Skip to main content
SpringerLink
Log in

Cellular Mechanisms Involved in Morphine-Mediated Suppression of CTL Activity

  • Chapter
The Brain Immune Axis and Substance Abuse

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 373))

Abstract

Cellular immunity including MHC-unrestricted natural killer (NK) cells and antigen-specific, class I MHC-restricted cytotoxic T lymphocytes (CTLs) plays a central role in monitoring viral infections and tumor growth (1). NK activity has been shown to be modified by opioid compounds both in vitro and in vivo. The addition of endogenous opioid peptides (e.g., β-endorphin or [met]-enkephalin) to 4-hr 51Cr-release NK microcytotoxicity assays has been shown to augment NK activity; this augmentation is naloxone-sensitive (2). However, the acute administration of opioid drugs (e.g., morphine or fentanyl) in mice has been shown to suppress splenic NK activity through a naltrexone-sensitive mechanism (3-5). This suppression involves opioid receptors located in the periaqueductal gray matter of the mesencephalon (6). Pretreatment of the mice with the α-adrenoceptor antagonists phentolamine or prazocin blocks morphine-mediated suppression of splenic NK activity implicating α-adrenergic receptor involvement (7). Preadministration of mice with phentolamine (general α-adrenoceptor antagonist) but not doxazosin (peripheral-acting α-adrenergic receptor antagonist) inhibits morphine-mediated suppression of splenic NK activity further implicating central (brain) rather than peripheral α-adrenergic involvement (8). Alternatively, other neuroendocrine hormones may be utilized distal to the brain ultimately influencing NK effector cells. Specifically, splenic serotonin levels are elevated following acute morphine administration and such increases can be blocked by pretreating animals with phentolamine (8). These results suggest serotonin might be solicited by adrenergic processes ultimately resulting in suppression of splenic NK activity. Consistent with this notion, a recent study revealed serotonin suppressed NK activity in whole blood and such effects could be reversed with interferon-α (9). Certainly, this is a complicated issue involving many mediators which may have direct or indirect effects on the NK cells.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. T. Boon, J.-C-. Cerottini, B. Van den Eynde, P. van der Bruggen, and A. Van Pel, Tumor antigen recognized by T lymphocytes, Ann. Rev Immunol. 12:337 (1994).

    Article  CAS  Google Scholar 

  2. P. M. Mathews, C. J. Froelich, W. L. Sibbitt, and A. D. Bankhurst, Enhancement of natural cytotoxicity by β-endorphin, J. Immunol. 130:1658 (1983).

    PubMed  CAS  Google Scholar 

  3. Y. Shavit, A. Depaulis, F. C. Martin, G. W. Terman, R. N. Pechnick, C. J. Zane, R. P. Gale, and J. C. Liebeskind, Involvement of brain opiate receptors in the immune-suppressive effect of morphine, Proc. Natl. Acad. Sci. USA. 83:7114 (1986).

    Article  PubMed  CAS  Google Scholar 

  4. B. Beilin, F. C. Martin, Y. Shavit, R. P. Gale, and J. C. Liebeskind, Suppression of natural killer cell activity by high-dose narcotic anesthesia rats, Brain, Behavior, Immun. 3:129 (1989).

    Article  CAS  Google Scholar 

  5. R. J. Weber and A. Pert, The periaqueductal gray matter mediates opiate-induced immunosuppression, Science (Wash. DC) 245:188 (1989).

    Article  CAS  Google Scholar 

  6. D. J. J. Carr, M. L. Baker, C. Holmes, L. L. Brockunier, J. R. Bagley, and C. P. France, OHM3295: A fentanyl-related 4-heteroanilido piperidine with analgesic effects but not suppressive effects on splenic NK activity in mice, Int. J Immunopharmacol. 16:835 (1994).

    Article  PubMed  CAS  Google Scholar 

  7. D. J. J. Carr, B. M. Gebhardt, and D. Paul, Alpha adrenergic and mu-2 opioid receptors are involved in morphine-induced suppression of splenocyte natural killer activity, J. Pharmacol. Exp. Ther. 264:1179 (1993).

    PubMed  CAS  Google Scholar 

  8. D. J. J. Carr, S. Mayo, B. M. Gebhardt, and J. Porter, Central α-adrenergic involvement in morphinemediated suppression of splenic NK activity, J. Neuroimmunol. 53:53 (1994).

