in diabetic foot ulcers. J Vasc Surg. Oct 2018;68(4):1096-1103.
81. Niță O, Arhire LI, Mihalache L, et al. Evaluating Classification Systems of Diabetic Foot Ulcer Severity: A 12-Year Retrospective Study on Factors Impacting Survival. Healthcare (Basel). Jul 20 2023;11(14).
82. Rice JB, Desai U, Cummings AK, Birnbaum HG, Skornicki M, Parsons NB. Burden of diabetic foot ulcers for medicare and private insurers. Diabetes Care. 2014;37(3):651-658.
83. Game FL, Apelqvist J, Attinger C, et al. Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review. Diabetes Metab Res Rev. Jan 2016;32 Suppl 1:154-168.
84. Bandyk DF. The diabetic foot: Pathophysiology, evaluation, and treatment. Semin Vasc Surg. Jun-Dec 2018;31(2-4):43-48.
85. McLaughlin PJ, Pothering CA, Immonen JA, Zagon IS. Topical treatment with the opioid antagonist naltrexone facilitates closure of full-thickness wounds in diabetic rats. Exp. Biol. Med. (Maywood. ). 10/2011 2011;236(10):1122-1132.
86. McLaughlin PJ, Immonen JA, Zagon IS. Topical naltrexone accelerates full-thickness wound closure in type 1 diabetic rats by stimulating angiogenesis. Exp. Biol. Med. (Maywood. ). 7/2013 2013;238(7):733-743.
87. Immonen JA, Zagon IS, Lewis GS, McLaughlin PJ. Topical treatment with the opioid antagonist naltrexone accelerates the remodeling phase of full-thickness wound healing in type 1 diabetic rats. Exp. Biol. Med. (Maywood. ). 10/2013 2013;238(10):1127-1135.
88. Immonen JA, Zagon IS, McLaughlin PJ. Topical Naltrexone as Treatment for Type 2 Diabetic Cutaneous Wounds. Adv. Wound. Care (New Rochelle. ). 6/1/2014 2014;3(6):419-427.
89. McLaughlin PJ, Sassani JW, Zagon IS. Safety study of topical naltrexone therapy for diabetic skin wounds is confirmed in Göttingen mini-pigs. Public Underst Sci. Sep 2023;84(6):1279-1284.
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.
40. Zagon., I.S., Sassani., J.W., McLaughlin., P.J. Re-epithelialization of the rat cornea is accelerated by blockade of opioid receptors. Brain Research. 1998 1998;798:254-260.
41. Zagon IS, Sassani JW, Verderame MF, McLaughlin PJ. Particle-mediated gene transfer of opioid growth factor receptor cDNA regulates cell proliferation of the corneal epithelium. Cornea. 7/2005 2005;24 (5):614-619.
42. Zagon IS, Sassani JW, Malefyt KJ, McLaughlin PJ. Regulation of corneal repair by particle-mediated gene transfer of opioid growth factor receptor complementary DNA. Arch. Ophthalmol. 11/2006 2006;124(11):162 0-1624.
43. Zagon IS, Sassani JW, McLaughlin PJ. Reepithelialization of the human cornea is regulated by endogenous opioids. Investigative. Ophthalmology & Visual Science. 1/2000 2000;41(1):73-81.
44. Zagon IS, Jenkins JB, Sassani JW, et al. Naltrexone, an opioid antagonist, facilitates reepithelialization of the cornea in diabetic rat. Diabetes. 2002 2002;51:3055-3062.
45. Negri M, Tonnarini G, D'Alessandro M, Fallucca F. Plasma met-enkephalin in type I diabetes. Metabolism. 5/1992 1992;41(5):460-461.
46. Negri M, Fallucca F, Tonnarini G, Mariani P, D'Alessandro M, Pachi A. High levels of circulating met-enkephalin in pregnant and menstruating type 1 diabetic women. Gynecol. Endocrinol. 3/1990 1990;4(1):25-31.
47. Fallucca F, Tonnarini G, Di Biase N, D'Allessandro M, Negri M. Plasma met-enkephalin levels in diabetic patients: influence of autonomic neuropathy. Metabolism. 9/1996 1996;45(9):1065-1068.
48. Greenberg J, Ellyin F, Pullen G, Ehrenpreis S, Singh SP, Cheng J. Methionine-enkephalin and beta-endorphin levels in brain, pancreas, and adrenals of db/db mice. Endocrinology. 1/1985 1985;116(1):328-331.
49. Zagon IS, Sassani JW, McLaughlin PJ. Insulin treatment ameliorates impaired corneal reepithelialization in diabetic rats. Diabetes. 4/2006 2006;55(4):1141-1147.
50. Zagon IS, Klocek MS, Sassani JW, McLaughlin PJ. Use of topical insulin to normalize corneal epithelial healing in diabetes mellitus. Arch Ophthalmol. 8/2007 2007;125(8):1082-1088.
51. Klocek MS, Sassani JW, McLaughlin PJ, Zagon IS. Naltrexone and insulin are independently effective but not additive in accelerating corneal epithelial healing in type I diabetic rats. Exp. Eye Res. 11/2009 2009;89(5):686-692.
52. Purushothaman I, Zagon IS, Sassani JW, McLaughlin PJ. Ocular surface complications in diabetes: The interrelationship between insulin and enkephalin. Biochem Pharmacol. Oct 2021;192:114712.
53. Zagon IS, Klocek MS, Sassani JW, Mauger DT, McLaughlin PJ. Corneal safety of topically applied naltrexone. J. Ocul. Pharmacol. Ther. 10/2006 2006;22(5):377-387.
54. Zagon IS, Sassani JW, Myers RL, McLaughlin PJ. Naltrexone accelerates healing without compromise of adhesion complexes in normal and diabetic corneal epithelium. Brain Res. Bull. 4/2/2007 2007;72( 1):18-24.
55. Petropoulos IN, Alam U, Fadavi H, et al. Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy. Invest Ophthalmol. Vis. Sci. 4/3/2014 2014;55(4):2071-2078.
56. Tavakoli M, Quattrini C, Abbott C, et al. Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Diabetes Care. 8/2010 2010;33(8):1792-1797.
57. Tavakoli M, Kallinikos P, Iqbal A, et al. Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet. Med. 10/2011 2011;28(10):1261-1267.
58. Tavakoli M, Boulton AJ, Efron N, Malik RA. Increased Langerhan cell density and corneal nerve damage in diabetic patients: role of immune mechanisms in human diabetic neuropathy. Cont. Lens Anterior. Eye. 2/2011 2011;34(1):7-11.
59. Tavakoli M, Petropoulos IN, Malik RA. Assessing corneal nerve structure and function in diabetic neuropathy. Clin. Exp. Optom. 5/2012 2012;95(3):338-347.
60. Tavakoli M, Petropoulos IN, Malik RA. Corneal confocal microscopy to assess diabetic neuropathy: an eye on the foot. J. Diabetes Sci. Technol. 9/1/2013 2013;7(5):11 79-1189.
61. Cousen P, Cackett P, Bennett H, Swa K, Dhillon B. Tear production and corneal sensitivity in diabetes. J. Diabetes Complications. 11/2007 2007;21(6):371-373.
62. Pritchard N, Edwards K, Vagenas D, Russell AW, Malik RA, Efron N. Corneal sensitivity is related to established measures of diabetic peripheral neuropathy. Clin. Exp. Optom. 5/2012 2012;95(3):355-361.
63. Pritchard N, Edwards K, Shahidi AM, et al. Corneal markers of diabetic neuropathy. Ocul. Surf. 1/2011 2011;9(1):17-28.
64. Wang F, Gao N, Yin J, Yu FS. Reduced innervation and delayed re-innervation after epithelial wounding in type 2 diabetic Goto-Kakizaki rats. Am. J. Pathol. 12/2012 2012;181 (6):2058-2066.
65. Davidson EP, Coppey LJ, Kardon RH, Yorek MA. Differences and similarities in development of corneal nerve damage and peripheral neuropathy and in diet-induced obesity and type 2 diabetic rats. Invest Ophthalmol. Vis. Sci. 3/3/2014 2014;55(3):1222-1230.
66. Tavakoli M, Mitu-Pretorian M, Petropoulos IN, et al. Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes. 1/2013 2013;62(1):254-260.
67. Davidson EP, Coppey LJ, Yorek MA. Early loss of innervation of cornea epithelium in streptozotocin-induced type 1 diabetic rats: improvement with ilepatril treatment. Invest Ophthalmol. Vis. Sci. 12/7/2012 2012;53(13):8 067-8074.
68. Zagon IS, Sassani JW, Immonen JA, McLaughlin PJ. Ocular surface abnormalities related to type 2 diabetes are reversed by the opioid antagonist naltrexone. Clin. Experiment. Ophthalmol. 6/18/2013 2013:10.
69. Zagon IS, Campbell AM, Sassani JW, McLaughlin PJ. Spontaneous episodic decreased tear secretion in rats is related to opioidergic signaling pathways. Invest Ophthalmol. Vis. Sci. 5/31/2012 2012;53(6):32 34-3240.
70. Zagon IS, Klocek MS, Sassani JW, McLaughlin PJ. Dry eye reversal and corneal sensation restoration with topical naltrexone in diabetes mellitus. Arch. Ophthalmol. 11/20 09 2009;127(11):1468-1473.
71. McLaughlin PJ, Sassani JW, Titunick MB, Zagon IS. Efficacy and safety of a novel naltrexone treatment for dry eye in type 1 diabetes. BMC Ophthalmol. Jan 28 2019;19(1):35.
72. Zagon IS. Sex Differences in Diabetic Ocular Surface Complications and Dysregulation of the OGF-OGFr Pathway. Int Immunopharmacol. 2022;4(1):20-24.
73. Purushothaman I, Zagon IS, Sassani JW, Zhou S, McLaughlin PJ. Sex differences in the magnitude of diabetic ocular surface complications: Role of serum OGF. Physiol Behav. Aug 1 2021;237:113436.
74. Purushothaman I, Zagon IS, Sassani JW, McLaughlin PJ. Ocular surface complications result from dysregulation of the OGF-OGFr signaling pathway in female diabetic rats. Exp Ther Med. Jul 2021;22(1):687.
75. Zagon IS, Sassani JW, Purushothaman I, McLaughlin PJ. Blockade of OGFr delays the onset and reduces the severity of diabetic ocular surface complications. Exp Biol Med (Maywood). Mar 2021;246(5):629-636.
76. Liang D, Sassani JW, McLaughlin PJ, Zagon IS. Topical Application of Naltrexone to the Ocular Surface of Healthy Volunteers: A Tolerability Study. J Ocul Pharmacol Ther. Mar 2016;32(2):127-132.
77. Maldonado-Valer T, Pareja-Mujica LF, Corcuera-Ciudad R, et al. Prevalence of diabetic foot at risk of ulcer development and its components stratification according to the international working group on the diabetic foot (IWGDF): A systematic review with metanalysis. PLoS One. 2023;18(11):e0284054.
78. Armstrong DG, Tan TW, Boulton AJM, Bus SA. Diabetic Foot Ulcers: A Review. Jama. Jul 3 2023;330(1):62-75.
79. Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. Jun 15 2017;376(24):2367-2375.
80. Hicks CW, Canner JK, Mathioudakis N, et al. The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification independently predicts wound healing in diabetic foot ulcers. J Vasc Surg. Oct 2018;68(4):1096-1103.
81. Niță O, Arhire LI, Mihalache L, et al. Evaluating Classification Systems of Diabetic Foot Ulcer Severity: A 12-Year Retrospective Study on Factors Impacting Survival. Healthcare (Basel). Jul 20 2023;11(14).
82. Rice JB, Desai U, Cummings AK, Birnbaum HG, Skornicki M, Parsons NB. Burden of diabetic foot ulcers for medicare and private insurers. Diabetes Care. 2014;37(3):651-658.
83. Game FL, Apelqvist J, Attinger C, et al. Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review. Diabetes Metab Res Rev. Jan 2016;32 Suppl 1:154-168.
84. Bandyk DF. The diabetic foot: Pathophysiology, evaluation, and treatment. Semin Vasc Surg. Jun-Dec 2018;31(2-4):43-48.
85. McLaughlin PJ, Pothering CA, Immonen JA, Zagon IS. Topical treatment with the opioid antagonist naltrexone facilitates closure of full-thickness wounds in diabetic rats. Exp. Biol. Med. (Maywood. ). 10/2011 2011;236(10):1122-1132.
86. McLaughlin PJ, Immonen JA, Zagon IS. Topical naltrexone accelerates full-thickness wound closure in type 1 diabetic rats by stimulating angiogenesis. Exp. Biol. Med. (Maywood. ). 7/2013 2013;238(7):733-743.
87. Immonen JA, Zagon IS, Lewis GS, McLaughlin PJ. Topical treatment with the opioid antagonist naltrexone accelerates the remodeling phase of full-thickness wound healing in type 1 diabetic rats. Exp. Biol. Med. (Maywood. ). 10/2013 2013;238(10):1127-1135.
88. Immonen JA, Zagon IS, McLaughlin PJ. Topical Naltrexone as Treatment for Type 2 Diabetic Cutaneous Wounds. Adv. Wound. Care (New Rochelle. ). 6/1/2014 2014;3(6):419-427.
89. McLaughlin PJ, Sassani JW, Zagon IS. Safety study of topical naltrexone therapy for diabetic skin wounds is confirmed in Göttingen mini-pigs. Public Underst Sci. Sep 2023;84(6):1279-1284.