Main Article Content
Opium prescriptions date from the Sumerian era about 8,000 years ago, and they were commonly abused among wounded soldiers during the American Civil and Prussian French wars. With the isolation of morphine in 1805 by Setürner, the synthesis of morphine by Tschudi in 1952 and the manufacturing of synthetic derivatives called opioids, a new era of research began. In normal conditions, the endogenous opioid levels are elevated under stress conditions as a part of adaptive response. This mechanism implies in b-endorphin release, not only from the hypothalamus but also by immune circulating cells as lymphocytes. This system is powerful against pain, ischemic insult and oxidative imbalance protecting the tissues. The recognition of opioid receptors, particularly the delta subtype in retinal tissue, has broadened the potential for clinical applications. In the eye, opioid receptors were demonstrated to be present in optic nerve head, ganglion cells and pigmented epithelium cells. As such, studies have revealed that opioid receptors play a role in the pathogenesis of DR preserving the outer blood retinal barrier and also acting as a retinal neuroprotective agent. In this scenario, the modulation of the opioid receptor in the retina might become an attractive therapeutic target in the treatment of this devastating complication. Thus, this review assesses recent and scarce findings on this topic which deserves to be further investigated.
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.
2. Akil H, Watson SJ, Young E, Lewis ME. Khachaturian H, Walker JM. Endogenous opioids: biology and function. Annu. Rev. Neurosci.1984;7:223–255.
3. Bao YK, Mille CJr , S Narayanan, Gaddis M . Prevalence and Risk Factors of Major Depression in Patients with Diabetic Retinopathy in a Nationally Representative Survey. Ophthalmic Epidemiol 2023;26:1-6
4. Barchas JD, Evans C, Elliott GR, Berger PA Peptide neuroregulators: the opioid system as a model. Yale J Biol Med. 1985;58:579-596.
5. Bergers G., Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncol. 2005;7:452–464.
6. Cabot PJ, Carter L, Gaiddon C, Zhang Q, Schäfer M, Loeffler JP, Stein C. Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats. J Clin Invest. 1997;100:142-148.
7. Chen M, Muckersie E, Robertson M, Fraczek M, Forrester JV, Xu H. Characterization of a spontaneous mouse retinal pigment epithelial cell line B6-RPE07. Invest Opthalmol Vis Sci. 2008;49:3699–3706.
8. Chen TY, Goyagi T, Toung TJ, et al. Prolonged opportunity for ischemic neuroprotection with selective kappa-opioid receptor agonist in rats. Stroke 2004;35:1180-1185
9. Chen YM, He XZ, Wang SM, Xia Y . δ-Opioid Receptors, microRNAs, and Neuroinflammation in Cerebral Ischemia/Hypoxia. Front Immunol. 2020;11:421.
10. Crider JY, Yorio T, Sharif NA, Griffin BW. The effects of elevated glucose on Na+/K+-ATPase of cultured bovine retinal pigment epithelial cells measured by a new nonradioactive rubidium uptake assay. J Ocul Pharmacol Ther. 1997;13:337–352
11. Dore-Duffy P., Katychev A., Wang X., Van Buren E. CNS microvascular pericytes exhibit multipotential stem cell activity. J. Cereb. Blood Flow Metab. 2006;26:613–624.
