Endomorphins: structure, localization, immunoregulatory activity

Cover Page
Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access


Endomorphins – endogenous tetrapeptides with the highest affinity for the µ-opioid receptor. Currently, two tetrapeptides that differ in one amino acid residue have been isolated and characterized. The structure of endomorphins differs from the structure of members of three main families of opioid peptides: endorphins, enkephalins, and dynorphins, which contain the same N-terminal sequence. In the central nervous system, endomorphins are distributed everywhere, where they are primarily responsible for antinociception. 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 the functions of the cells of the immune system. Peptides predominantly suppress adaptive immunity reactions. There effects on the functions of innate immunity cells (granulocytes, macrophages, monocytes, dendritic cells) depending on the conditions and can have either an inhibitory or stimulating orientation. Thus, endomorphins can be promising compounds that can effectively regulate both nociceptive signals and processes in the immune system.

Full Text

Restricted Access

About the authors

Sergey V. 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 State University

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

MD, PhD, Professor

Tatyana A. 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

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

Russian Federation, 614081, Perm, Goleva street, 13



  1. Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci U S A. 1993;90(12):5391−5393. doi: https://doi.org/10.1073/pnas.90.12.5391
  2. Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous agonist for the mu-opiate receptor. Nature (Lond). 1997;386:499–502. doi: https://doi.org/10.1038/386499a0
  3. Smith EM. Neuropeptides as signal molecules in common with leukocytes and the hypothalamic-pituitary-adrenal axis. Brain Behav Immun. 2008;22(1):3−14. doi: https://doi.org/10.1016/j.bbi.2007.08.005
  4. Hackler L, Zadina JE, Ge LJ, Kastin AJ. Isolation of relatively large amounts of endomorphin-1 and endomorphin-2 from human brain cortex. Peptides. 1997;18(10):1635−1639. doi: https://doi.org/10.1016/s0196-9781(97)00259-3
  5. Mizusawa K. Endomorphin. In: Takei Y, Ando H, Tsutsui K, ed. Handbook of hormones: comparative endocrinology for basic and clinical research. Oxford: Academic Press; 2016. Рp. 62−63
  6. Fichna J, Janecka A, Costentin J, Do Rego JC. The endomorphin system and its evolving neurophysiological role. Pharmacol Rev. 2007;59(1):88−123. doi: https://doi.org/10.1124/pr.59.1.3
  7. Mizoguchi H, Sakurada T, Sakurada S. Endomorphins. In: Kastin A, ed. Handbook of biologically active peptides Oxford: Academic Press; 2013. Рp. 1556−1561.
  8. Finley JC, Lindstrom P, Petrusz P. Immunocytochemical localization of β-endorphin-containing neurons in the rat brain. Neuroendocrinology. 1981;33(1):28−42. doi: https://doi.org/10.1159/000123197
  9. 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(1−2):53−59. doi: https://doi.org/10.1016/s0165-5728(99)00216-7
  10. Mousa SA, Machelska H, Schafer M, Stein C. Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J Neuroimmunol. 2002;126(1−2):5−15. doi: https://doi.org/10.1016/s0165-5728(02)00049-8
  11. Seale JV, Jessop DS, Harbuz MS. Immunohistochemical staining of endomorphin 1 and 2 in the immune cells of the spleen. Peptides. 2004;25(1):91−94. doi: https://doi.org/10.1016/j.peptides.2003.11.016
  12. 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: https://doi.org/10.1111/j.1749-6632.2002.tb04247.x
  13. Van 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(7):1390−1399. doi: https://doi.org/10.1016/j.peptides.2010.03.029
  14. Botros M, Hallberg M, Johansson T, et al. Endomorphin-1 and endomorphin-2 differentially interact with specific binding sites for substance P (SP) aminoterminal SP1-7 in rat spinal cord. Peptides. 2006;27(4):753−759. doi: https://doi.org/10.1016/j.peptides.2005.08.009
  15. Janecka A, Staniszewska R, Gach K, Fichna J. Enzymatic degradation of endomorphins. Peptides. 2008;29(11):2066−2073. doi: https://doi.org/10.1016/j.peptides.2008.07.015
  16. 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(4):1528−1534. doi: https://doi.org/10.1016/j.bmc.2010.12.042
  17. Falconer RA, Toth I. Design, synthesis and biological evaluation of novel lipoamino acid-based glycolipids for oral drug delivery. Bioorg Med Chem. 2007;15(22):7012−7020. doi: https://doi.org/10.1016/j.bmc.2007.07.048
  18. Varamini Р, Hussein WM, Mansfeld FM, Toth I. Synthesis, biological activity and structure-activity relationship of endomorphin-1/substance P derivatives. Bioorg Med Chem. 2012;20(21):6335−6343. doi: https://doi.org/10.1016/j.bmc.2012.09.003
  19. Varamini P, Toth I. Lipid-and sugar-modified endomorphins: novel targets for the treatment of neuropathic pain. Front Pharmacol. 2013;4:155. doi: https://doi.org/10.3389/fphar.2013.00155
  20. Horvath G. Endomorphin-1 and endomorphin-2: pharmacology of the selective endogenous mu-opioid receptor agonists. Pharmacol Ther. 2000;88(3):437−463. doi: https://doi.org/10.1016/s0163-7258(00)00100-5
  21. Sharp BM, Roy S, Bidlack JM. Evidence for opioid receptors on cells involved in host defense and the immune system. J Neuroimmunol. 1998;83(1−2):45−56. doi: https://doi.org/10.1016/s0165-5728(97)00220-8
  22. 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: https://doi.org/10.1016/s0014-2999(99)00181-8
  23. Pasternak GW. Opioids and their receptors: are we there yet? Neuropharmacology. 2014;76 Pt B:198−203. doi: https://doi.org/10.1016/j.neuropharm.2013.03.039
  24. Geppetti P, Veldhuis NA, Lieu TM, Bunnett NW. G-Protein coupled receptors. Dynamic machines for signaling pain and itch. Neuron. 2015;88(4):635−649. doi: https://doi.org/10.1016/j.neuron.2015.11.001
  25. 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: https://doi.org/10.1016/j.peptides.2008.03.019
  26. Shang Y, Filizola M. Opioid receptors: structural and mechanistic insights into pharmacology and signaling. Eur J Pharmacol. 2015;763(Pt B):206−213. doi: https://doi.org/10.1016/j.ejphar.2015.05.012
  27. 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: https://doi.org/10.1016/j.pnpbp.2014.11.009
  28. 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(1):123−126. doi: https://doi.org/10.1016/s0014-2999(97)01556-2
  29. 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(2):121−132. doi: https://doi.org/10.1016/j.brainres.2004.07.055
  30. Lengyel I, Toth F, Biyashev D, et al. A novel non-opioid binding site for endomorphin-1. J Physiol Pharmacol. 2016;67:605−616
  31. Kosson P, Bonney I, Carr DB, et al. Endomorphins interact with tachykinin receptors. Peptides. 2005;26(9):1667−1669. doi: https://doi.org/10.1016/j.peptides.2005.02.006
  32. Law PY, Loh H. Neuroactive proteins and peptides. In: Lajtha A, Lim R, ed. Handbook of neurochemistry and molecular neurobiology. Germany: Springer; 2006. Рp. 357–389
  33. 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(9):689–699. doi: https://doi.org/10.1002/syn.20543
  34. McDonald J, Lambert DG. Opioid mechanisms and opioid drugs. Anaesthesia Intensive Care Medicine. 2011;12(1):31–35. doi: https://doi.org/10.1016/j.mpaic.2010.10.008
  35. Sharp BM. Multiple opioid receptors on immune cells modulate intracellular signaling. Brain Behav Immun. 2006;20:9–14. doi: https://doi.org/10.1016/j.bbi.2005.02.002
  36. 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(3):364–371. doi: https://doi.org/10.1016/s0028-3908(99)00155-0
  37. 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(4):1990–2000. doi: https://doi.org/10.1074/jbc.M807971200
  38. 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: https://doi.org/10.1016/j.neuroscience.2011.12.058
  39. 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(3):516–523. doi: https://doi.org/10.1016/j.bcp.2009.09.013
  40. Anton B, Leff P, Calva JC, 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(6):824–832. doi: https://doi.org/10.1016/j.bbi.2008.02.004
  41. 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: https://doi.org/10.1016/j.ejps.2016.08.012.
  42. 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(11):1018−1025. doi: https://doi.org/10.1139/y04-087
  43. Shaffer AD, Ness TJ, Robbins MT, Randich A. Early in life bladder inflammation alters opioid peptide content in the spinal cord and bladder of adult female rats. J Urol. 2013;189(1):352−358. doi: https://doi.org/10.1016/j.juro.2012.08.190
  44. 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(3):209–260. doi: https://doi.org/10.1046/j.1365-3083.2002.01128.x
  45. Azuma Y, Ohura K. Endomorphin-2 modulates productions of TNF-alpha, IL-1beta, IL-10, and IL-12, and alters functions related to innate immune of macrophages. Inflammation. 2002;26(5):223−232. doi: https://doi.org/10.1023/a:1019766602138
  46. Beutler B. Application of transcriptional and posttranscriptional reporter constructs to the analysis of tumor necrosis factor gene regulation. Am J Med Sci. 1992;303(2):129–133. doi: https://doi.org/10.1097/00000441-199202000-00015
  47. 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(2):673–677. doi: https://doi.org/10.1073/pnas.89.2.673
  48. 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(1):56−64. doi: https://doi.org/10.1016/j.curtheres.2008.02.004
  49. 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(1):80–85. doi: https://doi.org/10.1016/j.peptides.2010.09.024
  50. Neudeck BL, Loeb JM. Endomorphin-1 alters interleukin-8 secretion in caco-2 cells via a receptor mediated process. Immunol Lett. 2002;84(3):217–221. doi: https://doi.org/10.1016/s0165-2478(02)00198-0
  51. 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(8):1133−1142. doi: https://doi.org/10.1016/S1567-5769(02)00065-6
  52. Azuma Y, Wang P-L, Shinohara M, Ohura K. Immunomodulation of the neutrophil respiratory burst by endomorphins 1 and 2. Immunol Lett. 2000;75(1):55–59. doi: https://doi.org/10.1016/s0165-2478(00)00274-1
  53. Azuma Y, Ohura K, Wang PL, Shinohara M. Endomorphins delay constitutive apoptosis and alter the innate host defense functions of neutrophils. Immunol Lett. 2002;81(1):31–40. doi: https://doi.org/10.1016/s0165-2478(01)00335-2
  54. 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(2):576−583
  55. 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(2):563−574. doi: https://doi.org/10.1006/bbrc.1995.1538
  56. Šaric A, Balog T, Sobocanec S, Marotti T. Endomorphin 1 activates nitric oxide synthase 2 activity аnd downregulates nitric oxide synthase 2 mRNA еxpression. Neuroscience. 2007;144(4):1454–1461. doi: https://doi.org/10.1016/j.neuroscience.2006.11.020
  57. Balog T, Saric A, Sobocanec S, et al. Endomorphin-suppressed nitric oxide release from mice peritoneal macrophages. Neuropeptides. 2010;44(1):25–29. doi: https://doi.org/10.1016/j.npep.2009.11.004
  58. Yang L, Wang Y, Pan Z, et al. [Endomorphine-1 inhibits maturation and functions of human peripheral blood-derived dendritic cells. (In Chinese)]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2016;32(4):527−531
  59. 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. (In Chinese)]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2018;26(3):886−893. doi: https://doi.org/10.7534/j.issn.1009-2137.2018.03.043
  60. 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(2):273–278. doi: https://doi.org/10.1016/s0028-3908(98)00167-1
  61. Dai X, Song HJ, Cui SG, et al. The stimulative effects of endogenous opioids on endothelial cell proliferation, migration and angiogenesis in vitro. Eur J Pharmacol. 2010;628(1−3):42–50. doi: https://doi.org/10.1016/j.ejphar.2009.11.035
  62. Carrigan KA, Nelson CJ, Lysle DT. Endomorphin-1 induces antinociception without immunomodulatory effects in the rat. Psychopharmacology. 2000;151(4):299–305. doi: https://doi.org/10.1007/s002130000487
  63. Hernandez MC, Flores LR, Bayer BM. Immunosuppression by morphine is mediated by central pathways. J Pharmacol Exp Ther. 1993;267(3):1336–1341
  64. Plein LM, Rittner HL. Opioids and the immune system — friend or foe. Br J Pharmacol. 2018;175(14):2717–2725. doi: https://doi.org/10.1111/bph.13750
  65. Гейн С.В., Баева Т.А., Гейн О.Н., Черешнев В.А. Роль моноцитов в реализации эффектов β-эндорфина и селективных агонистов μ- и δ-опиатных рецепторов на пролиферативную активность лимфоцитов периферической крови // Физиология человека. — 2006. — Т.32. — №3. — С. 111−116. [Gein SV, Baeva TA, Gein ON, Chereshnev VA. The role of monocytes in the effects of β-endorphin and selective agonists of μ-and δ-opiate receptors on the proliferative activity of peripheral blood lymphocytes. Human Physiology. 2006;32(3):111–116. (In Russ.)]
  66. 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):212−222. doi: https://doi.org/10.1016/j.canlet.2013.10.029
  67. Manglik A, Kruse AC, Kobilka TS, et al. Crystal structure of the m-opioid receptor bound to a morphinan antagonist. Nature. 2012;485(7398):321−326. doi: https://doi.org/10.1038/nature10954
  68. Bechara C, Sagan S. Cell-penetrating peptides: 20 years later, where do we stand? FEBS Lett. 2013;587(12):1693−1702. doi: https://doi.org/10.1016/j.febslet.2013.04.031
  69. 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 U S A. 2000;97(24):13003–13008. doi: https://doi.org/10.1073/pnas.97.24.13003
  70. Gu ZH, Wang B, Kou ZZ, et al. Endomorphins: promising endogenous opioid peptides for the development of novel analgesics. Neurosignals. 2017;25(1):98−116. doi: https://doi.org/10.1159/000484909

Supplementary files

Supplementary Files Action
Figure 1. Structure of endomorphins.

View (144KB) Indexing metadata
Figure 2. The ratio of stimulating and depressing effects between groups of endogenous opioid peptides: (+) - stimulation, (-) - inhibition.

View (30KB) Indexing metadata



Abstract - 301

PDF (Russian) - 0




Copyright (c) 2020 Gein S.V., Baeva T.A.

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