ENDOMORPHINS: STRUCTURE, LOCALIZATION, IMMUNOREGULATORY ACTIVITY

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Abstract


Endomorphins – endogenous tetrapeptides with the highest affinity for the µ-opioid receptor. Distribution of endomorphins in the immune system, similar to that of other opioid peptides, has allowed to suggest their active participation in the processes of immune regulation. This review summarizes modern views on the structure of endomorphins, their localization, possible intracellular mechanisms of signal transmission and their effects on the processes of activation, proliferation and differentiation of cells of innate and adaptive immunity. Endomorphins actively modulate functions of the cells of the immune system, while peptides predominantly suppress adaptive immunity reactions, but the effects on innate immunity can be either depressing or stimulating. Thus, endomorphins can be promising compounds that can effectively regulate both nociceptive signals and processes in the immune system.

 


Full Text

About the authors

Sergey Vladimirovich Gein

Institute of ecology and genetics of microorganisms - branch of the Perm Federal Research Center of the Ural Branch of the Russian Academy of Sciences, Perm, Russia;
Perm State University, Perm, Russia

Author for correspondence.
Email: gein@iegm.ru
ORCID iD: 0000-0002-0799-3397
SPIN-code: 2323-9572
Scopus Author ID: 7801629183
ResearcherId: A-8002-2014

Russian Federation, 614081, Perm, Goleva street, 13;   614990, Perm, Bukireva street, 15.

Professor, Deputy Director for Research, Laboratory of microorganisms' biochemical development

Tatyana Baeva

Institute of ecology and genetics of microorganisms - branch of the Perm Federal Research Center of the Ural Branch of the Russian Academy of Sciences, Perm, Russia