12. Duarte DA, Silva KC, Rosales MA, Lopes de Faria JB, Lopes de Faria JM. The concomitance of hypertension and diabetes exacerbating retinopathy: the role of inflammation and oxidative stress. Curr Clin Pharmacol. 2013;8:266 -277
13. Duarte DA, Rosales MA, Papadimitriou A et al. Polyphenol-enriched cocoa protects the diabetic retina from glial reaction through the sirtuin pathway..J Nutr Biochem. 2015;26(1):64-74
14. Dripps IJ, Jutkiewicz EM. Delta Opioid Receptors and Modulation of Mood and Emotion. Handb Exp Pharmacol. 2018;247:179-197
15. Durham JT, Dulmovits BM, Cronk SM, Sheets AR, Herman IM. Invest Ophthalmol Vis Sci. 2015;56:3441-3459
16. Dvoriantchikova G, Ivanov D. Tumor necrosis factor-alpha mediates activation of NF-κB and JNK signaling cascades in retinal ganglion cells and astrocytes in opposite ways. Eur J Neurosci. 2014;40:3171-178
17. Emrich HM, Vogt P, Herz A. Possible antidepressive effects of opioids: action of buprenorphine. Ann. N. Y. Acad. Sci. 1982;398:108–112
18. Ford KM, Saint-Geniez M, Walshe T, Zahr A, D'Amore PA. Expression and role of VEGF in the adult retinal pigment epithelium. Invest Opthalmol Vis Sci. 2011; 52: 9478–9487
19. Forrester JV, Kuffova L, Delibegovic M. The role of inflammation in diabetic retinopathy.Front Immunol. 2020;11:583687
20. Fuchs C, Forster V, Balse E, Sahel JA, Picaud S, Tessier LH. Retinal-cell-conditioned medium prevents TNF-alpha-induced apoptosis of purified ganglion cells. Invest Ophthalmol Vis Sci. 2005; 46: 2983–2991
21. Goureau O, Lepoivre M, Becquet F, Courtois Y. Differential regulation of inducible nitric oxide synthase by fibroblast growth factors and transforming growth factor b in bovine retinal pigmented epithelial cells: inverse correlation with cellular proliferation. Proc Natl Acad Sci USA 1993; 90:4276–4280
22. Heijnen CJ, Kavelaars A, Ballieux RE. Beta-endorphin: cytokine and neuropeptide. Immunol Rev. 1991;119:41-63.
23. Holaday JW. Cardiovascular effects of endogenous opiate systems. Annu. Rev. Pharmacol. Toxicol 1983;23:541–594.
24. Holtkamp GM Kijlstra A Peek R de Vos AF. Retinal pigment epithelium-immune system interactions: cytokine production and cytokine-induced changes. Prog Retin Eye Res. 2001;20:29–48
25. Hoogendoorn CJ, Schechter CB, Llabre MM, Walker EA , Gonzalez JS. Distress and Type 2 Diabetes Self-Care: Putting the Pieces Together Ann Behav Med 2021;55(10):938-948
26. Howells RD, Groth J, Hiller JM, Simon EJ. Opiate binding sites in the retina: properties and distribution. J Pharmacol Exp Ther. 1980;215:60-64
27. Husain S, Potter DE. The opioidergic system: potential roles and therapeutic indications in the eye. J. Ocul. Pharmacol. Ther. 2008;24:117–140
28. Husain S, Potter DE, Crosson CE. Opioid receptor-activation: retina protected from ischemic injury. Invest. Ophthalmol. Vis. Sci.2009; 50:3853–3859
29. Husain S, Abdul Y and Crosson CE. Preservation of retina ganglion cell function by morphine in a chronic ocular-hypertensive rat model. Invest. Ophthalmol. Vis. Sci. 2012;53:4289–4298
30. Husain S, Abdul Y, Potter DE. Non-analgesic effects of opioids: neuroprotection in the retina. Curr Pharm Des. 2012;18:6101-6108
31. Iturralde E, Rausch JR, Weissberg-Benchell J, Hood KK. Diabetes-Related Emotional Distress Over Time. Pediatrics. 2019;143:e20183011
32. Kim DI, Lim SK, Park MJ, Han HJ, Kim GY, Park SH. The involvement of phosphatidylinositol 3-kinase/Akt signaling in high glucose-induced downregulation of GLUT-1 expression in ARPE cells. Life Sci. 2007;80:626–632
33. Kitaoka Y., Kwong JM, Ross-Cisneros FN et al. TNF-alpha-induced optic nerve degeneration and nuclear factor-kappaB p65. Invest. Ophthalmol Vis. Sci. 2006;47:1448–1457
34. Lai Z, Gu L, Yu L, Chen H, Yu Z, Zhang C, Xu X, Zhang M, Zhang M, Ma M, Zhao Z, Zhang J. Delta opioid peptide [d-Ala2, d-Leu5] enkephalin confers neuroprotection by activating delta opioid receptor-AMPK-autophagy axis against global ischemia. Cell Biosci. 2020;10:79
35. Lavie Y, ]Fiucci G, Liscovitch M. Upregulation of caveolin in multidrug resistant cancer cells: functional implications. Adv Drug Deliv 2001;49:317-323
36. Lee J, Choi J-H, Joo C-K. TGF-β1 regulates cell fate during epithelial–mesenchymal transition by upregulating surviving. Cell Death Dis. 2013;4:e714
37. Liang BT, Gross GJ. Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels. Circ Res 1999;84:1396-1400
38. Liversidge J Grabowski P Ralston S Benjamin N Forrester JV. Rats' retinal pigment epithelial cells express an inducible form of nitric oxide synthase and produce nitric oxide in response to inflammatory cytokines and activated T cells. Immunology.1994;83:404–409
39. Lolait SJ, Clements A, Markwick AJ et al. Pro-opiomelanocortin messenger ribonucleic acid and posttranslational processing of beta endorphin in spleen macrophages. J Clin Invest 1986;77:1776-1779
40. Lopes de Faria JM, Duarte DA, Simó R et al. δ Opioid Receptor Agonism Preserves the Retinal Pigmented Epithelial Cell Tight Junctions and Ameliorates the Retinopathy in Experimental Diabetes. Invest Ophthalmol Vis Sci 2019;60(12):3842-3853
41. Matos AL, Bruno DF, Ambrósio AF, Santos PF The Benefits of Flavonoids in Diabetic Retinopathy. Nutrients. 2020;12:3169
42. Mak TW. Yeh WC. Signaling for survival and apoptosis in the immune system. Arthritis Res. 2002;4:S243–S252
43. Malinowski K, Shock EJ, Rochelle P, Kearns CF, Guirnalda PD, McKeever K.H. Plasma beta-endorphin, cortisol and immune responses to acute exercise are altered by age and exercise training in horses. Equine Vet. J. Suppl. 2006;36:267–273
44. Marmorstein AD. The polarity of the retinal pigment epithelium. Traffic. 2001;2:867–872
45. Maslov LN, Lishmanov YB. Change in opioid peptide level in the heart and blood plasma during acute myocardial ischaemia complicated by ventricular fibrillation. Clin Exp Pharmacol Physiol 1995; 22:812-816.
46. Mathew B, Chennakesavalu M, Sharma M, Torres LA, Stelman CR, Tran S, Patel R, Burg N, Salkovski M, Kadzielawa K, Seiler F, Aldrich LN, Roth S. Autophagy and post-ischemic conditioning in retinal ischemia. Autophagy. 2021;17:1479-1499.
47. Mattson MP, Meffert MK. Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ. 2006;13:852–860.
48. Matveev S, Li X, Everson W, Smart EJ. The role of caveolae and caveolin in vesicle-dependent and vesicle-independent trafficking. Advanced Drug Delivery Reviews 2001;49:237–250
49. McBee JK , Preston Van Hooser J, G-F, Palczewski K. Isomerization of 11-cis-Retinoids to All-trans-retinoids in Vitro and in Vivo*. J Biol Chem. 2001;276: 48483–48493
50. Meriney SD, Gray DB, Pilar G. Morphine-induced delay of normal cell death in the avian ciliary ganglion. Science 1985;228:1451-1453.
51. Minami M, Satoh M. Molecular biology of the opioid receptors: structures, functions and distributions. Neurosci Res 1995;23:121-145
52. Monickaraj F, McGuire P, Das A. Cathepsin D plays a role in endothelial-pericyte interactions during alteration of the blood-retinal barrier in diabetic retinopathy. FASEB J. 2018;32:2539–2548
53. Mousa SA, Shakibaei M, Sitte N, Schäfer M, Stein C. Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain. Endocrinology. 2004;145:1331-1341
54. Murray RB, Adler MW, Korczyn AD. The pupillary effects of opioids. Life Sci. 1983;33:495-509
55. Panneerselvam M, Yasuo M, Tsutsumi YM et al. Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation. Am J Physiol Heart Circ Physiol 2010;299:H1604-1609
56. Peng PH, Huang HS, Lee YJ, Chen YS, Ma MC . Novel role for the delta-opioid receptor in hypoxic preconditioning in rat retinas. J Neurochem. 2009;108:741-754
57. Ponnalagu M, Subramani M, Jayadev C, Shetty R, Das D. Retinal pigment epithelium-secretome: a diabetic retinopathy perspective. Cytokine. 2017;95:126–135.
58. Raina R, Sen D. Can crosstalk between DOR and PARP reduce oxidative stress mediated neurodegeneration? Neurochem Int. 2018;112:206-218.
59. Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. .Mol Pharmacol. 1994 Feb;45:330-4.
60. Reichstein D, Ren L, Filippopoulos T, Mittag T, Danias J. Apoptotic retinal ganglion cell death in the DBA/2 mouse model of glaucoma. Exp Eye Res. 2007;84:13–21.
61. Rosales MAB, Silva KC, Duarte DA, Rossato FA, Lopes de Faria JB, Lopes de Faria JM. Endocytosis of tight junctions caveolin nitrosylation dependent is improved by cocoa via opioid receptor on RPE cells in diabetic conditions. Invest Opthalmol Vis Sci. 2014;55:6090–6100.
62. Sakamoto K, Kuroki T, Sagawa T, Ito H, Mori A, Nakahara T, Ishii K.Opioid receptor activation is involved in neuroprotection induced by TRPV1 channel activation against excitotoxicity in the tat retina. .Eur J Pharmacol. 2017;812:57-63
63. Sassani JW, Zagon IS, McLaughlin PJ. Opioid growth factor modulation of corneal epithelium: uppers and downers. Curr Eye Res. 2003;26:249-262.
64. Scarone S, Gambini O, Calabrese G et al. Asymmetrical distribution of beta-endorphin in cerebral hemispheres of suicides: preliminary data. Psychiatry Res.1990;32:159–166.
65. Sertürner FWA. J Pharm. Arzte. Apoth. Chem.1806;14:47-93
66. Silva KC, Rosales MA, Hamassaki DE et al. Green tea is neuroprotective in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2013;54:1325-1336
67. Simo R, Villarroel M, Corraliza L, Hernandez C, Garcia-Ramirez M. The retinal pigment epithelium: something more than a constituent of the blood retinal barrier—implications for the pathogenesis of diabetic retinopathy. J Biomed Biotechnol . 2010; 2010:190724
68. Steinle JJ. Role of HMGB1 signaling in the inflammatory process in diabetic retinopathy. Cell Signal. 2020;73:109687
69. Strauss O. The retinal pigment epithelium in visual function. Physiol Rev . 2005;85:845–881
70. Teo ZL, Yih-Chun, ThamYC et al . Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis. Ophthalmology 2021;128(11):1580-1591.
71. Tezel G, Li LY, Patil RV, Wax MB. TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci. 2001; 42: 1787–1794
72. Trost A, Bruckner D, Rivera FJ, Reitsamer HA. Pericytes in the Retina. Adv. Exp. Med. Biol. 2019;1122:1–26
73. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H. Vandenabeele P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat. Rev. Mol. Cell Bio. 2014;15:135–147
74. Varela HJ. Hernandez MR. Astrocyte responses in human optic nerve head with primary open-angle glaucoma. J. Glaucoma. 1997;6:303–313
75. Wamsley JK, Palacios JM, Kuhar MJ. Autoradiographic localization of opioid receptors in the mammalian retina. Neurosci Lett 1981;27:19-24
76. Yuan Z Feng W Hong J Zheng Q Shuai J Ge Y. p38MAPK and ERK promote nitric oxide production in cultured human retinal pigmented epithelial cells induced by high concentration glucose. Nitric Oxide. 2009;20:9–15
77. Xu HZ Le YZ. Significance of outer blood-retina barrier breakdown in diabetes and ischemia. Invest Ophthalmol Vis Sci . 2011; 52: 2160–2164.
78. Xu S , Xue X, Kai You K, Fu J . Caveolin-1 regulates the expression of tight junction proteins during hyperoxia-induced pulmonary epithelial barrier breakdown. Respir Res. 2016;17:50.
79. Zagon IS, Sassani JW, Kane ER, McLaughlin PJ. Homeostasis of ocular surface epithelium in the rat is regulated by opioid growth factor. PJ.Brain Res. 1997;759:92-102
80. Zhang J, Gibney GT, Zhao P, Xia Y. Neuroprotective role of delta opioid receptors in cortical neurons. Am J Physiol Cell Physiol 2002;282:C1225-1234.
81. Zhang J, Qian H, Zhao P, Hong SS, Xia Y. Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor. Stroke 2006;37:1094-1099.
82. Zhou X, Li F, Kong L, Tomita H, Li C, Cao W. Involvement of inflammation, degradation, and apoptosis in a mouse model of glaucoma. J Biol Chem. 2005;280: 31240–31248
83. Zhu DD, Wang YZ, Zou C, She XP, Zheng Z . The role of uric acid in the pathogenesis of diabetic retinopathy based on Notch pathway. Biochem Biophys Res Commun. 2018;503:921-929