Effects of Centrally Administered Opioid Agonists on Macrophage Nitric Oxide Production and Splenic Lymphocyte Proliferation

  • Gabrielle M. Schneider
  • Donald T. Lysle
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 402)


In recent years nitric oxide has received a great deal of attention. Although nitric oxide has been well known to environmental scientists for some time, the impact of nitric oxide in the biological sciences is recent and overwhelming. In fact, Science named nitric oxide the molecule of the year in 1992, and over 4,000 papers have been published since that time. Nitric oxide has been shown to play a role in a wide variety of biological activities, being produced and utilized in practically every major organ system in the body. Despite the short half life and simplistic chemical structure of nitric oxide, it has become clear that this molecule plays an important role in immune processes.


Nitric Oxide Opioid Receptor Lymphocyte Proliferation Nitric Oxide Production 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.
    Hibbs, J.B., Tiantor, R.R., & Vavrin, Z. (1987). Macrophage cytotoxicity: Role for L-arginine deaminase and iminonitrogenoxidation of nitrite. Science, 235, 473–476.PubMedCrossRefGoogle Scholar
  2. 2.
    Iyengar, R., Stuehr, D.J., & Marietta, M.A. (1987). Macrophage synthesis of nitrite, nitrate, and N-nitrosamines• precursors and role of the respiratory burst. Proc. Natl. Acad. Sci. USA 84, 6369–6373.PubMedCrossRefGoogle Scholar
  3. 3.
    Marietta, M. A., Yoon, P.S., Iyengar, R., Leaf, C.D., & Wishnok, J.S. (1988). Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate, Biochem., 27, 8706–8711.CrossRefGoogle Scholar
  4. 4.
    Goretski, J., & Hollocher, T.C. (1988). Trapping of nitric oxide produced during denitrification by extracellular hemoglobin. J. Biol. Chem., 263, 2316–2323.PubMedGoogle Scholar
  5. 5.
    Pellat, C., Henry, Y., & Drapier, J.C. (1990). IFN-y-activated macrophages: detection by electron paramagnetic resonance of complexes between L-arginine-derived nitric oxide and non-hem e iron proteins. Biochem. Biophys. Res. Comm., 166, 119–125.PubMedCrossRefGoogle Scholar
  6. 6.
    Green, L.C., Wagner, D.A., Glogowski, J., Skipper, P.L.,Wishnok, J.S., & Tannenbaum, S.R. (1982). Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal. Biochem., 126, 131–136.PubMedCrossRefGoogle Scholar
  7. 7.
    Nathan, C. (1992). Nitric oxide as a secretory product of mammalian cells. FASEB J. 6, 3051–3064.PubMedGoogle Scholar
  8. 8.
    Fecho, K., Maslonek, K.A., Coussons-Read, M.E., Dykstra, L.A., & Lysie, D.T. (1994). Macrophage-derived nitric oxide is involved in the depressed Con A-responsiveness of splenic lymphocytes from rats administered morphine in-vivo. Journal of Immunology, 152, 5845–5852.Google Scholar
  9. 9.
    Fecho, K., Maslonek, K.A., Dykstra, L.A., & Lysle, D.T. (1995). Mechanisms whereby macrophage-derived nitric oxide is involved in morphine-induced suppression of splenic lymphocyte proliferation. Journal of Pharmacology and Experimental Therapeutics, 272, 477–483.PubMedGoogle Scholar
  10. 10.
    Wybran, J., Appelboom, T. Famey, J.P. & Govaerts, A. (1979). Suggestive evidence for receptors for morphine and methionine enkephalin on normal human blood T-lymphocytes. J. Immunol., 123, 1068–1070.PubMedGoogle Scholar
  11. 11.
    Eisenstein, T.K., Taub, D.D., Adler, M.W. and Rogers, T.J. (1991). The effect of morphine and DAGO on the proliferative response of murine splenocytes. Adv. Exp. Med. Biol., 288, 203–209.PubMedGoogle Scholar
  12. 12.
    Bayer, B.M., Gastonguay, M.R. and Hernandez, M.C. (1992). Distinction between the in vitro and in vivo inhibitory effects of morphine on lymphocyte proliferation based on agonist sensitivity and naltrexone reversibility. Immunopharmacology, 23, 117–124.PubMedCrossRefGoogle Scholar
  13. 13.
    Peterson, P.K., Sharp, B., Gekker, G., & Keane, W.F. (1987). Opioid-mediated suppression of cultured peripheral blood mononuclear cell respiratory burst activity. Jlmmunology, 138, 3907–3912.Google Scholar
  14. 14.
    Ader, R., Felten, D. & Cohen, N. (1990). Interactions between the brain and the immune system. Annu. Rev. Pharmacol. Toxicol., 30, 561–602.PubMedCrossRefGoogle Scholar
  15. 15.
    Felten, D.L., Felten, S.Y., Bellinger, D.L., Carlson, S.L., Ackerman, K.D., Madden, K.S., Olschowki, J.A., & Livnat, S., (1987). Noradrenergic sympathetic neural interactions with the immune system: Structure and function. Immunological Reviews, 100, 225–260.PubMedCrossRefGoogle Scholar
  16. 16.
    Shavit, Y., DePaulis, A., Martin, F. C., Terman, G. W., Pechnick, R. N., Zane, C. J., Gale, R. P. and Liebeskind, J. C. (1986). Involvement of brain opiate receptors in the immune-suppressive effect of morphine. Proc. Natl. Acad. Sci, 83, 7114–7117.PubMedCrossRefGoogle Scholar
  17. 17.
    Weber, R.J. & Pert, A. (1989). The periaqueductal grey matter mediates opiate-induced immunosuppression. Science, 245, 188–190.PubMedCrossRefGoogle Scholar
  18. 18.
    Hernandez, M.C., Flores, L.H., Bayer, B.M. (1993). Immunosuppression by morphine is mediated by central pathways. J. Pharmacol. Exp. Then, 267, 1336–1341.Google Scholar
  19. 19.
    Lysle, D.T., Hoffman, K.E., & Dykstra, L.A. Evidence for the involvement of the caudal region of the periaqueductal gray in a subset of morphine-induced alterations of immune status. Journal of Pharmacology and Experimental Therapeutics, in press.Google Scholar
  20. 20.
    Fecho, K., Maslonek, K.A., Dykstra, L.A. and Lysle, D.T. Assessment of the involvement of the central nervous system and peripheral opioid receptors in the immunomodulatory effects of acute morphine treatment in rats. J. Pharmacol. Exp. Then, in press.Google Scholar
  21. 21.
    Jaffe, J.H. and Martin, W.R. (1990). Opioid analgesics and antagonists. In A.G. Gilman, T.W. Rall, A.S. Nies, & P. Taylor (Eds.) Goodman and Gilman’s The Pharmacological Basis of Therapeutics. pp. 485–521, Pergamon Press: New York.Google Scholar
  22. 22.
    Goldstein, A. (1987). Binding selectivity profiles for ligands of multiple receptor types: Focus on opioid receptors. Trends in Pharmacol Sci, 8, 456–466.CrossRefGoogle Scholar
  23. 23.
    Marrack, P. & Kappler, J. (1990). The staphylococcal enterotoxins and their relatives. Science, 248, 705–711.PubMedCrossRefGoogle Scholar
  24. 24.
    White, H., Herman, A., Pullen, A.M., Kubo, R., Kappler, J.W., & Marrack, P. (1989). The Vß specific superantigen staphylococcal enterotoxin B: Stimulation of mature T cells and clonal deletion in neonatal mice. Cell, 56, 27–35.PubMedCrossRefGoogle Scholar
  25. 25.
    Leonard, B.A.B., Lee, P.K., Jenkins, M.K., & Schlievert, P.M. (1991). Cell and receptor requirement for streptococcal pyrogenic exotoxin T-cell mitogenicity. Infection & Immunity, 59, 1210.Google Scholar
  26. 26.
    Green, S.J., Meltzer, M.S. Hibbs, J.B, & Nacy, C.A. (1990). Activated macrophages destroy intracellular Leishmania major amastigotes by an L-arginine-dependent killing mechanism. Journal of Immunology, 144, 278–283.Google Scholar
  27. 27.
    James, S.L. & Glaven, J. (1989). Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates. Journal of Immunology, 143, 4208–4212.Google Scholar
  28. 28.
    Vincendeau, P., Daulouede, S., Veyret, B., Darde, M.L., Bouteille, B., & Lemesre, J.L. (1992). Nitric oxide-mediated cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei. Experimental Parasitology, 75, 353–360.Google Scholar
  29. 29.
    MacMicking, J.D., Nathan, C., Hom, G. Chartrain, N., Fletcher, D.S., Trumbauer, M., Stevens, K.. Xie, Q.W., Sokol, K., Hutchinson, N. Chen, H., & Mudgett, J.S. (1995). Altered responses to baterial infection and endotoxic shock in mice lacking inducible nitric oxide syntase. Cell, 81, 641–650.PubMedCrossRefGoogle Scholar
  30. 30.
    Wei, X.Q., Charles, LG., Smith, A., Ure, J., Feng, G.J., Huang, F.P., Xu, D., Muller, W., Mocado, S., Liew. F.Y. (1995). Altered immune responses in mice lacking inducible nitric oxide synthase. Nature, 375, 408–411.PubMedCrossRefGoogle Scholar
  31. 31.
    Weinberg, J.B., Granger, D.L., Pisetsky, D.S., Seldin, M.F., Misuknois, M.A., Mason, S.N., Pippen, A.M., Ruiz, P. Wood, E.R., & Gilkeson., G.S. (1994). The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: Increased nitric oxide production and nitric oxide synthase expression in MRL-1pr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered N°-monomethyl-Larginine Journal of Experimental Medicine, 179, 651–660.PubMedCrossRefGoogle Scholar
  32. 32.
    Al-Ramadi, B.K., Meissler, J.J., Huang, D., Eisenstein, T.K. (1992). Immunosuppression induced by nitric oxide and its inhibition by interleukin-4. European Journal of Immunology, 22, 2249–2254.PubMedCrossRefGoogle Scholar
  33. 33.
    Eisenstein, T.K., Huang, D. Meissler, J.J., & Al-Ramadi, B. (1994). Macrophage nitric oxide mediates immunosuppression in infectious inflammation. Immunobiol., 191, 493–502.Google Scholar
  34. 34.
    Albina, J.E. & Henry, W.L. (1991). Suppression of lymphocyte proliferation through the nitric oxide synthesizing pathway. Journal of Surgical Research, 50, 403–409.PubMedCrossRefGoogle Scholar
  35. 35.
    Fu, Y. & Blankenhorn, E.P. (1992). Nitric oxide-induced anti-mitogenic effects in high and low responder strains. Journal of Immunology, 148, 2217–2222.Google Scholar
  36. 36.
    Pascual, D.W., Pascual, V.H., Bost, K.L., McGhee J.R., & Oparil, S. (1992). Nitric oxide mediates immune dysfunction in the spontaneously hypertensive rat. Hypertension, 21, 185–194.Google Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • Gabrielle M. Schneider
    • 1
  • Donald T. Lysle
    • 1
  1. 1.Department of PsychologyUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations