Delta Opioid Agonists Inhibit Proliferation of Highlypurified Murine CD4+ and CD8+ T-Cells

  • N. A. Shahabi
  • B. M. Sharp
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 373)


A substantial body of evidence demonstrates that opiates and opioid peptides modulate immune function. The present study used highly purified murine CD4+ and CD8+ T-cells to determine the effects of delta opioid receptor (DOR) agonists on proliferation. Splenic T-cells, obtained from male or female C57BL/6 or CD1 mice, were separated by a fluorescence activated cell sorter. Cells were stimulated to proliferate in serum free medium by cross-linking the T-cell receptor using plate-coated anti-CD3-ε; 3H-thymidine uptake was determined at 48 hours. Previous experiments had shown that deltorphin and [D-A1a2]-met-enkephalinamide (DAME), at concentrations from 10-11 to 10-7 M, dose dependently inhibited the proliferation of CD4+ and CD8+ T-cells obtained from female C57BL/6 or CD1 mice. Similarly, the experiments herein demonstrate that proliferation of CD4+ T-cells from female CD1 mice was inhibited by 2,5 DPDP-enkephalin (DPDP-E), in direct relation to dose. In contrast, the anti-proliferative response of cells from C57BL/6 mice demonstrated an inverse relationship to dose. At 10-11 M, the most effective dose of DPDP-E studied, 3Hthymidine uptake was inhibited by 50%. The selective DOR antagonist, naltrindole (10-12 M), abolished this. DAME was used to compare the effects of DOR agonists on CD8+ T-cells from both strains of female mice. 3H-Thymidine uptake was dose-dependently inhibited to a similar degree in both strains; 10-7 M DAME maximally reduced proliferation by 70%. DAME had similar effects on both CD8+ and CD4+ T-cells from male mice, and its inhibitory effect was markedly attenuated after 72 hours. In summary, the dose-response profiles for the anti-proliferative effects of DAME and deltorphin are similar in CD1 and C57BL/6 mice, whereas the profiles are distinctively different for DPDP-E. The effects of DPDP-E appear to be mediated through a δ-like opiate receptor.


Thymidine Uptake Delta Opioid Receptor Delta Opioid Delta Opioid Receptor Agonist Delta Opioid Agonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Wybran, J., Appelboom, T., Famaey, J.-P. and Govaerts, A: Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T lymphocytes. J. Immunol. 123: 1068–1070, 1979.PubMedGoogle Scholar
  2. 2.
    Peterson, P.K., Sharp, B.M., Gekker, G., Brummitt, C. and Keane, W.F.: Opioid-mediated suppression of interferon-7 production by cultured peripheral blood mononuclear cells. J Clin Invest 80: 824–831, 1986.CrossRefGoogle Scholar
  3. 3.
    Bessler, H., Sztein, M.B. and Serrate, S.A.: β-Endorphin modulation of IL-1-induced IL-2 production. Immunopharmacology 19: 4–14, 1990.CrossRefGoogle Scholar
  4. 4.
    Gilman, S.C., Schwartz, J.M., Milner, R.J., Bloom, F.E. and Feldman, J.D.: β-Endorphin enhances lymphocyte proliferative response. Proc Natl Acad Sci USA 79: 4226–30, 1982.PubMedCrossRefGoogle Scholar
  5. 5.
    Gilmore, W., Moloney, M. and Bernstein, T.: The enhancement of polyclonal T cell proliferation by beta-endorphin. Brain Res Bull 24: 687–692, 1990.PubMedCrossRefGoogle Scholar
  6. 6.
    Shahabi, N.A., Burtness M.Z., Sharp, B.M.: N-acetyl-β-endorphin antagonizes the suppressive effect of β-endorphin1–31 on murine splenocyte proliferation via a naloxone-resistant receptor. Biochem Biophys Res Commun 175: 936–942, 1991.PubMedCrossRefGoogle Scholar
  7. 7.
    Hemmick, L.M. and Bidlack, J.M.: β-Endorphin modulation of mitogen-stimulated calcium uptake by rat thymoctes. Life Sci 41: 1971–8, 1987.PubMedCrossRefGoogle Scholar
  8. 8.
    Gilmore, W. and Weiner, L.P.: β-Endorphin enhances interleukin-2 (IL-2) production in murine lymphocytes. J. Neuroimmunology, 18: 125–138, 1988.CrossRefGoogle Scholar
  9. 9.
    Brown, S.L. and Van Epps, D.E.: Opioid peptides modulate production of interferon-gamma by human mononuclear cells. Cell Immunol. 103: 19–26, 1986.PubMedCrossRefGoogle Scholar
  10. 10.
    Shahabi, N.A., Linner K.M. and Sharp, B.M.: Murine splenocytes express a naloxone-insensitive binding site for β-endrophin. Endocrinology 126: 1442–1448, 1990a.CrossRefGoogle Scholar
  11. 11.
    Shahabi, N.A., Peterson, P.K. and Sharp, B.M.: β-endorphin binding to naloxone-insensitive sites on human mononuclear cell line (U937): Effect of cations and guanosine triphosphate. Endocrinology 126: 3006–3016, 1990bCrossRefGoogle Scholar
  12. 12.
    Faith, R.E., Murgo, A.J., Clinkscales, C.W. and Plotnikoff, N.P.: Enhancement of host resistance to viral and tumor challenge by treatment with methionine-enkephalin. Ann NY Acad Sci 496: 137–143. 1987.PubMedCrossRefGoogle Scholar
  13. 13.
    Oleson, D.R. and Johnson, D.R.: Regulation of human natural cytotoxicity by enkephalins and selective opiate agonists. Brain Behav Immun 2: 171–186, 1988.PubMedCrossRefGoogle Scholar
  14. 14.
    Rowland, R.R.R., Chukwuocha, R. and Tokuda, S.: Modulation of the in vitro murine immune response by met-enkephalin. Brain Behav Immun 1: 342–348, 1987.PubMedCrossRefGoogle Scholar
  15. 15.
    Leo, O., Foo, M., Sachs, D., Samelson, L. and Bluestone, J.: Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci USA 84: 1374–8, 1987.PubMedCrossRefGoogle Scholar
  16. 16.
    Shahabi, N.A. and Sharp, B.M.: Anti-proliferative effects of delta opioids on highly purified CD4+ and CD8+ murine T-cells. J.Pharm. Exp. Then, in press, 1995.Google Scholar
  17. 17.
    Portoghese, P.S., Sultana, M. and Takemori, A.E.: Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist.Eur. J. Pharmacol. 146: 185–186, 1988.PubMedCrossRefGoogle Scholar
  18. 18.
    Caroleo, M.C., Arbitrio, M., Melchiorri, D. and Nistico, G.: A reappraisal of the role of the various opioid receptor subtypes in cell-mediated immunity. Neuroimmunomodul 1: 141–147, 1994.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • N. A. Shahabi
    • 1
  • B. M. Sharp
    • 1
  1. 1.Endocrine-Neuroscience Research Laboratory, Minneapolis Medical Research Foundation and Departments of MedicineHennepin County Medical Center and the University of MinnesotaMinneapolisUSA

Personalised recommendations