Skip to main content
SpringerLink
Log in

Opioid-Induced Apoptosis of Immune System Cells

  • Published:
Biology Bulletin Reviews Aims and scope Submit manuscript

Abstract

Opioid-receptor ligands are important factors in the regulation of immune responses. It is known that opioid peptides are secreted into the blood during stress; in addition, they are produced in inflammation foci by cells of the immune system and have antinociceptive and immunoregulatory effects of the paracrine and endocrine type via interaction with the opioid receptors expressed on immunocytes. Many types of stress (restraint, hypothermia, social stress) cause naloxone-dependent suppression of the immune system, which manifests itself in the form of a decrease in the proliferative activity of lymphocytes, the suppression of cytokine synthesis, antibody production, and the microbicidal potential. Thus, opioids are involved in the response of the immune system to stress and can induce immunosuppression, and one of the possible mechanisms of its implementation is apoptosis. In addition, ligands of nonpeptide opioid receptors (morphine and its derivatives) are widely used as analgesics in clinical practice for the treatment of a number of pathological conditions. This work systematizes data on the effect of ligands of opioid receptors of peptide and nonpeptide nature on the apoptosis of cells of adaptive and innate immunity and analyzes the possible molecular mechanisms of their apoptogenic effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Arora, P.K., Fride, E., Petitto, J., et al., Morphine-induced immune alterations in vivo, Cell Immunol., 1990, vol. 126, no. 2, pp. 343–353.

    Article  CAS  PubMed  Google Scholar 

  2. Azuma, Y., Ohura, K., Wang, P.-L., and Shinohara, M., Endomorphins delay constitutive apoptosis and alter the innate host defense functions of neutrophils, Immunol. Lett., 2002, vol. 81, no. 1, pp. 31–40.

    Article  CAS  PubMed  Google Scholar 

  3. Bhaskaran, M., Reddy, K., Sharma, S., et al., Morphine-induced degradation of the host defense barrier: role of macrophage injury, J. Infect. Dis., 2001, vol. 184, no. 12, pp. 1524–1531.

    Article  CAS  PubMed  Google Scholar 

  4. Bhat, R.S., Bhaskaran, M., Mongia, A., et al., Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation, J. Leukocyte Biol., 2004, vol. 75, no. 6, pp. 1131–1138.

    Article  CAS  PubMed  Google Scholar 

  5. Bodnar, R.J., Endogenous opiates and behavior: 2016, Peptides, 2018, vol. 101, pp. 167–212.

    Article  CAS  PubMed  Google Scholar 

  6. Bryant, H.U., Bernton, E.W., and Holaday, J.W., Immunosuppressive effects of chronic morphine treatment in mice, Life Sci., 1987, vol. 41, no. 14, pp. 1731–1738.

    Article  CAS  PubMed  Google Scholar 

  7. Bryant, H.U., Bernton, E.W., and Holaday, J.W., Morphine pellet-induced immunomodulation in mice: temporal relationships, J. Pharmacol. Exp. Ther., 1988a, vol. 245, no. 3, pp. 913–920.

    CAS  PubMed  Google Scholar 

  8. Bryant, H.U., Yoburn, B.C., Inturrisi, C.E., et al., Morphine-induced immunomodulation is not related to serum morphine concentrations, Eur. J. Pharmacol., 1988b, vol. 149, nos. 1–2, pp. 165–169.

    Article  CAS  PubMed  Google Scholar 

  9. Chang, M., Chen, Y., Huang, C., et al., The influences of morphine on dendritic cell-mediated immunity, Cancer Res., 2012, vol. 72, no. 8, p. 5401.

    Article  Google Scholar 

  10. Chang, M., Chen, Y., Chiang, Y., et al., Anti-CD40 antibody and toll-like receptor 3 ligand restore dendritic cell-mediated anti-tumor immunity suppressed by morphine, Am. J. Canc. Res., 2016, vol. 6, no. 2, pp. 157–172.

    CAS  Google Scholar 

  11. Cheng, W.F., Chen, L.K., Chen, C.A., et al., Chimeric DNA vaccine reverses morphine-induced immunosuppression and tumorigenesis, Mol. Ther., 2006, vol. 13, no. 1, pp. 203–210.

    Article  CAS  PubMed  Google Scholar 

  12. Declue, A.E., Yu, D.H., Prochnow, S., et al., Effects of opioids on phagocytic function, oxidative burst capacity, cytokine production and apoptosis in canine leukocytes, Vet. J., 2014, vol. 200, no. 2, pp. 270–275.

    Article  CAS  PubMed  Google Scholar 

  13. Freier, D.O. and Fuchs, B.A., Morphine-induced alterations in thymocyte subpopulations of B6C3F1 mice, J. Pharmacol. Exp. Ther., 1993, vol. 265, no. 1, pp. 81–88.