    Article  PubMed  CAS  Google Scholar 

  9. S. I. Garssadi, Y. Mandi, K. Regely, B. Barodi, and I. Beladi, The inhibitory effect of interferon-alpha on the serotonin-induced impairment of human NK cell activity in whole blood, Brain, Behavior Immun. 7:164 (1993).

    Article  CAS  Google Scholar 

  10. M. M. Whalen, R. N. Doshi, Y. Homma, and A. D. Bankhurst, Phospholipase C activation in the cytotoxic response of human natural killer cells requires protein-tyrosine kinase activity, Immunol. 79:542 (1993).

    CAS  Google Scholar 

  11. F. Borrego, J. Pena, and R. Solana, Regulation of CD69 expression on human natural killer cells: differential involvement of protein kinase C and protein tyrosine kinase, Eur. J. Immunol. 23:1039 (1993).

    Article  PubMed  CAS  Google Scholar 

  12. D. J. J. Carr and G. R. Klimpel, Enhancement of the generation of cytotoxic T cells by endogenous opiates, J. Neuroimmunol. 12:75 (1986).

    Article  PubMed  CAS  Google Scholar 

  13. G. W. Carpenter, H. H. Garza, Jr., B. M. Gebhardt, and D. J. J. Carr, Chronic morphine treatment suppresses CTL-mediated cytolysis, granulation, and cAMP responses to alloantigen, Brain, Behavior, Immun. 8:185 (1994).

    Article  CAS  Google Scholar 

  14. P. S. Portoghese, M. Sultana, H. Nagase, and A. E. Takemori, A highly selective δ1 -ropioid receptor antagonist: 7-benzylidenenaltrexone, Eur. J. Pharmacol. 218:195 (1992).

    Article  PubMed  CAS  Google Scholar 

  15. R. M. Donahoe, Neuroimmunomodulation by opiates: Relationship to HIV-1 infection and AIDS, Adv. Neuroimmunol. 3:31 (1992).

    Article  Google Scholar 

  16. R. M. Perlmutter, S. D. Levin, M. W. Appleby, S. J. Anderson, and J. Alberola-Ila, Regulation of lymphocyte function by protein phosphorylation, Ann. Rev. Immunol. 11:451 (1993).

    Article  CAS  Google Scholar 

  17. R. M. Donahoe, J. J. Madden, F. Hollingsworth, D. Shafer, and A. Falek, Morphine depression of T cell E-rosetting: definition of the process, Fed. Proc. 44:95 (1985).

    PubMed  CAS  Google Scholar 

  18. Y. Sei, T. McIntyre, E. Fride, K. Yoshimoto, P. Skolnick, and P. K. Arora, Inhibition of calcium mobilization is an early event in opiate-induced immunosuppression, FASEB J. 5:2194 (1991).

    PubMed  CAS  Google Scholar 

  19. G. Berke, The binding and lysis of target cells by cytotoxic lymphocytes: Molecular and cellular aspects, Ann. Rev Immunol. 12:735 (1994).

    Article  CAS  Google Scholar 

  20. M. S. Pastemack, C. R. Verret, M. A. Liu, and H. N. Eisen, Serine esterase in cytotoxic T lymphocytes, Nature (London) 322:740 (1986).

    Article  Google Scholar 

  21. S. Valititutti, M. Dessing, and A. Lanzavecchia, Role of cAMP in regulating cytotoxic T lymphocyte adhesion and motility, Eur. J. Immunol. 23:790 (1993).

    Article  Google Scholar 

  22. H. U. Bryant, E. W. Bemton, J. R. Kenner, and J. W. Holaday, Role of adrenal cortical activation in the immunosuppressive effects of chronic morphine treatment, Endocrinol. 128:3253 (1991).

    Article  CAS  Google Scholar 

  23. Y. Sei, K. Yoshimoto, T. McIntyre, P. Skolnick, and P. K. Arora, Morphine-induced thymic hypoplasia is glucocorticoid-dependent, J. Immunol. 146:194 (1991)

    PubMed  CAS  Google Scholar 

  24. B. A. Fuchs and S. B. Pruett, Morphine induces apoptosis in murine thymocytes in vivo but not in vitro: Involvement of both opiate and glucocorticoid receptors, J. Pharmacol. Exp. Ther. 266:417 (1993).

    PubMed  CAS  Google Scholar 

  25. D. J. J. Carr, The role of opioids and their receptors in the immune system, Proc. Soc. Exp. Biol. Med. 198:710 (1991).

