Neurochemical Research

, Volume 21, Issue 11, pp 1375–1386 | Cite as

Effects of opioids on the immune system

  • Sabita Roy
  • Horace H. Loh
Physiology and Behavior


Both therapeutic and chronic uses of opioids compromise the optimal functioning of the immune system. Overwhelming evidence suggests that opioid use affects both innate immunity and adaptive immunity. Chronic administration of opioids decreases the proliferative capacity of macrophage progenitor cells and lymphocytes. Additionally, the differentiated function of immune cells is significantly affected by opioids. These effects are mediated by either a direct action of opioids on the target cells or by indirect centrally mediated pathways. Molecular biological and biochemical characterization suggest that immune cells differentially express classical opioid receptors. Interestingly, these studies also reveal the presence of a novel class of opioid receptors in immune cells. We believe that this low affinity morphine binding site mediates the antiproliferative effects of morphine.

Key Words

Opioids immune system 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sibinga, N. E. S., and Goldstein, A. 1988. Opioid peptides and opioid receptors in cells of the immune system. Ann. Rev. Immunol. 6:219–249.CrossRefGoogle Scholar
  2. 2.
    Loh, H. H., Smith, A. P., and Lee, N. M. 1993. Effects of opioids on proliferation of mature and immature immune cells. Adv. Exp. Med. Biol. 335, 29–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Peterson, P. K., Molitor, T. W. and Chao C. C. 1993. Mechanisms of morphine induced immunomodulation. Biochem. Pharmacol., 46:343–348.PubMedCrossRefGoogle Scholar
  4. 4.
    Petrov, R. V., Mikhailova, A. A., Zakharova, L. A., Vasilenko, A. M., and Katlinsky, A. V. 1986. Myelopeptides-bone marrow mediators with immunostimulating and endorphin like activity. Scand. J. Immunol. 24:237–243.PubMedCrossRefGoogle Scholar
  5. 5.
    Roy, S., Ramakrishnan, S., Loh, H. H., and Lee, N. M. 1991. Chronic morphine treatment selectively suppresses macrophage colony formation in bone marrow. Eur. J. Pharmacol. 195:359–363.PubMedCrossRefGoogle Scholar
  6. 6.
    Roy, S., Sedqi, M., Ramakrishnan, S., Barke, R. A., and Loh, H. H. 1996. Differential effects of opioids on the proliferation of a macrophage cell line. Cell. Immunol. 169 271–277.PubMedCrossRefGoogle Scholar
  7. 7.
    Roy, S., Ge, B. L., Loh, L. L., and Lee, N. M. 1992. Characterization of3H-Morphine binding to Interleukin-1 activated thymocytes. J. of Pharmacol. and Expt. Therap., 263:451–456.Google Scholar
  8. 8.
    Makman, M. H., Dvorkin, B., and Stefano, G. B. 1995. Murine macrophage cell lines contain μ3-opiate receptors. Eur. J. Pharmacol., 273:5–6.CrossRefGoogle Scholar
  9. 9.
    Szabo, I., Rojavin, M., Bussiere, J. L., Eisenstein, T. K., Adler, M. W., and Rojers, T. J., 19??. Supression of peritoneal macrophage phagocytosis of Candida albicans by opioids. J. Pharmacol. Expt. Therap., 267:703–706.Google Scholar
  10. 10.
    Sharp, B. M., Keane, W. F., Suh, H. J., Gekker, G., Tsukayama, D., and Peterson, P. K. 1985. Opioid peptides rapidly stimulate superoxide production by human polymorphonuclear leukocytes and macrophages. Endocrinology, 117:793–795.PubMedCrossRefGoogle Scholar
  11. 11.
    Mandler, R. N., Biddison, W. E., Mandler, R., and Serrate, S. A. 1986. Beta-Endorphin augments the cytolytic activity and interferon production of natural killer cells. J. Immunol., 136, 934–939.PubMedGoogle Scholar
  12. 12.
    Koff, W. C., and Dunegon, M. A., 1985. Modulation of macrophage-mediated tumoricidal activity by neuropeptides and neurohormones. J. Immunol. 135, 350–354.PubMedGoogle Scholar
  13. 13.
    Fecho, K., Maslonek, K. A., Coussons-Read, M. E., Dykstra, L. A., and Lysle, D. T. 1994. Macrophage-derived nitric oxide is in the depressed on A-responsiveness of splenic lymphocytes from rats administered morphine in vivo. J. Immunol. 152:5845–5852.PubMedGoogle Scholar
  14. 14.
    Lanier, L. L. 1995. Unusual lymphocytes-gd T cells and NK cells. The Immunologist 3:182–184.Google Scholar
  15. 15.
    Bayer, B. M., Daussin, S., Hernandez, M., and Irvin, L. 1990. Morphine inhibition of lymphocyte activity is mediated by an opioid dependent mechanism. NeuroPharmacology. 29:369–374.PubMedCrossRefGoogle Scholar
  16. 16.
    Lysle, D. T., Coussons, M. E., Watts, V. J., Bennett, E. H., and Dykstra, L. A. 1993. Morphine-induced alterations of immune status: Dose dependency, compartment specificity and antagonism by naltrexone. J. Pharmacol. Exp. Therap., 265:1071–1078.Google Scholar
  17. 17.
    Pacifici, R., Patrini, G., Venier, I., Parolaro, D., Zuccarro, P., and Gori, E. 1994. Effect of morphine and methadone acute treatment on immunological activity in mice: pharmacokinetic and pharmacodynamic correlates. J. Pharmacol. Exp. Ther., 269:1112–1116.PubMedGoogle Scholar
  18. 18.
    Carr, D. J., and France, C. P. 1993. Immune alterations in chronic morphine treated rhesus monkeys. Adv. Exp. Med. Biol., 335:35–39.PubMedCrossRefGoogle Scholar
  19. 19.
    Page, G. G., Ben-Eliyahu, S., and Yirmiya, R. 1993. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain, 54:21–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Colocchio, T. A., Yeager, M. P., and Hildebrandt, L. W. 1994. Perioperative immunomodulation in cancer surgery. Am. J. Surg. 167:174–179.CrossRefGoogle Scholar
  21. 21.
    Fuchs, B. A., and Pruett, S. B. 1993. Morphine induces apoptosis in murine thymocytes in vivo but not in vitro: involvement of both opiate and glucocorticoid receptors. J. Pharmacol. Exp. Therap., 266:417–423.Google Scholar
  22. 22.
    Bryant, H. U., Yoburn, B. C., Intrissi, C. E., Bernton, E. W., and Holaday, J. W. 1988. Immunosuppressive effects of chronic morphine treatment. Eur. J. Pharm., 149:165–169.CrossRefGoogle Scholar
  23. 23.
    Bryant, H. U., Bernton, E. W., Kenner, J. R., and Holaday, J. W. 1991. Role of adrenal cortical activation in the immunosuppressive effects of chronic morphine treatment. Endocrinology., 128: 3253–3258.PubMedCrossRefGoogle Scholar
  24. 24.
    Lafferty, K. J. 1995. Role of second signals in the induction of T cells and graft rejection. The Immunologist. 3:256–258.Google Scholar
  25. 25.
    Sei, Y., Yoshimoto, K., McIntyre, T., Skolnick, P., and Arora, P. K. 1991. Morphine induced thymic hypoplasia is glucocorticoid dependent. J. Immunol., 146:194–198.PubMedGoogle Scholar
  26. 26.
    Meuer, S. C., and Meyer zum Buschenfelde K. H. 1993. T-cell receptor induces responsiveness to IL-1 and IL-2 but does not lead to T-cell proliferation. J. Immunol., 136:4106–4112.Google Scholar
  27. 27.
    Smith, K. A. 1989. The IL-2 receptor. Ann. Rev. Cell. Biol. 5:397–425.PubMedCrossRefGoogle Scholar
  28. 28.
    Roy, S., Loh, H. H., and Barke, R. A. 1995. Morphine-induced suppression of thymocyte proliferation is mediated by inhibition of IL-2 synthesis. Adv. in Exp. Medicine. Biology. 373:41–8.CrossRefGoogle Scholar
  29. 29.
    Roy, S., Chapin, R., Cain, K., Charboneau, R., and Horace H. Loh Barke, R. A. 1996. Morphine inhibits transcriptional regulation of IL-2 synthesis.J. Imm. (submitted)Google Scholar
  30. 30.
    Madden, J. J., and Donahue, R. M. 1990. Opioid binding to cells of the immune system in Drugs of Abuse and the Immune system pages 212–224in Watson, R. R., ed. CRC Press, Boca Raton, FI.Google Scholar
  31. 31.
    Shahabi, N. A., and Sharp, B. M. 1995. Antiproliferative effects of δ opioids on highly purified CD4 and CD8 murine T cells. J. Pharmacol. Exp. Therap., 273:1105–1113.Google Scholar
  32. 32.
    Adler, M. W., Geller, E. B., Rogers, T. J., Henderson, E. E., and Eisenstein, T. K. 1993. Opioids receptor and immunity. Adv. Exp. Med. Biol. 335:13–20.PubMedCrossRefGoogle Scholar
  33. 33.
    Bussiere, J. L., Adler, M. W., Rogers, R. J., and Eisenstein, T. K. 1993. Cytokine reversal of morphineinduced supression of the Antibody response. J. Pharmacol. Exp. Therap., 264:591–597.Google Scholar
  34. 34.
    Taub, D. D., Eisenstein, T. K., Geller, E. B., Adler, M. W., and Rogers, T. J. 1991. Immunomodulatory activity of μ and κ-selective opioid agonists. Proc. Natl. Acad. Sci. (USA) 88:360–364.CrossRefGoogle Scholar
  35. 35.
    Paul W. E., Ohara, J., 1987. B cell stimulatory factor. Ann. Rev. Immunol., 5:429.CrossRefGoogle Scholar
  36. 36.
    Park, L. S., Friend, D., Gillis, S., and Urdal, D. L. 1986. Characterization of the cell surface receptor for a multi lineage colony stimulating factor. J. Biol. Chem., 261:205.PubMedGoogle Scholar
  37. 37.
    Sedqui, M., Roy, S., Ramakrishnan, S., Elde, R., and Loh, H. H. 1995. Complementary cloning of a mu-opioid receptor from rat peritoneal macrophage. Biochem. Biophys. Res. Commun., 208: 563–574.CrossRefGoogle Scholar
  38. 38.
    Wick, M. J., Minnerath, S. R., Roy, S., Ramakrishnan, S., and Loh, H. H. 1996. Differential expression of opioid receptor genes in human lymphoid cell lines and peripheral blood lymphocytes. Neuroimmunology 64:29–36.CrossRefGoogle Scholar
  39. 39.
    Chuang, T. K., Killam, K. F., Chuang, L. F., Kung, H.-F., Sheng, W. S., Chao, C. C., Yu, L., and Chuang, R. Y. 1995. Mu opioid receptor gene expression in immune cells. Biochem. Biophys. Res. Commun., 216:922–930.PubMedCrossRefGoogle Scholar
  40. 40.
    Sedqi, M., S. Roy, S. Ramakrishnan, R., and Loh, H. H. 1996. Expression cloning of full-length cDNA encoding delta opioid receptor from mouse thymocytes. J. Neuroimmunol. (in press).Google Scholar
  41. 41.
    Meunier, J. C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J. L., Guillemot, J. C., Ferrara, P., and Monsarrat, B., et al., 1995. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377:532–535.PubMedCrossRefGoogle Scholar
  42. 42.
    Wick, M. J., Minnerath, S. R., Roy, S., Ramakrishnan, S., and Loh, H. H. 1995. Expression of alternate forms of brain opioid “orphan” receptor mRNA in activated human peripheral blood lymphocytes and lymphocytic cell lines. Mol. Brain. Res., 32:342–347.PubMedCrossRefGoogle Scholar
  43. 43.
    Milligan, C. E., Webster, L., Piros, E. T., Evans, C. J., Cunningham, T. J., and Levitt, P. 1995. Induction of opioid receptor mediated macrophage chemotatic activity after neonatal brain injury. J. Immunol., 154:6571–81.PubMedGoogle Scholar
  44. 44.
    Zhou, Y., Scamurra, R., Molitor, T. W., and Murtaugh, M. P. 1992. Characterization of transforming growth factor beta 1 gene expression in porcine imune cells. Mol. Immunol., 29:965–70.PubMedCrossRefGoogle Scholar
  45. 45.
    Iuvone, T., Capasso, A., D'Acquisto, F., and Carnuccio, R. 1995. Opioids inhibit the induction of nitric oxide synthase in J774 macrophages. Biochem. Biophys. Res. Comm. 212:975–80.PubMedCrossRefGoogle Scholar
  46. 46.
    Pacifici, R., Di Carlo, S., Bacosi, A., and Zuccaro, P. 1993. Macrophage functions in drugs of abuse-treated mice. Int. J. Immunopharmacol. 15:711–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Belkowski, S. M., Alicea, C., Eisenstein, T. K., Rogers, T. J. 19??. Inhibition of interleukin I and Tumor necrosis factor alpha synthesis following treatment of macrophages with the kappa opioid ligand U50, 488H. J. Pharmacol. Exp. Therap. 273:1491–96.Google Scholar
  48. 48.
    Levier, D. G., Brown, R. D., McCay, J. A., Fuchs, B. A., Harris, L. S., and Munson, A. E. 1993. Hepatic and splenic phagocytosis in female B6C3F1 mice implanted with morphine sulfate pellets. J. Pharmacol. Exp. Therap. 267:357–63.Google Scholar
  49. 49.
    Rojavin, M., Szabo, I., Bussiere, J. L., Rogers, T. J., Adler, M. W., and Eisentein, T. K. 1993. Morphine treatment in vitro or in vivo decreases phagocytic functions of murine macrophages. Life Sci. 53:997–1006.PubMedCrossRefGoogle Scholar
  50. 50.
    Stefano, G. B., Bilfinger, T. V. 1993. Human neutrophil and macrophage chemokinesis induced by cardiopulmonary bypass: loss of DAME and IL-1 chemotaxis. J. Neuroimmunol., 47:189–97.PubMedCrossRefGoogle Scholar
  51. 51.
    Singhal, P. C., Pan, C., and Gibbons, N. 1993. Effect of morphine on uptake of immunoglobulin G complexes by mesangial cells and macrophages. Am. J. Physiol., 264:F859–66.PubMedGoogle Scholar
  52. 52.
    Sergeeva, M. G., Terentjeva, I. V., Mevkh, A. T., and Varfolomeev, S. D. 1993. Direct influence of morphine on the release of arachidonic acid and its metabolites. FEBS Lett., 323:163–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Yeager, M. P., Colacchio, T. A., Yu, C. T., Hildebrandt, L., Howell, A. L., Weiss, J., and Guyre, P. M. 1995. Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers. Anesthesiology. 83:500–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Flores, L. R., Hernandez, M. C., and Bayer, B. M. 1994. Acute immunosuppressive effects of morphine: lack of involvement of pituitary and adrenal factors. J. Pharmacol. Exp. Therap. 26:1129–34.Google Scholar
  55. 55.
    Garza, H. H., Jr., Prakash, O., and Carr, D. J. 1994. Immunologic characterization of TAT72-transgenic mice: effects of morphine on cell-mediated immunity. Int. J. Immunopharmacol., 16:1061–70.PubMedCrossRefGoogle Scholar
  56. 56.
    di Francesco, P., Gaziano, R., Casalinuovo, I. A., Belogi, L., Palamara, A. T., Favalli, C., and Garaci E. 1994. Combined effect of fluconazole and thymosin alpha 1 on systemic candidiasis in mice immunosuppressed by morphine treatment. Clinical Experimental Immunol., 97:347–52.CrossRefGoogle Scholar
  57. 57.
    Freier, D. O., Fuchs, B. A. 1994. A mechanism of action for morphine-induced immunosuppression: corticosterone mediates morphine-induced suppression of natural killer cell activity. J. Pharmacol. Experimental Therap. 270:1127–33.Google Scholar
  58. 58.
    Kimes, A. S., Smith, W. J., Winchell, C. J., and London, E. D. 1992. Effects of morphine on the phenotypic expression of cell surface markers on murine lymphocytes. Life Sci. 51:807–15.PubMedCrossRefGoogle Scholar
  59. 59.
    Chuang, L. F., Killam, K. F., Jr., and Chuang, R. Y. 1993. Opioid dependency and T-helper cell functions in rhesus monkey. In Vivo. 7:159–66.PubMedGoogle Scholar
  60. 60.
    Freier, D. O., and Fuchs, B. A. 1993. Morphine-induced alterations in thymocyte subpopulations of B6C3F1 mice. J. Pharmacol. Exp. Therap. 265:81–8.Google Scholar
  61. 61.
    Luza, J. 1992. The effect of morphine on lymphocyte viability in vitro. Acta Universitatis Palackinae Olomucensis Facultatis Medicae. 134:43–5.Google Scholar
  62. 62.
    Lopez, M. C., Chen, G. J., Colombo, L. L., Huang, D. S. Darban, H. R., Watzl, B., and Watson, R. R. 1993. Spleen and thymus cell subsets modified by long-term morphine administration and murine AIDS—II. International J. Immunopharmacol. 15(8):909–18.CrossRefGoogle Scholar
  63. 63.
    Carpenter, G. W., Garza, H. H., Jr., Gebhardt, B. M., and Carr, D. J. 1994. Chronic morphine treatment suppresses CTL-mediated cytolysis, granulation, and cAMP responses to alloantigen. Brain, Behavior, Immunity. 8:185–203.CrossRefGoogle Scholar
  64. 64.
    Carr, D. J., Carpenter, G. W., Garza, H. H., Jr., Baker, M. L., and Gebhardt, B. M. 1995. Cellular mechanisms involved in morphine-mediated suppression of CTL activity. [Review] Adv. Exp. Med. & Biol. 373:131–9.CrossRefGoogle Scholar
  65. 65.
    Flores, L. R., Wahl, S. M., and Bayer, B. M. 1995. Mechanisms of morphine-induced immunosuppression: effect of acute morphine administration on lymphocyte trafficking. J. Pharmacol. & Exp. Therap. 272:1246–51.Google Scholar
  66. 66.
    Madden, J. J., Ketelsen, D., Whaley, W. L., Donahoe, R. M., and Oleson, D. 1995. Mitogenic activation of human T lymphocytes induces a high affinity morphine binding site. Adv. Exp. Medicine & Biology. 373:37–40.CrossRefGoogle Scholar
  67. 67.
    Carr, D. J., and France, C. P. 1993. Immune alterations in morphinetreated rhesus monkeys. J. Pharmacol. Exp. Therap. 267:9–15.Google Scholar
  68. 68.
    Bhargava, H. N., House, R. V., Thorat, S. N., and Thomas, P. T. 1995. Effects of naltrexone on morphine-induced tolerance and physical dependence and changes in cellular immune function in mice. Brain Res., 690:121–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Sawant, S. G., and Couch, D. B. 1995. Induction of micronuclei in murine lymphocytes by morphine. Env. & Mol. Mutagenesis. 25:279–83.CrossRefGoogle Scholar
  70. 70.
    Shaker, M., Shahabi, N. A., and Sharp, B. M. 1994. Expression of naloxone-resistant beta-endorphin binding sites on A20 cells: effects of concanavalin A and dexamethasone. Immunopharmacol. 28:183–92.CrossRefGoogle Scholar
  71. 71.
    Przewlocki, R., Hassan, A. H., Lason, W., Epplen, C., Herz, A., and Stein, C. 1992. Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception. Neuroscience. 48:491–500.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Sabita Roy
    • 1
  • Horace H. Loh
    • 1
  1. 1.Department of PharmacologyUniversity of MinnesotaMinneapolis

Personalised recommendations