    CAS  PubMed  Google Scholar 

  14. Frenklakh, L., Bhat, R.S., Bhaskaran, M., et al., Morphine-induced degradation of the host defense barrier role of intestinal mucosal injury, Dig. Dis. Sci., 2006, vol. 51, no. 2, pp. 318–325.

    Article  CAS  PubMed  Google Scholar 

  15. Fuchs, B.A. and Pruett, S.B., Morphine induces apoptosis in murine thymocytes in vivo but not in vitro: involvement of both opiate and glucocorticoid receptors, J. Pharmacol. Exp. Ther., 1993, vol. 266, no. 1, pp. 417–423.

    CAS  PubMed  Google Scholar 

  16. Gein, S.V. and Sharav’eva, I.L., Immunomodulating effects of cold stress, Biol. Bull. Rev., 2018, vol. 8, no. 6, pp. 482–488.

    Article  Google Scholar 

  17. Gein, S.V., Baeva, T.A., and Nebogatikov, V.O., The influence of β-endorphin on the proliferative and secretory activities of splenocytes in vivo, Immunologiya, 2012, vol. 33, no. 2, pp. 102–103.

    CAS  Google Scholar 

  18. He, L., Li, H., Chen, L., et al., Toll-like receptor 9 is required for opioid-induced microglia apoptosis, PLoS One, 2011, vol. 6, no. 4, p. e18190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hu, S., Sheng, W.S., Lokensgard, J.R., and Peterson, P.K., Morphine induces apoptosis of human microglia and neurons, Neuropharmacology, 2002, vol. 42, no. 6, pp. 829–836.

    Article  CAS  PubMed  Google Scholar 

  20. Ientile, R., Ginoprelli, T., Cannavò, G., et al., Effect of beta-endorphin on cell growth and cell death in human peripheral blood lymphocytes, J. Neuroimmunol., 1997a, vol. 80, nos. 1–2, pp. 87–92.

    Article  CAS  PubMed  Google Scholar 

  21. Ientile, R., Ginoprelli, T., Cannavò, G., et al., β-Endorphin enhances polyamine transport in human lymphocytes, Life Sci., 1997b, vol. 60, no. 18, pp. 1545–1551.

    Article  CAS  PubMed  Google Scholar 

  22. Kapasi, A.A., Coscia, S.A., Pandya, M.P., and Singhal, P.C., Morphine modulates HIV-1 gp160-induced murine macrophage and human monocyte apoptosis by disparate ways, J. Neuroimmunol., 2004, vol. 148, nos. 1–2, pp. 86–96.

    Article  CAS  PubMed  Google Scholar 

  23. Khurdayan, V.K., Buch, S., El-Hage, N., et al., Preferential vulnerability of astroglia and glial precursors to combined opioid and HIV-1 Tat exposure in vitro, Eur. J. Neurosci., 2004, vol. 19, no. 12, pp. 3171–3182.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Leis, K., Mazur, E., Jabłońska, M.J., et al., Endocrine systems of the skin, Adv. Dermatol. Allergol., 2019, vol. 36, no. 5, pp. 519–523.

    Article  Google Scholar 

  25. Li, H., Zhao, J., Chen, M., et al., Toll-like receptor 9 is required for chronic stress-induced immune suppression, Neuroimmunomodulation, 2014, vol. 21, no. 1, pp. 1–7.

    Article  PubMed  Google Scholar 

  26. Li, M.C., Yu, J.H., Yu, S.S., et al., MicroRNA-873 inhibits morphine-induced macrophage apoptosis by elevating A20 expression, Pain Med., 2015, vol. 16, no. 10, pp. 1993–1999.

    Article  PubMed  Google Scholar 

  27. Li, P.F., Hao, Y.S., Zhang, F.X., et al., Signaling pathway involved in methionine enkephalin-promoted survival of lymphocytes infected by simian immunodeficiency virus in the early stage in vitro, Int. Immunopharmacol., 2004, vol. 4, no. 1, pp. 79–90.

    Article  CAS  PubMed  Google Scholar 

  28. Li, Z., Zhou, L., Zhang, B., et al., Effect and mechanism of nociceptin/orphanin FQ reversing multi-drug resistance in K562/ADM cell, Pharmazie, 2008, vol. 63, no. 9, pp. 676–685.

    CAS  PubMed  Google Scholar 

  29. Lin, X., Chen, Q., Xue, L.Y., et al., Endomorphins, endogenous opioid peptides, induce apoptosis in human leukemia HL-60 cells, Can. J. Physiol. Pharmacol., 2004, vol. 82, no. 11, pp. 1018−1025.

    Article  CAS  PubMed  Google Scholar 

  30. Ma, K., Ma, P., Lu, H., et al., Fentanyl suppresses the survival of CD4+ T cells isolated from human umbilical cord blood through inhibition of IKKs-mediated NF-κB activation, Scand. J. Immunol., 2017, vol. 85, no. 5, pp. 343–349.

    Article  CAS  PubMed  Google Scholar 

  31. Malik, A.A., Radhakrishnan, N., Reddy, K., et al., Morphine-induced macrophage apoptosis modulates migration of macrophages: use of in vitro model of urinary tract infection, J. Endourol., 2002, vol. 16, no. 8, pp. 605–610.

    Article  PubMed  Google Scholar 

  32. Messmer, U.K., Reed, U.K., and Brüne, B., Bcl-2 protects macrophages from nitric oxide-induced apoptosis, J. Biol. Chem., 1996, vol. 271, no. 33, pp. 20192–20197.

    Article  CAS  PubMed  Google Scholar 

  33. Monibi, F.A., Dodam, J.R., Axiak-Bechtel, S.M., et al., Morphine and buprenorphine do not alter leukocyte cytokine production capacity, early apoptosis, or neutrophil phagocytic function in healthy dogs, Res. Vet. Sci., 2015, vol. 99, pp. 70–76.

    Article  CAS  PubMed  Google Scholar 

  34. Nair, M.P., Schwartz, S.A., Polasani, R., et al., Immunoregulatory effects of morphine on human lymphocytes, Clin. Diagn. Lab. Immunol., 1997, vol. 4, no. 2, pp. 127–132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ohara, T., Itoh, T., and Takahashi, M., Immunosuppression by morphine-induced lymphocyte apoptosis: is it a real issue? Anesth. Analg. (Philadelphia), 2005, vol. 101, no. 4, pp. 1117–1122.

    Article  CAS  Google Scholar 

  36. Ohmori, H., Fujii, K., Sasahira, T., et al., Methionine-enkephalin secreted by human colorectal cancer cells suppresses T lymphocytes, Cancer Sci., 2009, vol. 100, no. 3, pp. 497–502.

    Article  CAS  PubMed  Google Scholar 

  37. Patel, K., Bhaskaran, M., Dani, D., et al., Role of heme oxygenase-1 in morphine-modulated apoptosis and migration of macrophages, J. Infect. Dis., 2003, vol. 187, no. 1, pp. 47–54.

    Article  CAS  PubMed  Google Scholar 

  38. Roy, S., Wang, J.H., Balasubramanian, S., et al., Role of hypothalamic-pituitary axis in morphine-induced alteration in thymic cell distribution using mu-opioid receptor knockout mice, J. Neuroimmunol., 2001, vol. 116, no. 2, pp. 147–155.

    Article  CAS  PubMed  Google Scholar 

  39. Sei, Y., Yoshimoto, K., McIntyre, T., et al., Morphine-induced thymic hypoplasia is glucocorticoid-dependent, J. Immunol., 1991, vol. 146, no. 1, pp. 194–198.

    Article  CAS  PubMed  Google Scholar 

  40. Singhal, P.C., Reddy, K., Franki, N., et al., Morphine induces splenocyte apoptosis and enhanced mRNA expression of cathepsin-B, Inflammation, 1997, vol. 21, no. 6, pp. 609–617.

    Article  CAS  PubMed  Google Scholar 

  41. Singhal, P.C., Sharma P., Kapasi, A.A., et al., Morphine enhances macrophage apoptosis, J. Immunol., 1998, vol. 160, no. 4, pp. 1886–1893.

    Article  CAS  PubMed  Google Scholar 

  42. Singhal, P.C., Kapasi, A.A., Reddy, K., et al., Morphine promotes apoptosis in Jurkat cells, J. Leukocyte Biol., 1999, vol. 66, no. 4, pp. 650–658.

    Article  CAS  PubMed  Google Scholar 

  43. Singhal, P.C., Kapasi, A.A., Franki, N., and Reddy, K., Morphine-induced macrophage apoptosis: the role of transforming growth factor-beta, Immunology, 2000, vol. 100, no. 1, pp. 57–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Singhal, P., Kapasi, A., Reddy, K., and Franki, N., Opiates promote T cell apoptosis through JNK and caspase pathway, Adv. Exp. Med. Biol., 2001, vol. 493, pp. 127–135.

    Article  CAS  PubMed  Google Scholar 

  45. Smith, E.M., Neuropeptides as signal molecules in common with leukocytes and the hypothalamic–pituitary–adrenal axis, Brain Behav. Immun., 2008, vol. 22, no. 1, pp. 3–14.

