Article Test

Home  >  Medical Research Archives  >  Issue 149  > Opium and Opioid Receptors: From the Ancient Times to a Possible Novel Therapeutic Target for Diabetic Retinopathy
Published in the Medical Research Archives
Aug 2023 Issue

Opium and Opioid Receptors: From the Ancient Times to a Possible Novel Therapeutic Target for Diabetic Retinopathy

Published on Aug 29, 2023

DOI 

Abstract

 

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.

Author info

Jacqueline De Faria

History of opioid receptors
The precise beginnings of opium’s use as a drug and its connections to religion,mysticism or even recreation are uncertain, but the registration date has  been identified as  from ancient times, nearly 5,000 years ago. It is believed that Arab traders brought opium to India and China, and in the 10th century, opium found its way from Asia to all parts of Europe. In 1806, SETÜRNer achieved isolation of its   active   compound,   naming   it   morphine   in reference  to  Morpheus,  the  God  of  dreams  65. After the achievement of morphine synthesis more recently, as well as the identification of endogenous peptides  with opioid receptor  activity, more than 20  synthetic  peptides  with  similar  activities  have been   developed,   all   generated   from   three precursors    (proenkephalin.    prodynorphin    and proopiomelanocortin).   Each   of   these   synthetic peptides acts through the transmembrane G protein receptors (opioid receptors), distributed throughout the  body   with  different  affinities,   and  opioid receptors  that  have  already  been  cloned  include the delta (), mu () and kappa () receptors and their subtypes (1-2, 1-3  and 1-3).

Physiologically, studies have shown that endogenous opioid levels are augmented under stressful conditions2,23 through the adaptive responses to stress involving the release of - endorphin, a small opioid peptide that is proteolytically cleaved22 and that is primarily synthetised in the hypothalamus and pituitary4 as well as in immune-circulating cells 6,39,43. Macrophages, lymphocytes and monocytes represent all the components necessary for the synthesis, processing and release of -endorphin 53 which interacts better with the  and  opioid receptors59.

The increased levels of endogenous opioid peptides counteract with damaging inflammatory pathways, such as tumour necrosis factor alpha (TNF-)29 and nuclear kappa-light-chain-enhancer of activated B cells (NF-k)1. Unlike the other receptors, delta opioid receptors (DORs) possess unique beneficial antidepressant14,    antioxidant58    and neuroprotective properties in the presence of cytotoxicity and hypoxia 8-9,34. Interestingly, endogenous opioid peptide levels are reduced in patients suffering from depression or other psychological conditions 17,64, common among patients with diabetes, especially those to whom are visually under threatening 3,25,31.

Clinically, opioids are powerful analgesics, but they also produce a variety of non-analgesic effects, such as the modulation of stress responses following ischemia in brain9,50,80,81, heart37,45 or eye26,51,56,62,75. In addition, endogenous opioids (endorphins, enkephalins and dynorphins) act via specific opioid receptors distributed throughout the body, controlling the neuroendocrine axis, immunomodulation and behaviour.

DORs and the eyes
In the eyes, previous data have demonstrated the function of endogenous opioids and their receptors in the regulation of iris function, accommodative power, aqueous humour dynamics, corneal wound healing, retinal development and retinal neuroprotection 27,30,54,63,79. Therefore, endogenous opioids and their specific receptors are involved in a wide variety of physiological and pathological processes, including dry eye, retinal ischemic diseases, glaucoma and visual accommodation. However, the mechanisms of action by which opioid receptors elicit pharmacological actions require more clarification.

DORs in an experimental glaucoma model Glaucoma, a neurodegenerative ocular disease that irreversibly compromises vision. It is characterised by the ‘cupping’ of the optic nerve head (ONH) due to the loss of ganglion cells and axons, thus worsening the synapses in the lateral geniculate body. As a result, significant visual field loss is observed. Among the described mechanisms involved in this disease are inflammation and apoptosis20,60,71,82 of the ganglion cells, but currently, the only therapeutic strategy is to reduce intraocular pressure to slow disease progression. In the presence of glaucomatous injury, the astrocytes present in the ONH become activated, producing proinflammatory cytokines, chemokines, immune mediators, nitric oxide (NO) and reactive oxygen species, all of which act synergically towards ganglion cell death.

Husain and colleagues29 demonstrated the presence of opioid receptors in the retina, ONH and astrocytes, and they demonstrated the effect of the systemic administration of morphine in experimental models of ischemia/reperfusion and ocular hypertension-related injury on the mitigation of retinal damage. Using the technique of electrophysiology (pattern electroretinography, which detects ganglion cell activity and enables estimation of the number of active ganglion cells), ocular hypertensive rats displayed a significant reduction in pattern electroretinogram (ERG) potentials in comparison to normal rats 1,29, indicating a significant loss of ganglion cells in the retinas of ocular hypertensive rats. More specifically, the ocular hypertensive rats treated with SNC-121, a selective DOR agonist, promoted a sustained retinal neuroprotective effect in the animal model1 thus preserving ganglion cell function. In conclusion, the agonism of DORs in ocular hypertensive rats is efficient in protecting the ganglion cells against hypertensive ocular conditions.

It is already known that TNF-, an inflammatory cytokine, is associated with several neurodegenerative retinal diseases, including glaucoma, ischemic retinal diseases and diabetic retinopathy (DR)13,16,19, 71,73,74,83, the major causes of irreversible blindness around the world70. For this reason, it is important to better better understand the molecular mechanisms involved, especially retinal ganglion cell toxicity and death via the TNF- a axis. Published data have elucidated the presence of TNF- receptors in ganglion cells42, activating inflammatory signalling and upregulating NFK-b nuclear translocation, as well as several stress-induced apoptotic transcription factors47,33,68.

Experimental studies have demonstrated that the specific ligand for DORs, SNC-121, is efficient in preventing the upregulation and phosphorylation of STAT 3, as well as its downstream inflammatory signalling (interleukin [IL]-1, IL-6 and TNF-), in a model of ocular hypertensive glaucoma, thus protecting the ganglion cells from apoptosis29. In the same context, Husain and colleagues showed that the use of the SNC-121 DOR activator, ONH astrocytes do not produce proinflammatory IL-1 and IL-61. Thus, these sets of experiments suggest the activation of DORs as a possible new neuroprotective strategy in glaucoma treatment.

Blood retinal barriers
The immune privilege of the eyes is maintained by the blood retinal barriers (BRBs), namely the inner and outer retinal barriers, both of which are functional and structural, maintaining retinal integrity. The inner BRB is comprised by endothelial cells, whose tight junctions are layered on the basal membrane and wrapped by the pericytes 5,52, multi-functional cells with plastic and regenerative potential that are pivotal in the maintenance of the neuro-glial-vascular functional retinal unit and that can dedifferentiate into myoblast or mesenchymal stem cells, 11, 72, thus enabling pathological angiogenesis15.

The outer BRB is formed by monolayer retinal pigmented epithelium (RPE) cells with their intercellular tight junctions layered on Bruchs membrane. Recently, the outer BRB has deserved more focus in the DR field, as several studies have demonstrated the role of RPE cells in diabetic milieu conditions 67,77. The RPE cells are highly specialised polarised cells, directing the apical polo towards the subretinal space and the basal side towards Bruch’s membrane and the choroid.

Among RPE cell functions are light absorption, thus protecting the neuroretina from photo-oxidation 68 and the production of growth factors, including pigment epithelium-derived factor (PEDF)57 , vascular endothelium growth factor (VEGF) 18, transforming growth factor beta (TGF-)36, insulin- like growth factor-1 (IGF-1)7 and brain-derived neurotrophic factor (BDNF), as well as proinflammatory cytokines, such as inducible nitric oxide synthase (iNOS) 21,24,38,76. Characteristically, RPE cells play a central role in photoreceptor vitality, for which purpose they experience high autophagic activity as a mechanism of the recycling of external photoreceptor segments and the isomerization of the 11-cis- retinol to trans-retinol exchange for the proper visual cycle functioning in the photoreceptors46,49.

The outer BRB transports water and electrolytes from the neuroretina to the choriocapillaris and glucose, ascorbic acid and fatty acids towards the neuroretina. Glucose transport is dependent on the GLUT1 and GLUT 3 receptors, which are highly diminished in diabetic conditions32. This is significantly deleterious to neurons, including photoreceptors, cells with the highest energy demand throughout the entire body. The water produced during photoreceptor metabolism is actively transported by the sodium–potassium pump (Na+-K+-ATPase), located at the apical side of the RPE cells 44, which produces an adhesive force between RPE cells and photoreceptors that is weakened or lost in diabetic conditions11. This later feature of the outer BRB is central to the pathogenesis of diabetic macular oedema, a primary cause of significant visual reduction among DR patients.

DOR blockage/activation in RPE cells under diabetic milieu conditions
RPE cells express iNOS, thus producing NO in response to inflammatory insults20,38. Hussain and collaborators28 (2011) described that the activation of DORs inhibits the upregulation of TNF- in the ONH, astrocytes and microglia from retinas using experimental model of ischemia/reperfusion.
Our group demonstrated the mechanism involved in outer BRB breakdown in the presence of high glucose conditions 61. In this study, caveolin-1 (CAV-1), a structural component of the caveolae having a lipophilic hairpin shape and embedded in the cell membrane, is implicated in the CAV trafficking of endosomes48, and drugs35, as well as in the regulation of tight junctions78. In that study, Rosales and colleagues exposed ARPE-19 cells and primary porcine RPE cells to high-glucose conditions, and after 24 h of exposure, immunofluorescence assays were performed. As expected, a monolayer of epithelial cells, tightened by the intercellular junctions and adhesion proteins, was organised, and the presence of high glucose, mimicking diabetic conditions, invoked a dramatic reduction in the Claudin-1 and Occludin expressions, two important tight junction proteins, accompanied by augmentations of the iNOS expression and NO levels. To understand further the mechanism behind tight junction reduction, we evaluated nitrosative stress and the possible S-nitrosylation of Cav-1, an important anchoring protein of the caveolae membrane structure. Under diabetic conditions, there is internalisation of Claudin-1 and Occludin through post-translational modifications to S-Cav-1.

As DORs agonists have been described to inhibit NO production via iNOS in astrocytes and microglial cells28 under ischemia, we investigated whether DORs could act in the pathogenesis of the outer BRB in diabetic milieu conditions. ARPE-19 cells co-treated with the opioid receptor activator epicatechin, a well-known antioxidant polyphenol present in cocoa and green tea13,41,66 and a specific DOR ligand55. The presence of epicatechin in retinal cells exposed to high glucose conditions prevented the production of NO-dependent iNOS, thus avoiding the S-nitrosylation of CAV-1. As a result, intercellular ARPE-19 tight junctions were maintained, either structurally and functionally, as evaluated using permeability and transcellular electrical resistance assays61. These compelling data identify DORs as potential therapeutic targets in the treatment/maintenance of outer BRB integrity in diabetic conditions.

DOR activation protects the retina against the toxicity from diabetes
In studying experimental models of DR, our group demonstrated evidence that the activation of DORs is beneficial in preventing the early markers of DR, such as glial fibrillary acidic protein (GFAP) and VEGF, as well as in the maintenance of the outer BRB 40 . For this study, we induced diabetes in C57BL/6JUnib mice via an intraperitoneal injection of streptozotocin. After the confirmation of the successful of the DM induction, the mice were randomized to receive not oral administration of epicatechin in drinking water. Treatment with the DOR activator epicatechin was efficient in augmenting the DOR expression and mitigating the DR markers, namely increment of VEGF and GFAP and diminishing PEDF expressions. In order to verify whether the oral administration of epicatechin had its beneficial effect via DOR agonism, the animals were submitted to an intravitreal injection of a short hairpin RNA (shRNA) construction for the mouse retinal DOR gene. The outer BRB structure was also targeted by the DOR activator, preventing augmentation of the tight junctions Claudin-1, Occludin and ZO-1 to normal levels. The diabetic animals submitted to the intraocular transfection of DOR-shRNA did not exhibit the beneficial effects of the epicatechin as a DOR activator, meaning DOR activation might be considered a potential new therapeutic target to the treatment of DR.

Because DOR presents types 1 and 2 subtypes, we further investigated which DOR subtype activation could be beneficial in the maintenance of outer BRB properties. ARPE-19 cells were cultured and exposed to diabetic milieu and co-treated with naltrindole, a non-specific DOR blocker, in the presence of the DOR-1, D-Ala(2) and D- Leu(5)]enkephalin or DOR-2, D-Ala(2) and Deltorphin II activators. Only the DOR-1 activator was efficient in preventing the upregulation of the inflammatory signalling and functional properties of the ARPE-19 barrier under diabetic milieu co- treated with naltrindole in high glucose conditions. To translate these experimental observations, DOR was immunolabeled in human retina. For the first time, DOR was shown to be present in RPEs and in the neuroretina of human retinal specimens, which is relevant evidence projecting DOR as a potential novel therapeutic strategy to treat the retinas of DR patients.

Concluding remarks and future directions Nowadays, there is increasing interest in new therapeutic targets for the prevention and treatment of visual dysfunction among patients with diabetes. Although there are therapies available for diabetic eye care such as retinal laser photocoagulation, vitrectomy or even intraocular injection of anti-angiogenic drugs, diabetic vision- threatening is still a clinical challenge.
This review underlined the role and the possible beneficial effects of the delta opioid receptor in retinal tissue from experimental studies and evidences suggest that it may be relevant in human retinal tissue. The data available is scarce, thus further experimental and in vitro studies are needed in order to better understand how to control its activity in the presence of the diabetic milieu through specific ligands, avoiding extra-ocular undesirable effects. 
References
1. Abdul Y, Akhter N, Husain S. Delta-opioid agonist SNC-121 protects retinal ganglion cell function in a chronic ocular hypertensive rat model. Invest. Ophthalmol. Vis. Sci. 2013;54:1816–1828

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

Have an article to submit?

Submission Guidelines

Submit a manuscript

Become a member

Call for papers

Have a manuscript to publish in the society's journal?