Biology of the Opioid Growth Factor – Opioid Growth Factor Receptor Axis: Bench to Bedside and Back
Main Article Content
Abstract
The Opioid Growth Factor – Opioid Growth Factor Receptor axis was identified nearly 30 years ago in our laboratory when we demonstrated that an endogenous opioid pentapeptide had inhibitory growth activity following injection into normal animals. In addition to validating this action for the peptide, identification, characterization and cloning of the specific receptor related to the opioid growth factor, chemically termed [Met5]-enkephalin, revealed that the receptor was unique in its biochemical and molecular structure, but had pharmacological properties similar to other opioid receptors. Mechanisms associated with binding of the opioid growth factor to its receptor located on the outer nuclear envelop and the transport into the nucleus were identified. The selectively of the peptide for the receptor was demonstrated in normal and cancer cell lines. This uniqueness of the peptide-receptor interaction was evidenced by the duration of receptor blockade in that intermittent blockade resulted in decreased cell replication and complete blockade resulted in accelerated proliferation. Investigations on the mechanism of action, as well as the dysregulation of the Opioid Growth Factor – Opioid Growth Factor Receptor axis in human pathology, have resulted in bench to bedside and bedside to bench discoveries. Receptor blockade by naltrexone has been used clinically for treatment of fatigue and other immune deficiencies in many autoimmune disorders. The research has gone from bench to bedside and has returned to the bench for additional investigation of mechanisms driving the action of the axis and resultant function following receptor blockade.
Keywords:
[Met5]-enkephalin, diabetes, dry eye, multiple sclerosis, low-dose naltrexone
Article Details
How to Cite
ZAGON, Ian S.; MCLAUGHLIN, Patricia J..
Biology of the Opioid Growth Factor – Opioid Growth Factor Receptor Axis: Bench to Bedside and Back.
Medical Research Archives, [S.l.], v. 12, n. 6, june 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5369>. Date accessed: 02 july 2024.
doi: https://doi.org/10.18103/mra.v12i6.5369.
Section
Research 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. Zagon IS, Verderame MF, McLaughlin PJ. The biology of the opioid growth factor receptor (OGFr). Brain Res Rev 2002;38:351-376. PMID:11890982
2. Zagon IS, McLaughlin PJ. Naltrexone modulates growth in infant rats. Life Sci. 1983;33:2449-2454. PMID: 6316064
3. Zagon IS, McLaughlin PJ. Increased brain size and cellular content in infant rats treated with an opiate antagonist. Science 1983;221:1179-1180. PMID: 6612331
4. Zagon IS, McLaughlin PJ. Naltrexone modulates tumor response in mice with neuroblastoma. Science 1983;221:671-673. PMID: 6867737
5. Zagon IS, McLaughlin PJ. Opioid antagonist (naltrexone) modulation of cerebellar development: Histological and morphometric studies. J. Neurosci. 1983;6:1424-1432.
6. Zagon IS, Rhodes RE, McLaughlin PJ. Distribution of enkephalin immunoreactivity in germinative cells of developing rat cerebellum. Science 1985;227:1049-1051.
7. 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 2003;967:37-47. PMID: 12650984
8. Cheng F, McLaughlin PJ, Banks WA, Zagon IS. Internalization of the opioid growth factor, [Met5]-enkephalin, is dependent on clathrin-mediated endocytosis for downregulation of cell proliferation. Amer J Physiol 2010;299:R774-R785. PMID: 20592180
9. Cheng F, McLaughlin PJ, Verderame MF, Zagon IS. Dependence on nuclear localization signals of the opioid growth factor receptor in the regulation of cell proliferation. Exp. Biol. Med 2009;234:532-541. PMID: 19244545
10. Cheng F, McLaughlin PJ, Zagon IS. Regulation of cell proliferation by the opioid growth factor is dependent on karyopherin β and Ran for nucleocytoplasmic trafficking. Exp. Biol. Med., 2010;235:1093-1101. PMID: 20705629
11. Cheng F, Zagon IS, Verderame MF, McLaughlin PJ. The opioid growth factor (OGF)-OGF receptor axis uses the p16 pathway to inhibit head and neck cancer. Cancer Res 2007;67:10511-10518. PMID: 17974995
12. Cheng F, McLaughlin PJ, Verderame MF, Zagon IS. The OGF-OGFr axis utilizes the p21 pathway to restrict progression of human pancreatic cancer. Mol Cancer 2008;7:5-17. PMCID: PMC2253557 PMID: 18190706.
13. Cheng F, McLaughlin PJ, Verderame MF, Zagon IS. The OGF-OGFr axis utilizes the p16INK4a and p21WAF1/CIP1 pathways to restrict normal cell proliferation. Mol Bio Cell 2009; 20:319-327. PMCID:PMC2613082 PMID: 18923142.
14. U.S. Food & Drug Administration. Drug Approval Package – Vivitrol. 2006. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021897_toc_Vivitrol.cfm
15. McLaughlin PJ, Zagon IS. Duration of opioid receptor blockade determines clinical response. Biochem Pharmacol 2015;97:236-246.
16. Cheng F, McLaughlin PJ, Banks WA, Zagon IS. Passive diffusion of naltrexone into human and animal cells and upregulation of cell proliferation. Amer J Physiol Regul Integr Physiol 2009;297:R844-R852. PMID: 19605761
17. Zagon IS, Donahue RN, McLaughlin PJ. Opioid growth factor-opioid growth factor receptor axis is a physiological determinant of cell proliferation in diverse human cancers. Amer J Physiol Regul Integr Physiol 2009;297:R1154-R1161. PMID: 19675283
18. Kren NP, Zagon IS, McLaughlin PJ. Mutations in the opioid growth factor receptor in human cancers alter receptor function. Int J Mol Med 2015:36:289-293.
19. Kren NP, Zagon, McLaughlin PJ. Nuclear export of opioid growth factor receptor is CRM1 dependent. Exp Biol Med 2016;241:273-281.
20. McLaughlin PJ, Verderame MF, Hankins JL, Zagon IS. Overexpression of the opioid growth factor receptor downregulates cell proliferation of human squamous carcinoma cells of the head and neck. Int J Mol Med 2007;19:421-428. PMID: 17273790
21. Donahue RN, McLaughlin PJ, Zagon IS. Under-expression of the opioid growth factor receptor promotes progression of human ovarian cancer. Exp. Biol. Med. 2012;237:167-177. PMID: 22328595
22. Donahue RN, McLaughlin PJ, Zagon IS. Low-dose naltrexone targets the opioid growth factor –opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model. Exp Biol Med 2011;236:1036-1050.
23. Bihari B. Efficacy of low dose naltrexone as an immune stabilizing agent for the treatment of HIV/AIDS. AIDS Patient Care 1995:3
24. Yang J, Shin KM, Do A, Bierle DM, Abu Dabrh AM, Yin Z, Bauer BA, Muhabbaat AR. The safety and efficacy of low dose naltrexone in patients with fibromyalgia: A systematic review. J Pain Res 2023;16:1017-1023.
25. Driver CN, D’Souza RS. Efficacy of low-dose naltrexone and predictors of treatment success or discontinuation in fibromyalgia and other chronic pain conditions: A fourteen-year, enterprise-wide retrospective analysis. Biomedicines 2023; 11:1087
26. Dara P, Farooqui Z, Mwale F, Choe C, van Wijnen AJ, Im H-J. Opiate antagonists for chronic pain: A review on the benefits of low-dose naltrexone in arthritis versus non-arthritic diseases. Biomedicines 2023; 11:1620.
27. Srinivasan A, Dutta P, Bansal D, Chakrabarti A, Bhansali AK, Hota D. Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active=control, crossover clinical trial. J Diabetes 2021;13:770-778.
28. Isman A, Nyquist A, Strecker B, Harinath G, Lee V, Zhang X, Zalzala S. Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19. Brain Behavior Immunity – Health 2024; 36:100733
29. Bonilla H, Tian L, Marconi VC, Shafer R, McComsey GA, Miglis M, Yang P, Bonilla A, Eggert L, Geng LN. Low-dose naltrexone use for the management of post-acute sequelae of COVID-19. Int Immunopharmacol. 124;2023: 110966.
30. McLaughlin PJ, Odom LB, Arnett PA, Orehek S, Thomas GA, Zagon IS. Low-dose naltrexone reduced anxiety in persons with multiple sclerosis during the COVID-19 pandemic. Int Immunopharmacol 113;2022:109438
31. McLaughlin PJ, Odom LB, Arnett PA, Thomas GA, Orehek S, Zagon IS. Length of disease more than therapy impacts anxiety and depression in persons with multiple sclerosis. Neurol Neurosci 2023;4 (1):1-6.
32. Zagon IS, Donahue RN, Bonneau RH, McLaughlin PJ. T lymphocyte proliferation is suppressed by the opioid growth factor ([Met5]-enkephalin)-opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases. Immunobiology 2011;216:579-590.
33. Zagon IS, Donahue RN, Bonneau RH, McLaughlin. B lymphocyte proliferation is suppressed by the opioid growth factor-opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases. Immunobiology 2011;216:173-183.
34. Zagon IS, Rahn KA, Turel AP, McLaughlin PJ. Endogenous opioids regulate expression of experimental autoimmune encephalomyelitis: A new paradigm for the treatment of multiple sclerosis. Exp. Biol. Med. 2009;234:1383-1392. PMID: 19855075
35. Rahn KA, McLaughlin PJ, Zagon IS. Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis. Brain Res. 2011;1381:243-253. PMID: 21256121
36. Ludwig MD, Turel AP, Zagon IS, McLaughlin PJ. Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis. Mult Scler J: Experimental, Translational and Clinical 2016;2:1-11
37. Patel C, Zagon IS, Pearce-Clawson M, McLaughlin PJ. Timing of treatment with an endogenous opioid alters immune response and spinal cord pathology in female mice with experimental autoimmune encephalomyelitis. J. Neurosci. Res. 2021;100:551-563. Doi:10.1002/jnr.24983.
38. Wang Y-S, Hung T-W, Bae E-K, Wu K-J, Hsieh W, Yu S-J. Naltrexone is neuroprotective against traumatic brain injury in mu opioid receptor knockout mice. CNS Neurosci Ther 2021;27:831-841.
39. Mustafa S, Evans S, Barry B, Barratt D, Wang Y, Lin C, Want X, Hutchinson MR. Toll-like receptor 4 in pain: Bridging molecules-to-cells-to systems. Handbook Exp Pharmacol 2022;276:239-273.
40. Negri M, Falluca F, Tonnarini G, Mariani P, D’Allessandro M, Pachi A. High levels of circulating met-enkephalin in pregnant and menstruating type 1 diabetic women. Gynecol Endocrinol 1990;4:25-31.
41. Negri M, Tonnarini G, De Blasé N, D’Allessandro M, Fallucca F. Plasma met-enkephalin in type 1 diabetes. Metabolism 1992;41:460-461.
42. Centers for Disease Control and Prevention. National diabetes statistics report. https://www.cdc.gov/diabetes/data/statistics-report/index.html. Reviewed by CDC November 29, 2023.
43. Ljubimov AV. Diabetic complications in the cornea. Vis Res 2017 Oct;139:138-152.
44. Yamamoto T, Otake H, Hiramatsu N, Yamamoto N, Taga A, NagaiN. 2018. A proteomic approach for understanding the mechanisms of delayed corneal wound healing in diabetic keratopathy using diabetic rat model. Int J Mol Sci 19:3635
45. Zagon IS, Sassani JW, McLaughlin PJ. Cellular dynamics of corneal wound re-epithelialization in the rat. I. Fate of ocular surface epithelial cells synthesizing DNA prior to wounding. Brain Res. 1999;822:149-162.
46. Zagon, I.S., J.W. Sassani and P.J. McLaughlin. 2000. Reepithelialization of the human cornea is regulated by endogenous opioids. Invest. Ophthalmol. Vis. Sci. 2000;41:73-81.
47. Zagon, I.S., J.W. Sassani and P.J. McLaughlin. Re-epithelialization of the rat cornea is accelerated by blockade of opioid receptors. Brain Res. 1998;798:254-260.