    PubMed  CAS  Google Scholar 

  26. J. J. Madden, R. M. Donahoe, J. Zwemer-Collins, D. A. Shafer, and A. Falek, Binding of naloxone to human T lymphocytes, Biochem. Pharmacol. 36:4103 (1987).

    Article  PubMed  CAS  Google Scholar 

  27. J. M. Bidlack, L. D. Sairpalli, D. M. P. Lawrence, and D. B. Joseph, The mouse thymoma cell line R1.1 expresses a κ opioid receptor, Adv. Biosciences 86:585 (1993).

    CAS  Google Scholar 

  28. C. J. Evans, D. E. Keith, H. Morrison, K. Magendzo, and R. H. Edwards, Cloning of a delta opioid receptor by functional expression, Science (Wash. DC) 258:1952 (1992).

    Article  CAS  Google Scholar 

  29. H. U. Bryant and R. E. Roudebush, Suppressive effects of morphine pellet implants on in vivo parameters of immune function, J. Pharmacol. Exp. Ther. 255:410 (1990).

    PubMed  CAS  Google Scholar 

  30. D. L. Felten, S. Y. Felten, S. Y. Carlson, J. A. Olschowka, and S. Livnat, Noradrenergic and peptidergic innervation of lymphoid tissue, J. Immunol. 135:755s (1985).

    Google Scholar 

  31. K. Fecho, K. A. Maslonek, L. A. Dykstra, and D. T. Lysle, Alterations of immune status induced by the sympathetic nervous system: Immunomodulatory effects of DMPP alone and in combination with morphine, Brain, Behavior, Immun. 7:253 (1993).

    Article  CAS  Google Scholar 

  32. K. Fecho, L. A. Dykstra, and D. T. Lysle, Evidence for beta adrenergic receptor involvement in the immunomodulatory effects of morphine, J. Pharmacol. Exp. Ther. 265:1079 (1993).

    PubMed  CAS  Google Scholar 

  33. G.W. Carpenter and D.J.J. Carr, Pretreatment with 13-fimaltrexamine blocks morphine-mediated suppression of CTL activity in alloimmunized mice. Immunopharmacol. 29:129 (1995).

    Article  CAS  Google Scholar 

  34. D. J. J. Carr and G. W. Carpenter, Morphine-induced suppression of cytotoxic T lymphocyte activity in alloimmunized mice is not mediated through a naltrindole-sensitive delta poioid receptor. Neuroimmunomodulation in press (1995).

    Google Scholar 

  35. W. P. Halford, B. M. Gebhardt, and D. J. J. Carr, Functional role and sequence analysis of a lymphocyte orphan opioid receptor. J. Neuroimmunol. in press (1995).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Microbiology,Immunology,and Parasitology, USA

    Daniel J. J. Carr, Greg W. Carpenter & Hildegardo H. Garza Jr.

  2. LSU Neuroscience Center, USA

    Daniel J. J. Carr, Marc L. Baker & Bryan M. Gebhardt

  3. Department of Ophthalmology, LSU Medical Center, New Orleans, Louisianna, 70112-1393, USA

    Bryan M. Gebhardt

Authors
  1. Daniel J. J. Carr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Greg W. Carpenter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hildegardo H. Garza Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marc L. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bryan M. Gebhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Hennepin County Medical Center and University of Minnesota, Minneapolis, Minnesota, USA

    Burt M. Sharp

  2. Temple University School of Medicine, Philadelphia, Pennsylvania, USA

    Toby K. Eisenstein

  3. Emory University School of Medicine, Atlanta, Georgia, USA

    John J. Madden

  4. University of South Florida College of Medicine, Tampa, Florida, USA

    Herman Friedman

Rights and permissions

Reprints and permissions

Copyright information

© 1995 Springer Science+Business Media New York

About this chapter

Cite this chapter

Carr, D.J.J., Carpenter, G.W., Garza, H.H., Baker, M.L., Gebhardt, B.M. (1995). Cellular Mechanisms Involved in Morphine-Mediated Suppression of CTL Activity. In: Sharp, B.M., Eisenstein, T.K., Madden, J.J., Friedman, H. (eds) The Brain Immune Axis and Substance Abuse. Advances in Experimental Medicine and Biology, vol 373. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1951-5_18

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-1951-5_18

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5801-5

  • Online ISBN: 978-1-4615-1951-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation