Immunosuppressive Effects of the Opiopeptins

  • Hulon W. McCain
  • Ira B. Lamster
  • Joanne Bilotta


The immune system has long been considered an organ system differing significantly from others in the immediacy of its regulation by the central nervous system. Whereas other organs have, to differing degrees, well characterized neural and hormonal afferent as well as efferent regulatory pathways, immune function has traditionally been viewed as an internally regulated effector system essentially devoid of CNS modulation with the possible exception of the CRF-ACTHcorticosteroid link. Such views were reinforced by Jerne’s natural antibody selection theory (Jerne, 1955), and the observed ability of immune elements to display significant levels of activity in varied in vitro assay systems (Nowell, 1960). Astute clinicians, however, have for centuries reported antecdotal evidence of increased disease susceptibility associated with diverse physiological and psychological stimuli (Shigami, 1919) including those of stress and emotional distress (Locke, 1982). Patients suffering stressful injury such as burns, and operative or accidental trauma, exhibit decreased immune responsiveness which is often well correlated with post-traumatic susceptibility to bacterial, viral and fungal infections (Constantian et al., 1977; Wolfe et al., 1981; Alexander, 1968; and Goodman et al., 1968). Cancer patients have generally suppressed immunocompetence and, conversely, a large body of experimental data indicates that stress reduces the rate of implanted tumor rejection (Visintaner et al., 1982), and increases tumor growth (Riley, 1981) along with other correlates of invasiveness (Shavit et al., 1983).


Migration Inhibition Factor Adrenal Medulla Partially Purify Derivative Human Peripheral Blood Lymphocyte Migration Inhibition 
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. Akil, H., Hirohito, S. and Matthews, J., 1985, Induction of the intermediate pituitary by stress: synthesis and release of a nonopioid form of B-endorphin, Sci., 227: 424.CrossRefGoogle Scholar
  2. Alexander, J.W., 1968, Effect of thermal injury upon the early resistance to infection, J. Surg. Res. 8:128.Google Scholar
  3. Bellanti, J.A., and Rocklin, R.E., 1985, Cell mediated immune reactions, in: “Immunology,” J.A. Bellanti, ed., W.B. Saunders, New York.Google Scholar
  4. Bennett, B., and Bloom, B.R., 1968, Reactions in vivo and in vitro produced by a soluble substance associated with delayed-type hypersensitivity, Proc. Natl. Acad. Sci. (USA), 59:756.Google Scholar
  5. Chaminade, M., Foutz, A.S., and Rossier, J., 1983, Co-release of enkephalins and precursors of catecholamines by the perfused rat adrenal in situ, Life Sci., 33: 21.PubMedCrossRefGoogle Scholar
  6. Constantian, M.B., Manzoian, J.O., Nimberg, R.B., Schmid, K., and Mannick, J.A., 1977, Association of a circulating immunosuppressive polypeptide with operative and accidental trauma, J. Surg. 185:73.Google Scholar
  7. Cooperband, S.R., Badger, A.M., and Mannick, J.A., 1976, Non-hormonal serum suppressive factors, in: “Mitogens in Immunobiology,” J. Oppeheim and D.L. Rosenstreich, Eds., Acad. Press, New York.Google Scholar
  8. David, J.R., 1966, Delayed hypersensitivity in vitro: its mediation by cell free substances formed by lymphoid cell-antigen interaction, Proc. Natl. Acad. Sci. (USA) 56:72.Google Scholar
  9. Evans, C.J., Erdelyi, E., Weber, E. and Barchas, J.D., 1983, Identification of proopiomelanocortin-derived peptides in the human adrenal medulla, Sci., 221: 957.CrossRefGoogle Scholar
  10. Evans, S.F., Medbak, S. Hinds, C.J., Tomlin, S.J., Varley, J.F. and Rees, L.H., 1984, Plasma levels and biochemical characterization of circulating met-enkephalin in canine endotoxin shock, Life Sci. 34: 1481.Google Scholar
  11. Fleminger, G., Howells, R.D., Kilpatrick, D.L., and Udenfriend, S., 1984, Intact proenkephalin is the major enkephalin-containing peptide produced in rat adrenal glands after denervation, Proc. Natl. Acad. Sci. (USA), 81:7985.Google Scholar
  12. Fraser-Smith, E., and Matthews, T.R., 1981, Protective Effect of muramyl dipeptide analogs against infection of pseudomanas aeruginosa or candida albicans in mice, Infection and Immunity 34: 676.Google Scholar
  13. Gilman, S.C., Schwartz, J.M., Milner, R.J., Bloom, F.E., and Feldman, J.D., 1982, B-endorphin enhances lymphocyte proliferative responses, Proc. Natl. Acad. Sci. (USA), 79:4226.Google Scholar
  14. Goodman, J.S., Schaffner, W., Collins, H.A., Battersby, E.J., and Koenig, M.G., 1968, Infection after cardiovascular surgery: clinical study including examination of antimicrobial prophylaxis, N. Engl. J.Med. 278:117.Google Scholar
  15. Hanbauer, I., Kelly, G.D., Saiani, L., and Yang, H.Y.T., 1982, (Met)-enkephalinlike peptides of the adrenal medulla: release by nerve stimulation and functional implications, Peptides 3: 469.Google Scholar
  16. Hazum, E., Chang, K., and Cuatrecasas, P., 1979, Specific non-opiate receptors for B-endorphin, Sci., 205: 1033.CrossRefGoogle Scholar
  17. Ishigami, T., 1919, The inn luence of psychic acts on the progres of pulmonary tuberculosis, Am. Rev. Tuberculosis 2:470.Google Scholar
  18. Jerne, N.K., 1955, The national selection theory of antibody formation, Proc. Natl. Acad. Sci. (USA), 41:849.Google Scholar
  19. Johnson, N., Houghten, R., and Pasternack, G., 1982, Binding of 3H-B-endorphin in rat brain, Life Sci. 31: 1381.Google Scholar
  20. Keller, S.E., Weiss, J.M., Schleifer, S.J., Miller, N.E., and Stein, M., 1983, Stress-induced suppression of immunity in adrenalectomized rats, Sei., 221: 1301.Google Scholar
  21. Kilpatrick, D.L., Lewis, R.V., Stein, S., and Udenfriend, S., 1980, Release of enkephalins and enkephalin-containing peptides from perfused adrenal gland, Proc. Natl. Acad. Sci. (USA), 77:7473.Google Scholar
  22. Laudenslager, M.L., Ryan, S.M., Drugan, R.C., Hyson, R.L., and Mailer, S.F., 1983, Coping and immunosuppression: inescapable but not escapable shock suppresses lymphocyte proliferation, Sci., 221: 568.CrossRefGoogle Scholar
  23. Likhite, V., and Sehon, A., 1971, Migration inhibition and cell-mediated immunity: a review, Rev. Can. Biol. 30:135.Google Scholar
  24. Lock, S.E., 1982, Stress, adaptation and immunity: studies in humans, Gen. Hospital Psychiatry 4: 49.CrossRefGoogle Scholar
  25. McCain, H.W., Bilotta, J.M., and Lamster, I.B., 1985, Life Sci. (submitted for publication).Google Scholar
  26. McCain, H.W., Lamster, I.B., Bozzone, J.M., and Grbic, J.T., 1982, B-endorphin modulates human immune activity via non-opiate receptor mechanisms, Life Sci. 31: 1619.Google Scholar
  27. Morely, J., and Levine, A., 1980, Stress-induced eating is mediated through endogenous opiates, Sei., 209: 1259.Google Scholar