48. Zagon IS, Sassani JW, Verderame MF, McLaughlin PJ. 2005. Particle-mediated gene transfer of OGFr cDNA regulates cell proliferation of the corneal epithelium. Cornea 24(5):614-619. PMID: 15968171
49. Zagon, I.S., J.B. Jenkins, C.M. Lang, J.W. Sassani, J.D. Wylie, T.B. Ruth, J. L. Fry and P.J. McLaughlin. 2002. Naltrexone, an opioid antagonist, facilitates re-epithelialization of the cornea in diabetic rat. Diabetes 51:3055-3062. PMID: 12351447
50. Klocek, M.S., J.W. Sassani, P.J. McLaughlin, and I.S. Zagon. 2007. Topically applied naltrexone restores corneal reepithelialization in diabetic rats. J. Ocular Pharmacol. Ther. 23:89-102. PMID: 17444796
51. Zagon, I.S., J.W. Sassani, M.A. Carroll, and P.J. McLaughlin. 2010. Topical application of naltrexone facilitates reepithelialization of the cornea in diabetic rabbits. Brain Res. Bull. 81:248-255. PMCID: PMC2815253 PMID: 19853924
52. Klocek MS, Sassani JW, McLaughlin PJ, Zagon IS. Naltrexone and insulin are independently effective but not additive in accelerating corneal epithelial healing in type 1 diabetic rats. Exp Eye Res 2009;89:686-692.
53. McLaughlin PJ, Sassani JW, Diaz DP, Zagon IS. Elevated opioid growth factor alters the limbus in type 1 diabetic rats. J Diabetes Clin Res. 2023. doi: 10.1007/s11064-023-03938-4. PMID: 37166576
54. Zagon IS, Klocek MS, Sassani JW, McLaughlin PJ. Dry eye reversal and corneal sensation restoration with topical naltrexone in diabetes mellitus. Arch Ophthalmol 2009;127:1468-1473.
55. Zagon IS, Sassani JW, Purushothaman I, McLaughlin PJ. Dysregulation of the OGF-OGFr pathway correlates with elevated serum OGF and ocular surface complications in the diabetic rat. Exp Biol Med 2020;245:1414-1421 PMID: 32640891 PMCID:PMC7441350.
56. Zagon IS, Sassani JW, Immonen JA, McLaughlin PJ. Ocular surface abnormalities related to type 2 diabetes are reversed by the opioid antagonist naltrexone. Clin Exp Ophthalmol 2014;42:159-168.
57. Zagon IS, Sassani Purushothaman I, McLaughlin PJ. Blockade of the opioid growth factor receptor (OGFr) delays the onset and reduces the severity of diabetic ocular surface complications. Exp Biol Med 2021;246:629-636. PMID:33203224 Doi:10.1177/1535370220972060
58. Purushothaman I, Sassani JW, Zagon IS, McLaughlin PJ. Ocular surface complications result from dysregulation of the OGF-OGFr signaling pathway in female diabetic rats. Exp Ther Med 2021;22:687. doi: 10.3892/etm.2021.10119 PMID:33986852
59. 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 2016;32:127-132.
60. McLaughlin PJ, Pothering CA, Immonen JA, Zagon IS. Topical naltrexone, an opioid antagonist, enhances closure of full-thickness wounds in diabetic rats. Exp. Biol. Med. 2011;236:1122-1132. PMID:21927593
61. McLaughlin PJ, Immonen JA, Zagon IS. Topical naltrexone accelerates full-thickness wound closure in Type 1 diabetic rats by stimulating angiogenesis. Exp. Biol. Med. 2013;238:733-743. PMID: 23788174. Doi: 10.1177/1535370213492688
62. 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. 2013;238:1127-1135. PMID:23986225
63. Immonen JA, Zagon IS, McLaughlin PJ. Topical naltrexone as treatment for type 2 diabetic cutaneous wounds. Advances Wound Care 2014;3:419-427. PMID:24940556
64. McLaughlin PJ, Sassani JW, Zagon IS. Safety study of topical naltrexone therapy for diabetic skin wounds is confirmed in Göttingen mini-pigs. Drug Dev Res 2023;84 (6):1279-1284. doi:10.1002/ddr.22086. PMID: 37317059
2. Zagon IS, McLaughlin PJ. Naltrexone modulates growth in infant rats. Life Sci. 1983;33:2449-2454. PMID: 6316064
3. Zagon IS, McLaughlin PJ. Increased brain size and cellular content in infant rats treated with an opiate antagonist. Science 1983;221:1179-1180. PMID: 6612331
4. Zagon IS, McLaughlin PJ. Naltrexone modulates tumor response in mice with neuroblastoma. Science 1983;221:671-673. PMID: 6867737
5. Zagon IS, McLaughlin PJ. Opioid antagonist (naltrexone) modulation of cerebellar development: Histological and morphometric studies. J. Neurosci. 1983;6:1424-1432.
6. Zagon IS, Rhodes RE, McLaughlin PJ. Distribution of enkephalin immunoreactivity in germinative cells of developing rat cerebellum. Science 1985;227:1049-1051.
7. 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 2003;967:37-47. PMID: 12650984
8. Cheng F, McLaughlin PJ, Banks WA, Zagon IS. Internalization of the opioid growth factor, [Met5]-enkephalin, is dependent on clathrin-mediated endocytosis for downregulation of cell proliferation. Amer J Physiol 2010;299:R774-R785. PMID: 20592180
9. Cheng F, McLaughlin PJ, Verderame MF, Zagon IS. Dependence on nuclear localization signals of the opioid growth factor receptor in the regulation of cell proliferation. Exp. Biol. Med 2009;234:532-541. PMID: 19244545
10. Cheng F, McLaughlin PJ, Zagon IS. Regulation of cell proliferation by the opioid growth factor is dependent on karyopherin β and Ran for nucleocytoplasmic trafficking. Exp. Biol. Med., 2010;235:1093-1101. PMID: 20705629
11. Cheng F, Zagon IS, Verderame MF, McLaughlin PJ. The opioid growth factor (OGF)-OGF receptor axis uses the p16 pathway to inhibit head and neck cancer. Cancer Res 2007;67:10511-10518. PMID: 17974995
12. Cheng F, McLaughlin PJ, Verderame MF, Zagon IS. The OGF-OGFr axis utilizes the p21 pathway to restrict progression of human pancreatic cancer. Mol Cancer 2008;7:5-17. PMCID: PMC2253557 PMID: 18190706.
13. Cheng F, McLaughlin PJ, Verderame MF, Zagon IS. The OGF-OGFr axis utilizes the p16INK4a and p21WAF1/CIP1 pathways to restrict normal cell proliferation. Mol Bio Cell 2009; 20:319-327. PMCID:PMC2613082 PMID: 18923142.
14. U.S. Food & Drug Administration. Drug Approval Package – Vivitrol. 2006. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021897_toc_Vivitrol.cfm
15. McLaughlin PJ, Zagon IS. Duration of opioid receptor blockade determines clinical response. Biochem Pharmacol 2015;97:236-246.
16. Cheng F, McLaughlin PJ, Banks WA, Zagon IS. Passive diffusion of naltrexone into human and animal cells and upregulation of cell proliferation. Amer J Physiol Regul Integr Physiol 2009;297:R844-R852. PMID: 19605761
17. Zagon IS, Donahue RN, McLaughlin PJ. Opioid growth factor-opioid growth factor receptor axis is a physiological determinant of cell proliferation in diverse human cancers. Amer J Physiol Regul Integr Physiol 2009;297:R1154-R1161. PMID: 19675283
18. Kren NP, Zagon IS, McLaughlin PJ. Mutations in the opioid growth factor receptor in human cancers alter receptor function. Int J Mol Med 2015:36:289-293.
19. Kren NP, Zagon, McLaughlin PJ. Nuclear export of opioid growth factor receptor is CRM1 dependent. Exp Biol Med 2016;241:273-281.
20. McLaughlin PJ, Verderame MF, Hankins JL, Zagon IS. Overexpression of the opioid growth factor receptor downregulates cell proliferation of human squamous carcinoma cells of the head and neck. Int J Mol Med 2007;19:421-428. PMID: 17273790
21. Donahue RN, McLaughlin PJ, Zagon IS. Under-expression of the opioid growth factor receptor promotes progression of human ovarian cancer. Exp. Biol. Med. 2012;237:167-177. PMID: 22328595
22. Donahue RN, McLaughlin PJ, Zagon IS. Low-dose naltrexone targets the opioid growth factor –opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model. Exp Biol Med 2011;236:1036-1050.
23. Bihari B. Efficacy of low dose naltrexone as an immune stabilizing agent for the treatment of HIV/AIDS. AIDS Patient Care 1995:3
24. Yang J, Shin KM, Do A, Bierle DM, Abu Dabrh AM, Yin Z, Bauer BA, Muhabbaat AR. The safety and efficacy of low dose naltrexone in patients with fibromyalgia: A systematic review. J Pain Res 2023;16:1017-1023.
25. Driver CN, D’Souza RS. Efficacy of low-dose naltrexone and predictors of treatment success or discontinuation in fibromyalgia and other chronic pain conditions: A fourteen-year, enterprise-wide retrospective analysis. Biomedicines 2023; 11:1087
26. Dara P, Farooqui Z, Mwale F, Choe C, van Wijnen AJ, Im H-J. Opiate antagonists for chronic pain: A review on the benefits of low-dose naltrexone in arthritis versus non-arthritic diseases. Biomedicines 2023; 11:1620.
27. Srinivasan A, Dutta P, Bansal D, Chakrabarti A, Bhansali AK, Hota D. Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active=control, crossover clinical trial. J Diabetes 2021;13:770-778.
28. Isman A, Nyquist A, Strecker B, Harinath G, Lee V, Zhang X, Zalzala S. Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19. Brain Behavior Immunity – Health 2024; 36:100733
29. Bonilla H, Tian L, Marconi VC, Shafer R, McComsey GA, Miglis M, Yang P, Bonilla A, Eggert L, Geng LN. Low-dose naltrexone use for the management of post-acute sequelae of COVID-19. Int Immunopharmacol. 124;2023: 110966.
30. McLaughlin PJ, Odom LB, Arnett PA, Orehek S, Thomas GA, Zagon IS. Low-dose naltrexone reduced anxiety in persons with multiple sclerosis during the COVID-19 pandemic. Int Immunopharmacol 113;2022:109438
31. McLaughlin PJ, Odom LB, Arnett PA, Thomas GA, Orehek S, Zagon IS. Length of disease more than therapy impacts anxiety and depression in persons with multiple sclerosis. Neurol Neurosci 2023;4 (1):1-6.
32. Zagon IS, Donahue RN, Bonneau RH, McLaughlin PJ. T lymphocyte proliferation is suppressed by the opioid growth factor ([Met5]-enkephalin)-opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases. Immunobiology 2011;216:579-590.
33. Zagon IS, Donahue RN, Bonneau RH, McLaughlin. B lymphocyte proliferation is suppressed by the opioid growth factor-opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases. Immunobiology 2011;216:173-183.
34. Zagon IS, Rahn KA, Turel AP, McLaughlin PJ. Endogenous opioids regulate expression of experimental autoimmune encephalomyelitis: A new paradigm for the treatment of multiple sclerosis. Exp. Biol. Med. 2009;234:1383-1392. PMID: 19855075
35. Rahn KA, McLaughlin PJ, Zagon IS. Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis. Brain Res. 2011;1381:243-253. PMID: 21256121
36. Ludwig MD, Turel AP, Zagon IS, McLaughlin PJ. Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis. Mult Scler J: Experimental, Translational and Clinical 2016;2:1-11
37. Patel C, Zagon IS, Pearce-Clawson M, McLaughlin PJ. Timing of treatment with an endogenous opioid alters immune response and spinal cord pathology in female mice with experimental autoimmune encephalomyelitis. J. Neurosci. Res. 2021;100:551-563. Doi:10.1002/jnr.24983.
38. Wang Y-S, Hung T-W, Bae E-K, Wu K-J, Hsieh W, Yu S-J. Naltrexone is neuroprotective against traumatic brain injury in mu opioid receptor knockout mice. CNS Neurosci Ther 2021;27:831-841.
39. Mustafa S, Evans S, Barry B, Barratt D, Wang Y, Lin C, Want X, Hutchinson MR. Toll-like receptor 4 in pain: Bridging molecules-to-cells-to systems. Handbook Exp Pharmacol 2022;276:239-273.
40. Negri M, Falluca F, Tonnarini G, Mariani P, D’Allessandro M, Pachi A. High levels of circulating met-enkephalin in pregnant and menstruating type 1 diabetic women. Gynecol Endocrinol 1990;4:25-31.
41. Negri M, Tonnarini G, De Blasé N, D’Allessandro M, Fallucca F. Plasma met-enkephalin in type 1 diabetes. Metabolism 1992;41:460-461.
42. Centers for Disease Control and Prevention. National diabetes statistics report. https://www.cdc.gov/diabetes/data/statistics-report/index.html. Reviewed by CDC November 29, 2023.
43. Ljubimov AV. Diabetic complications in the cornea. Vis Res 2017 Oct;139:138-152.
44. Yamamoto T, Otake H, Hiramatsu N, Yamamoto N, Taga A, NagaiN. 2018. A proteomic approach for understanding the mechanisms of delayed corneal wound healing in diabetic keratopathy using diabetic rat model. Int J Mol Sci 19:3635
45. Zagon IS, Sassani JW, McLaughlin PJ. Cellular dynamics of corneal wound re-epithelialization in the rat. I. Fate of ocular surface epithelial cells synthesizing DNA prior to wounding. Brain Res. 1999;822:149-162.
46. Zagon, I.S., J.W. Sassani and P.J. McLaughlin. 2000. Reepithelialization of the human cornea is regulated by endogenous opioids. Invest. Ophthalmol. Vis. Sci. 2000;41:73-81.
47. Zagon, I.S., J.W. Sassani and P.J. McLaughlin. Re-epithelialization of the rat cornea is accelerated by blockade of opioid receptors. Brain Res. 1998;798:254-260.
48. Zagon IS, Sassani JW, Verderame MF, McLaughlin PJ. 2005. Particle-mediated gene transfer of OGFr cDNA regulates cell proliferation of the corneal epithelium. Cornea 24(5):614-619. PMID: 15968171
49. Zagon, I.S., J.B. Jenkins, C.M. Lang, J.W. Sassani, J.D. Wylie, T.B. Ruth, J. L. Fry and P.J. McLaughlin. 2002. Naltrexone, an opioid antagonist, facilitates re-epithelialization of the cornea in diabetic rat. Diabetes 51:3055-3062. PMID: 12351447
50. Klocek, M.S., J.W. Sassani, P.J. McLaughlin, and I.S. Zagon. 2007. Topically applied naltrexone restores corneal reepithelialization in diabetic rats. J. Ocular Pharmacol. Ther. 23:89-102. PMID: 17444796
51. Zagon, I.S., J.W. Sassani, M.A. Carroll, and P.J. McLaughlin. 2010. Topical application of naltrexone facilitates reepithelialization of the cornea in diabetic rabbits. Brain Res. Bull. 81:248-255. PMCID: PMC2815253 PMID: 19853924
52. Klocek MS, Sassani JW, McLaughlin PJ, Zagon IS. Naltrexone and insulin are independently effective but not additive in accelerating corneal epithelial healing in type 1 diabetic rats. Exp Eye Res 2009;89:686-692.
53. McLaughlin PJ, Sassani JW, Diaz DP, Zagon IS. Elevated opioid growth factor alters the limbus in type 1 diabetic rats. J Diabetes Clin Res. 2023. doi: 10.1007/s11064-023-03938-4. PMID: 37166576
54. Zagon IS, Klocek MS, Sassani JW, McLaughlin PJ. Dry eye reversal and corneal sensation restoration with topical naltrexone in diabetes mellitus. Arch Ophthalmol 2009;127:1468-1473.
55. Zagon IS, Sassani JW, Purushothaman I, McLaughlin PJ. Dysregulation of the OGF-OGFr pathway correlates with elevated serum OGF and ocular surface complications in the diabetic rat. Exp Biol Med 2020;245:1414-1421 PMID: 32640891 PMCID:PMC7441350.
56. Zagon IS, Sassani JW, Immonen JA, McLaughlin PJ. Ocular surface abnormalities related to type 2 diabetes are reversed by the opioid antagonist naltrexone. Clin Exp Ophthalmol 2014;42:159-168.
57. Zagon IS, Sassani Purushothaman I, McLaughlin PJ. Blockade of the opioid growth factor receptor (OGFr) delays the onset and reduces the severity of diabetic ocular surface complications. Exp Biol Med 2021;246:629-636. PMID:33203224 Doi:10.1177/1535370220972060
58. Purushothaman I, Sassani JW, Zagon IS, McLaughlin PJ. Ocular surface complications result from dysregulation of the OGF-OGFr signaling pathway in female diabetic rats. Exp Ther Med 2021;22:687. doi: 10.3892/etm.2021.10119 PMID:33986852
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