Email: simonjkaperm80@mail.ru
ORCID iD: 0000-0003-3827-7876
SPIN-code: 6280-1201

Russian Federation, 614081, Perm, Goleva street, 13

PhD, Laboratory of microorganisms' biochemical development

References

  • Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A. 1993; 90: 5391–5393. doi: 10.1073/pnas.90.12.5391.
  • Zadina JE, Hackler L, Ge L-J, et al. A potent and selective endogenous agonist for the mu-opiate receptor. Nature (Lond). 1997; 386: 499–502. doi: 10.1038/386499a0.
  • Smith EM. Neuropeptides as signal molecules in common with leukocytes and the hypothalamic–pituitary–adrenal axis. Brain Behav Immun. 2008; 22: 3–14. doi: 10.1016/j.bbi.2007.08.005.
  • Hackler L, Zadina JE, Ge L-J, et al. Isolation of relatively large amounts of endomorphin-1 and endomorphin-2 from human brain cortex. Peptides. 1997; 18: 1635–1639. doi: 10.1016/s0196-9781(97)00259-3.
  • Mizusawa K. Endomorphin. In: Takei Y, Ando H, Tsutsui K, editors. Handbook of Hormones: comparative endocrinology for basic and clinical research. Oxford: Academic Press; 2016. p. 62-63.
  • Fichna J, Janecka A, Costentin J. et al. The endomorphin system and its evolving neurophysiological role. Pharmacol Rev. 2007; 59: 88–123. doi: 10.1124/pr.59.1.3.
  • Mizoguchi H, Sakurada T, Sakurada S. Endomorphins. In: Kastin A, editor. Handbook of biologically active peptides Oxford: Academic Press; 2013. p. 1556-1561.
  • Finley JC, Lindstrom P, Petrusz P. Immunocytochemical localization of β-endorphin-containing neurons in the rat brain. Neuroendocrinology. 1981; 33: 28-42. doi: 10.1159/000123197.
  • Jessop DS, Major GN, Coventry TL, et al. Novel opioid peptides endomorphin-1 and endomorphin-2 are present in mammalian immune tissues. J Neuroimmunol. 2000; 106: 53-59. doi: 10.1016/s0165-5728(99)00216-7.
  • Mousa SA, Machelska H, Schafer M, et al. Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J Neuroimmunol. 2002; 126: 5-15. doi: 10.1016/s0165-5728(02)00049-8.
  • Seale JV, Jessop DS, Harbuz MS. Immunohistochemical staining of endomorphin 1 and 2 in the immune cells of the spleen. Peptides. 2004; 25: 91–94. doi: 10.1016/j.peptides.2003.11.016.
  • Jessop DS, Richards LJ, Harbuz MS. Opioid peptides endomorphin-1 and endomorphin-2 in the immune system in humans and in a rodent model of inflammation. Ann N Y Acad Sci. 2002; 966:, 456–463. doi: 10.1111/j.1749-6632.2002.tb04247.x.
  • Dorpe S, Adriaens A, Polis I, et al. Analytical characterization and comparison of the blood–brain barrier permeability of eight opioid peptides. Peptides. 2010; 31: 1390–1399. doi: 10.1016/j.peptides.2010.03.029.
  • Botros M, Hallberg M, Johansson T, et al. Endomorphin-1and endomorphin-2 differentially interact with specific binding sites for substance P (SP) aminoterminal SP1-7 in rat spinal cord. Peptides. 2006; 27: 753-759. doi: 10.1016/j.peptides.2005.08.009.
  • Janecka A, Staniszewska R, Gach K, et al. Enzymatic degradation of endomorphins. Peptides. 2008; 29: 2066 – 2073. doi: 10.1016/j.peptides.2008.07.015.
  • Cros CD, Toth I, Blanchfield JT. Lipophilic derivatives of leu- enkephalinamide: in vitro permeability, stability and in vivo nasal delivery. Bioorg Med Chem. 2011; 19: 1528–1534. doi: 10.1016/j.bmc.2010.12.042.
  • Falconer RA, Toth I. Design, synthesis and biological evaluation of novel lipoamino acid-based glycolipids for oral drug delivery. Bioorg Med Chem. 2007; 15: 7012–7020. doi: 10.1016/j.bmc.2007.07.048.
  • Varamini Р, Hussein WM, Mansfeld FM, et al. Synthesis, biological activity and structure–activity relationship of endomorphin-1/substance P derivatives. Bioorg Med Chem. 2012; 20: 6335–6343. doi: 10.1016/j.bmc.2012.09.003.