    Article  CAS  PubMed  Google Scholar 

  46. Sułowska, Z., Majewska, E., Krawczyk, K., et al., Influence of opioid peptides on human neutrophil apoptosis and activation in vitro, Mediators Inflammation, 2002, vol. 11, no. 4, pp. 245–250.

    Article  Google Scholar 

  47. Sułowska, Z., Majewska, E., Tchórzewski, H., and Klink, M., Effect of exogenous opioid peptides on TNF-α-induced human neutrophil apoptosis in vitro, Arch. Immunol. Ther. Exp., 2003, vol. 51, no. 4, pp. 267–272.

    Google Scholar 

  48. Suzuki, S., Chuang, L.F., Doi, R.H., and Chuang, R.Y., Morphine suppresses lymphocyte apoptosis by blocking p53-mediated death signaling, Biochem. Biophys. Res. Commun., 2003, vol. 308, no. 4, pp. 802–808.

    Article  CAS  PubMed  Google Scholar 

  49. Tsujikawa, H., Shoda, T., Mizota, T., and Fukuda, K., Morphine induces DNA damage and p53 activation in CD3+ T cells, Biochim. Biophys. Acta, Gen. Subj., 2009, vol. 1790, no. 8, pp. 793–799.

    Article  CAS  Google Scholar 

  50. Ugur, M., Derouiche, L., and Massotte, D., Heteromerization modulates mu opioid receptor functional properties in vivo, Front. Pharmacol., 2018, vol. 9, pp. 1–10.

    Article  Google Scholar 

  51. Wang, J., Charboneau, R., Barke, R.A., et al., Mu-opioid receptor mediates chronic restraint stress-induced lymphocyte apoptosis, J. Immunol., 2002, vol. 169, no. 7, pp. 3630–3636.

    Article  CAS  PubMed  Google Scholar 

  52. Weng H.L. and Wang, M.J., Effects of microRNA-338-3p on morphine induced apoptosis and its underlying mechanisms, Mol. Med. Rep., 2016, vol. 14, no. 3, pp. 2085–2092.

    Article  CAS  PubMed  Google Scholar 

  53. Xie, N., Li, H., Wei, D., et al., Glycogen synthase kinase-3 and p38 MAPK are required for opioid-induced microglia apoptosis, Neuropharmacology, 2010, vol. 59, no. 6, pp. 444–451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xu, J., Xin, S., Li, H., et al., Involvement of caspase-3 pathway in anti-apoptotic action of methionine enkephalin on CEM × 174 cells in prolonged infection with simian immunodeficiency virus in vitro, Cell Biol. Int., 2006, vol. 30, no. 2, pp. 114–121.

    Article  CAS  PubMed  Google Scholar 

  55. Xu, X., Gao, Y., Wen, L., et al., Methionine enkephalin regulates microglia polarization and function, Int. Immunopharmacol., 2016, vol. 40, pp. 90–97.

    Article  CAS  PubMed  Google Scholar 

  56. Yin, D., Tuthill, D., Mufson, R.A., and Shi, Y., Chronic restraint stress promotes lymphocyte apoptosis by modulating CD95 expression, J. Exp. Med., 2000, vol. 191, no. 8, pp. 1423–1428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yuzhaninova, S.V. and Gileva, S.G., Effect of beta-endorphin and dynorphin A on apoptosis of human peripheral blood lymphocytes in vitro, Ross. Imunol. Zh., 2020, vol. 23, no. 2, pp. 67–72.

    Google Scholar 

  58. Zhang, E.Y., Xiong, J., Parker, B.L., et al., Depletion and recovery of lymphoid subsets following morphine administration, Br. J. Pharmacol., 2011, vol. 164, no. 7, pp. 1829–1844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The search and analytical work on the preparation of the manuscript was performed within the framework of the state assignment (topic state registration no. АААА-А19-119112290007-7).

Author information

Authors and Affiliations

  1. Institute of Ecology and Genetics of Microorganisms, Branch of the Perm Federal Research Center, Ural Branch of the Russian Academy of Sciences, Perm, Russia

    S. V. Gein

  2. Perm State National Research University, Perm, Russia

    S. V. Gein

Authors
  1. S. V. Gein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. V. Gein.

Ethics declarations

Conflict of interests. The author declares that he has no conflict of interests.

Statement on the welfare of humans or animals. This article does not contain any studies involving humans or animals performed by the author.

Additional information

Translated by M. Batrukova

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gein, S.V. Opioid-Induced Apoptosis of Immune System Cells. Biol Bull Rev 11, 567–575 (2021). https://doi.org/10.1134/S2079086421060037

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S2079086421060037

Keywords:

Search

Navigation