  28. Nakatsu, K., Goldenburg, E., Penning, D., and Jhamandas, K., 1981, Enkephalininduced inhibition of the rat ileum is not blocked by naloxone, Can. J. Physiol. Pharmacol. 59:901.Google Scholar
  29. Johnson, N., Houghten, R., and Pasternack, G.W., 1982, Binding of 3H-B-endorphin in rat brain, Life Sci. 31: 1381.Google Scholar
  30. Nowell, P.C., 1960, Phytohemagglutinin: indication of mitosis in cutures of normal human leukocytes, Cancer Res., 20: 462.PubMedGoogle Scholar
  31. Parillo, J.E. and Fauci, A.S., 1978, Comparison of the effector cells in human spontaneous cellular cytotoxicity and antibody dependent cytotoxicity:Google Scholar
  32. Differential sensitivity of effector cells to in vivo and in vitro corticosteroids, Scand. J. Immunol. 8:99.Google Scholar
  33. Plotnickoff, N.P., Murgo, A.J., Miller, G.C., Corder, C.N., and Faith, R.C., 1985, Enkephalins: immunomodulators, Federation Proc. 44: 118.Google Scholar
  34. Quirion, R., and Weiss, A., 1983, Peptide E and other proenkephalin-derived peptides are potent kappa opiate receptor agonists, Peptides 4: 445.Google Scholar
  35. Riley, V., 1981, Psychoneuroendocrine influences on immunocompetence and neoplasia, Sei., 212: 1100.Google Scholar
  36. Rossier, J., French, E., Rivier, C., Ling, N., Guillemin, R., and Bloom, F.E., 1977, Foot-shock induced stress increases beta-endorphin levels in blood but not brain, Nature, 270: 618.PubMedCrossRefGoogle Scholar
  37. Schweigerer, L., Bhakdi, S., and Teschemacher, H., 1982, Specific non-opiate binding sites for human beta-endorphin on the terminal complex of human complement, Nature, 296: 572.PubMedCrossRefGoogle Scholar
  38. Selye, H., 1956, “ The stressss o fe,” McGraw-Hill, New York.Google Scholar
  39. Shavit, Y. Lewis, J.W., Terman, G.W., Gale, R.P., and Liebeskind, J.C., 1984, Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity, Sei., 223: 188.Google Scholar
  40. Shavit, Y., Lewis, J.W., Terman, G.W., Gale, R.P., Liebeskind, J.C., 1983, Endogenous opiates may mediate the effects of stress on tumor growth and immune function, Proc. West. Pharmacol. Soc. 26:53.Google Scholar
  41. Simpkins, C.O., Dickey, C.A., and Fink, M.P., 1984, Human neutrophil migration is enhanced by B-endorphin, Life Sci. 34: 2251.Google Scholar
  42. Sklar, L., and Anisman, H., 1979, Stress and coping factors influence tumor growth, Sei. 205: 513.Google Scholar
  43. Smith, A.D., and Winkler, H., 1967, A simple method for the isolation of adrenal chromaffin granules on a large scale, Biochem. J. 103:480.Google Scholar
  44. Smyth, D.G., Parish, D.C., Normanton, J.R., and Wolstencroft, J.H., 1983Google Scholar
  45. The C-terminal dipeptide of beta-endorphin: a neuropeptide with inhibitory activity, Life Sci. 33:575.Google Scholar
  46. Stern, A.S., Lewis, R.V., Kimura, S., Rossier, J., Gerber, L.D., Brink, L., Stern, S., and Udenfriend, S., 1979, Isolation of the opioid hepta-peptide metenkephalin-arg-6, Phe-7 from bovine adrenal medullary granules and striatum, Proc. Natl. Acad. Sci. (USA), 76:6680.Google Scholar
  47. Terman, G.W., Shavit, Y., Lewis, J.W., Cannon, J.T., and Liebeskind, J.C. 1984, Intrinsic mechanims of pain inhibition: activation by stress, Sei., 226: 1270.Google Scholar
  48. Udenfriend, S., and Kilpatrick, D.L., 1983, Biochemistry of the enkephalins andenkephalin-containing peptides, Arch. Biochem. Biophys. 221:309.Google Scholar
  49. Van Epps, D., Salaild, L., Taylor, C., and Williams, R., 1983, In vitro and in vivo effects of beta-endorphin and met-enkephalin on leukocyte locomation, Prog. Brain Res.. 59:361.Google Scholar
  50. Visintaner, M.A., Volpicelli, T.R., and Seligman, M.E.P., 1982, Tumor rejection in rats after inescapable or escapable shock, Sci., 216: 437.CrossRefGoogle Scholar
  51. Weber, R.J., and Pert, C.B., 1984, Opiatergic Modulation of the Immune System, in: “Central and peripheral endorphins: Basic and clinical aspects,” E.E. Muller and A.R. Genazzani, eds., Ravin Press, New York.Google Scholar
  52. Wolfe, J.H.N., Saporoschetz, I., Young, A.E., O’Connor, N.E., and Mannick, J.A., 1981, Suppressive serum, suppressor lymphocytes, and death from burns, Ann. Sug. 193:513.Google Scholar
  53. Wuster, M., Schulz, R., Herz, A., 1979, Specificity of opioids towards the mu-, delta-and epsilon-opiate receptors. Neurosci. Lett. 15:193.Google Scholar
  54. Wybran, J., Appelboom, T. Famaey, J., and Gavaerts, A.M. 1979, Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T-lymphocytes, J. Immunol., 123 (3): 1068.Google Scholar

Copyright information

© Springer Science+Business Media New York 1986

Authors and Affiliations

  • Hulon W. McCain
    • 1
    • 2
  • Ira B. Lamster
    • 2
    • 3
  • Joanne Bilotta
    • 3
  1. 1.Departments of PharmacologyFairleigh Dickinson University School of DentistryHackensackUSA
  2. 2.Periodontics and Oral MedicineFairleigh Dickinson University School of DentistryHackensackUSA
  3. 3.The Oral Health Research CenterFairleigh Dickinson University School of DentistryHackensackUSA

Personalised recommendations