  • Varamini P, Toth I, et al. Lipid-and sugar-modified endomorphins: novel targets for the treatment of neuropathic pain. Front Pharmacol. 2013; 4: 1-7. doi: 10.3389/fphar.2013.00155.
  • Horvath G. Endomorphin-1 and endomorphin-2: pharmacology of the selective endogenous mu-opioid receptor agonists. Pharmacol Ther. 2000; 88: 437–463. https://doi.org/10.1016/S0163-7258(00)00100-5
  • Sharp BM, Roy S, Bidlack JM. Evidence for opioid receptors on cells involved in host defense and the immune system. J Neuroimmunol. 1998; 83: 5-56. https://doi.org/10.1016/S0165-5728(97)00220-8
  • Sakurada S, Zadina JE, Kastin AJ, et al. Differential involvement of µ-opioid receptor subtypes in endomorphin-1-and -2-induced antinociception. Eur J Pharmacol. 1999; 372: 25-30. doi: 10.1016/s0014-2999(99)00181-8.
  • Pasternak GW. Opioids and their receptors: are we there yet? Neuropharmacology. 2014; 76: 198–203. doi: 10.1016/j.neuropharm.2013.03.039.
  • Geppetti P, Veldhuis NA, Lieu TM, et al. G Protein-coupled receptors. Dynamic machines for signaling pain and itch. Neuron. 2015; 88: 635-643. doi: 10.1016/j.neuron.2015.11.001.
  • Rutherford JM, Wang J, Xu H, et al. Evidence for a mu-opioid receptor complex in CHO cells co-expressing mu and delta opioid peptide receptors. Peptides. 2008; 29: 1424-1431. doi: 10.1016/j.peptides.2008.03.019.
  • Shang Y, Filizola M. Opioid receptors: Structural and mechanistic insights into pharmacology and signaling. Eur J Pharmacol. 2015; 763: 206–213. doi: 10.1016/j.ejphar.2015.05.012.
  • Convertino M, Samoshkin A, Gauthier J, et al. μ-Opioid receptor 6-transmembrane isoform: A potential therapeutic target for new effective opioids. Prog Neuropsychopharmacol Biol Psychiatry. 2015; 62: 61–67. doi: 10.1016/j.pnpbp.2014.11.009.
  • Burford NT, Tolber, LM, Sadee W. Specific G protein activation and A-opioid receptor internalization caused by morphine, DAMGO and endomorphin-I. Eur J Pharmacol. 1998; 342: 123–126. doi: 10.1016/s0014-2999(97)01556-2.
  • Horner KA, Zadina JE. Internalization and down-regulation of mu opioid receptors by endomorphins and morphine in SH-SY5Y human neuroblastoma cells. Brain Res. 2004; 1028: 121–132. doi: 10.1016/j.brainres.2004.07.055.
  • Lengyel I, Toth F, Biyashev D, et al. A novel non-opioid binding site for endomorphin-1. J Physiol Pharmacol. 2016; 67: 605-616.
  • Kosson P, Bonney I, Carr DB, et al. Endomorphins interact with tachykinin receptors. Peptides. 2005; 26: 1667-1669. doi: 10.1016/j.peptides.2005.02.006.
  • Law PY, Loh H. Neuroactive proteins and peptides. In: Lajtha A, Lim R, editors. Handbook of Neurochemistry and Molecular Neurobiology. Germany: Springer; 2006. p. 357–389.
  • Kitanaka N, Kitanaka J, Hall FS, et al. Alterations in the levels of heterotrimeric G protein subunits induced by psychostimulants, opiates, barbiturates, and ethanol: Implications for drug dependence, tolerance, and withdrawal. Synapse. 2008; 62: 689–699. doi: 10.1002/syn.20543.
  • McDonald J, Lambert DG. Opioid mechanisms and opioid drugs. Anaesthesia and Intensive Care Medicine. 2011; 12(1): 31–35.
  • Sharp BM. Multiple opioid receptors on immune cells modulate intracellular signaling. Brain Behav Immun. 2006; 20: 9–14. doi: 10.1016/j.bbi.2005.02.002.
  • Nevo I, Avidor-Reiss T, Levy R, et al. Acute and chronic activation of the mu-opioid receptor with the endogenous ligand endomorphin differentially regulates adenylyl cyclase isozymes. Neuropharmacology. 2000; 39: 364–371. doi: 10.1016/s0028-3908(99)00155-0.
  • Zhang L, Zhao H, Qiu Y, et al. Src phosphorylation of micro-receptor is responsible for the receptor switching from an inhibitory to a stimulatory signal. J Biol Chem. 2009; 23: 1990–2000. doi: 10.1074/jbc.M807971200.
  • Block L, Forshammar J, Westerlund A, et al. Naloxone in ultralow concentration restores endomorphin-1-evoked Ca2+ signaling in lipopolysaccharide pretreated astrocytes. Neuroscience. 2012; 205: 1–9. doi: 10.1016/j.neuroscience.2011.12.058.
  • Liu H, Li H, Guo L, et al. Mechanisms involved in phosphatidylinositol 3-kinase pathway mediated up-regulation of the mu opioid receptor in lymphocytes. Biochem Pharmacol. 2010; 79: 516–523. doi: 10.1016/j.bcp.2009.09.013.
  • Anton B, Leff Ph, Calva JC, Acevedo R, et al. Endomorphin 1 and endomorphin 2 suppress in vitro antibody formation at ultra-low concentrations: Anti-peptide antibodies but not opioid antagonists block the activity. Brain Behav Immun. 2008; 22: 824–832. doi: 10.1016/j.bbi.2008.02.004.
  • Kaczyńska K, Kogut E, Zając D, et al. Neurotensin-based hybrid peptide's anti-inflammatory activity in murine model of a contact sensitivity response. Eur J Pharm Sci. 2016; 93: 84-89. doi: 10.1016/j.ejps.2016.08.012.
  • Lin X, Chen Q, Xue LY, et al. Endomorphins, endogenous opioid peptides, induce apoptosis in human leukemia HL-60 cells. Can J Physiol Pharmacol. 2004; 82: 1018-1025. doi: 10.1139/y04-087.
  • Shaffer AD, Ness TJ, Robbins MT, et al. Early in life bladder inflammation alters opioid peptide content in the spinal cord and bladder of adult female rats. J Urol. 2013; 189: 352-358. doi: 10.1016/j.juro.2012.08.190.
  • Azuma Y, Ohura K. Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-jB DNA binding in THP-1 differentiated to macrophage-like cells. Scand J Immunol. 2002; 56: 209–260. doi: 10.1046/j.1365-3083.2002.01128.x.
  • Azuma Y, Ohura K. Endomorphin-2 modulates productions of TNF-a, IL-1b, IL-10, and IL-12, and alters functions related to innate immune of macrophages. Inflammation. 2002; 26: 223–23.
  • Beutler B. Application of transcriptional and posttranscriptional receptor constructs to the analysis of tumor necrosis factor gene regulation. Am J Med Sci. 1992; 303: 129–133.
  • Kruys V, Kemmer K, Shakhov A, et al. Constitutive activity of the tumor necrosis factor promoter is canceled by the 3’ untranslated region in non macrophage cell lines; a trans-dominant factor overcomes this suppressive effect. Proc Natl Acad Sci U S A. 1992; 89: 673–677. doi: 10.1073/pnas.89.2.673.
  • Li WY, Yang JJ, Zhu SH, et al. Endomorphins and ohmefentanyl in the inhibition of immunosuppressant function in rat peritoneal macrophages: An experimental in vitro study. Curr Ther Res. 2008; 69: 56-64. doi: 10.1016/j.curtheres.2008.02.004.
  • Chiurchiu V, Izzi V, Aquilio FD, et al. Endomorphin-1 prevents lipid accumulation via CD36 down-regulation and modulates cytokines release from human lipid-laden macrophages. Peptides. 2011; 32: 80–85. doi: 10.1016/j.peptides.2010.09.024.
  • Neudeck BL, Loeb JM. Endomorphin-1 alters interleukin-8 secretion in Caco-2 cells via a receptor mediated process. Immunol Lett. 2002; 84: 217–221. doi: 10.1016/s0165-2478(02)00198-0.
  • Inui Y, Azuma Y, Ohura K. Differential alteration of functions of rat peritoneal macrophages responsive to endogenous opioid peptide endomorphin-1. Int Immunopharmacol. 2002; 2: 1133-1142. https://doi.org/10.1016/S1567-5769(02)00065-6
  • Azuma Y, Wang P-L, Shinohara M, et al. Immunomodulation of the neutrophil respiratory burst by endomorphins 1 and 2. Immunol Lett, 2000; 75: 55–59. doi: 10.1016/s0165-2478(00)00274-1.
  • Azuma Y, Ohura K, Wang P-L, et al. Endomorphins delay constitutive apoptosis and alter the innate host defense functions of neutrophils. Immunol Lett. 2002; 81: 31–40. doi: 10.1016/s0165-2478(01)00335-2.
  • Tseng LF, Narita M, Suganuma C, et al. Differential antinociceptive effects of endomorphin-1 and endomorphin-2 in the mouse. J Pharmacol Exp Ther. 2000; 292: 576-583.
  • Sedqi M, Roy S, Ramakrishnan S, et al. Complementary DNA cloning of a mu-opioid receptor from rat peritoneal macrophages. Biochem Biophys Res Commun. 1995; 209: 563-574. doi: 10.1006/bbrc.1995.1538.
  • Šaric A, Balog T, Sobocanec S, et al. Endomorphin 1 activates nitric oxide synthase 2 activity аnd downregulates nitric oxide synthase 2 mRNA еxpression. Neuroscience. 2007; 144: 1454–1461. doi: 10.1016/j.neuroscience.2006.11.020.
  • Balog T, Saric A, Sobocanec S, et al. Endomorphin-suppressed nitric oxide release from mice peritoneal macrophages. Neuropeptides. 2010; 44: 25–29. doi: 10.1016/j.npep.2009.11.004.
  • Yang L, Wang Y, Pan Z, et al. Endomorphine-1 inhibits maturation and functions of human peripheral blood-derived dendritic cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2016; 32: 527-531.
  • Liu CM, Yang TH, Huang M, et al. Effect of Endomorphin-1 on Maturation and Expression of TLR4 in Peripheral Blood Dendritic Cells Induced by High Glucose. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2018; 26: 886-893. doi: 10.7534/j.issn.1009-2137.2018.03.043.
  • Peterson PK, Gekker G, Hu S, et al. Endomorphin-1 potentiates HIV-1 expression in human brain cell cultures: implications of an atypical mu-opioid receptor. Neuropharmacology. 1999; 38: 273–278. doi: 10.1016/s0028-3908(98)00167-1.
  • Dai X, Song H-J, Cui S-G, et al. The stimulative effects of endogenous opioids on endothelial cell proliferation, migration and angiogenesis in vitro. Eur J Pharmacol. 2010; 628: 42–50. doi: 10.1016/j.ejphar.2009.11.035.
  • Carrigan KA, Nelson CJ, Lysle DT. Endomorphin-1 induces antinociception without immunomodulatory effects in the rat. Psychopharmacology. 2000; 151: 299–305. doi: 10.1007/s002130000487.
  • Hernandez MC, Flores LR, Bayer BM. Immunosuppression by morphine is mediated by central pathways. J Pharmacol Exp Ther. 1993; 267: 1336–1341.
  • Plein LM, Rittner HL. Opioids and the immune system – friend or foe. Br J Pharmacol. 2018; 175: 2717–2725. doi: 10.1111/bph.13750.
  • Гейн С.В., Баева Т.А., Гейн О.Н., и др. Роль моноцитов в реализации эффектов -эндорфина и селективных агонистов - и -опиатных рецепторов на пролиферативную активность лимфоцитов периферической крови // Физиология человека. – 2006. – Т. 32, №3. - С 111-116. [Gein SV, Baeva TA, Gein ON, et. al. The role of monocytes in the effects of -endorphin and selective agonists of - and -opiate receptors on the proliferative activity of peripheral blood lymphocytes. Fiziologiya Cheloveka. 2006; 32 (3): 111–116. (In Russ.)]
  • Li W, Chen W, Herberman RB, et al. Immunotherapy of cancer via mediation of cytotoxic T lymphocytes by methionine enkephalin (MENK). Cancer Lett. 2014; 344(2):212-22. doi: 10.1016/j.canlet.2013.10.029.
  • Manglik A, Kruse AC, Kobilka TS, et al. Crystal structure of the m-opioid receptor bound to a morphinan antagonist. Nature. 2012; 485: 321-326. doi: 10.1038/nature10954.
  • Bechara C, Sagan S. Cell-penetrating peptides: 20 years later, where do we stand? FEBS Lett. 2013; 587(12): 1693-702. doi: 10.1016/j.febslet.2013.04.031.
  • Wender PA, Mitchell DJ, Pattabiraman K, et al. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc Natl Acad Sci USA. 2000; 97: 13003–13008. doi: 10.1073/pnas.97.24.13003.
  • Gu Z-H, Wang B, Kou Z-Z, et. al. Endomorphins: Promising Endogenous Opioid Peptides for the Development of Novel Analgesics. Neurosignals. 2017; 25: 98-116. doi: 10.1159/000484909.

Statistics

Views

Abstract - 119

PDF (Russian) - 0

PlumX

Dimensions


Copyright (c) Gein S.V., Baeva T.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies