Annals of the New York Academy of SciencesVolume 521, Issue 1 p. 312-322 Opioids: Immunomodulators A Proposed Role in Cancer and Aging NICHOLAS P. PLOTNIKOFF, NICHOLAS P. PLOTNIKOFF Department of Pharmacology Oral Roberts University School of Medicine Tulsa, Oklahoma 74137Search for more papers by this author NICHOLAS P. PLOTNIKOFF, NICHOLAS P. PLOTNIKOFF Department of Pharmacology Oral Roberts University School of Medicine Tulsa, Oklahoma 74137Search for more papers by this author First published: March 1988 https://doi.org/10.1111/j.1749-6632.1988.tb35288.xCitations: 6AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Spector, N. H. 1983. Anatomic and physiologic connections between the central nervous and the immune systems (neuroimmunomodulation). In Immunoregulation. N. Fabris, E. Garaci, J. Hadden & N. A. Mitchensen, Eds. Plenum Publishing Corporation. New York , NY . 2 Ader, R. & N. Cohen. 1981. Conditioned immunopharmacologic responses. In Psychoneuroimmunology. R. Ader, Ed. Academic Press. New York , NY . 3 Felten, D. L., S. Y. Felten, S. L. Carlson, J. A. Olschowka & S. Livnat. 1985. Noradrenergic and peptidergic innervation of lymphoid tissue. J. Immunol. 135: 755. 4 Plotnikoff, N. P. & A. J. Kastin. 1977. Neuropharmacological review of hypothalamic releasing factors. In Neuropeptide Influences on the Brain and Behavior. L. H. Miller, C. A. Sandman & A. J. Kastin, Eds. Raven Press. New York , NY . 5 Sachar, E. J. 1978. Neuroendocrine responses to psychotropic drugs. In Psychopharmacology. M. A. Lipton & A. DiMascio, Eds. Raven Press. New York , NY . 6 Dougherty, T. F. 1952. Effect of hormones on lymphatic tissue. Physiol. Rev. 32: 379. 7 Blalock, J. E., K. L. Bost & E. M. Smith. 1985. Neuroendocrine peptide hormones and their receptors in the immune system. J. Neuroimmunol. 10: 31–40. 8 Berczi, I. 1986. The influence of pituitary-adrenal axis on the immune system. In Pituitary Function and Immunity. I. Berczi, Ed. CRC Press. Boca Raton , FL . 9 Evans, C. J., E. Erdelyi & J. D. Barchas. 1986. Candidate opioid peptides for interaction with the immune system. In Enkephalins and Endorphins: Stress and the Immune System. N. Plotnikoff et al., Eds. Plenum Press. New York , NY . 10 Undenfriend, S. & D. L. Kirkpatrick. 1983. Biochemistry of the enkephalins and enkephalin-containing peptides. Biochem. Biophys. 221: 309. 11 Bloom, F. E. 1983. The endorphins: a growing family of pharmacologically pertinent peptides. Annu. Rev. Pharmacol. Toxicol. 23: 151–170. 12 Lewis, R. V. & A. J. Stern. 1983. Biosynthesis of the enkephalins and enkephalin-containing polypeptides. Annu. Rev. Pharmacol. Toxicol. 23: 353–372. 13 Akil, H., S. J. Watson, E. Young, M. E. Lewis, H. Khachaturian & J. M. Walker. 1984. Endogenous opioids: biology and function. Annu. Rev. Neurosci. 7: 223–255. 14 Hollt, V. 1986. Opioid peptide processing and receptor selectivity. Annu. Rev. Pharmacol. Toxicol. 26: 59–77. 15 Plotnikoff, N. P., G. C. Miller & J. Wybran. 1987. ACTH and endorphins. In Hormones and Immunity. I. Berczi & K. Kovacs, Eds. MTP Press. Norwell , MA . 16 Murgo, A. J., R. E. Faith & N. P. Plotnikoff. 1986. Enkephalins: mediators of stress-induced immunomodulation. In Enkephalins and Endorphins: Stress and the Immune System. N. P. Plotnikoff et al. Eds. Plenum Press. New York , NY . 17 Plotnikoff, N. P., A. J. Murgo & R. E. Faith. 1984. Neuroimmunomodulation with enkephalins: effects on thymus and spleen weights in mice. Clin. Immunol. Immunopath. 32: 52. 18 Murgo, A. J. 1985. Inhibition of B-16-BL6 melanoma growth in mice by methionine enkephalin. J. Natl. Cancer Inst. 65: 341. 19 Youkilis, E., J. Chapman, E. Wood & N. P. Plotnikoff. 1985. In vivo immunostimulation and increased in vitro production of interleukin I (IL-1) activity by metenkephalin. Int. J. Immunopharm. 7: 79. 20 Dafny, N., J. A. Georgiades & C. Reyes-Vazquez. 1984. Reduction of Opiate Addiction by Interferon. IUPHAR. London . 21 Plotnikoff, N. P. 1985. The Yin-Yang hypothesis of opioid peptide immunomodulation. Psychopharmacol. Bull. 21: 489. 22 Plotnikoff, N. P., G. C. Miller, S. Solomon, R. E. Faith, L. Edwards & A. J. Murgo. 1986. Methionine enkephalin: immunomodulator in normal volunteers. In Enkephalins and Endorphins: Stress and the Immune System. Plotnikoff et al.Eds. Plenum Press. New York , NY . 23 Plotnikoff, N. P., G. C. Miller, S. Solomon, R. E. Faith, L. Edwards & A. J. Murgo. 1986. Methionine enkephalin: enhancement of T-cells in patients with Kaposi's Sarcoma (AIDS). Psychopharmacol. Bull. 22: 695–697. 24 Wybran, J. & L. Schandene. 1986. Some immunological effects of methionine-enkephalin in man: potential therapeutical use. In Leukocytes and Host Defense. J. J. Oppenheim & D. M. Jacobs, Eds. Alan R. Liss. New York , NY . 25 Koyuncuoglu, H. & M. Gungor. 1986. Effects of morphine opiates on immune function. In Enkephalins and Endorphins: Stress and the Immune System. N. Plotnikoff et al., Eds. Plenum Press. New York , NY . 26 Singh, V. K., A. Jakubovic & D. A. Thomas. 1980. Suppressive effects of methadone on human blood lymphocytes. Immunol. Lett. 2: 177. 27 McDonough, R. J., J. J. Madden, A. Falek, D. A. Shafer, M. Pline, D. Gordon, P. Bokos, J. C. Keuhnle & J. Mendelson. 1980. Alterations of T and null lymphocyte frequencies in the peripheral blood of human opiate addicts: In vivo evidence of opiate receptor sites on T-lymphocytes. J. Immunol. 125: 2539. 28 Wybran, J. 1985. Enkephalins and endorphins as modifiers of the immune system: present and future. Fed. Proc. 44: 92–94. 29 Donahoe, R., J. Madden, F. Hollingsworth, D. Shafer & A. Falek. 1986. T-cell E-receptor modulation by opiates, opioids and other behaviorally active substances. In Enkephalins and Endorphins: Stress and the Immune System. N. Plotnikoff et al., Eds. Plenum Press. New York , NY . 30 Gungor, M., E. Genc, H. Sugduyu, L. Eroglu & H. Koyuncuoglu. 1980. Effect of chronic administration of morphine on primary immune response in mice. Experientia 36: 1309. 31 Lefkowitz, S. S. & D. Nemeth. 1976. Immunosuppression of rosette-forming cells. Adv. Exp. Med. Biol. 733: 269. 32 Lefkowitz, S. S. & C. Y. Chiang. 1975. Effects of certain abused drugs on hemolysin forming cells. Life Sci. 17: 1763. 33 Shavit, Y., J. W. Lewis, G. W. Terman, R. P. Gall & J. C. Liebeskind. 1984. Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity. Science 223: 188. 34 McCain, H. W., I. B. Lamster & J. Bilotta. 1986. Immunosuppressive effects of opiopeptins. In Enkephalins and Endorphins: Stress and the Immune System. N. Plotnikoff et al., Eds. Plenum Press. New York , NY . 35 Cubeddu, L. S., S. P. Wilson & O. H. Viveros. 1983. Opioid peptides and catecholamine in human pheochromocytoma. Life Sci. 33: 871–877. 36 Zagon, I. S. & P. J. McLaughlin. 1986. Endogenous opioid systems, stress, and cancer. In Enkephalins and Endorphins: Stress and the Immune System. N. Plotnikoff et al., Eds. Plenum Press. New York , NY . 37 Hazum, E., K. J. Chang & P. Cautrecasas. 1980. Cluster formation of opiate (enkephalin) receptors in neuroblastoma cells: differences between agonists and antagonists and possible relationships to biological functions. Proc. Natl. Acad. Sci. USA 77: 3038–3041. 38 Zagon, I. S. & P. J. McLaughlin. 1981. Naloxone prolongs the survival time of mice treated with neuroblastoma. Life Sci. 28: 1095–1102. 39 Zagon, I. S. & P. J. McLaughlin. 1984. Duration of opiate receptor blockade determines tumorigenic response in mice with neuroblastoma: a role for endogenous opioid systems in cancer. Life Sci. 35: 409–416. 40 Zagon, I. S. & P. J. McLaughlin. 1981. Heroin prolongs survival time and retards tumor growth in mice with neuroblastoma. Br. Res. Bull. 7: 25–32. 41 Simon, E. J. 1982. History. In Endorphins. J. B. Malick & R. M. S. Bell, Eds. Marcel Dekker. New York , NY . 42 Kazmi, S. M. I. & R. K. Mishra. 1986. Opioid receptors in human neuroblastoma SH-SY5Y cells: evidence for distinct morphine (mu) and enkephalin (delta) binding sites. Biochem. Biophys. Res. Commun. 137: 813–820. 43 Brooks, W. M., M. G. Netsky, D. E. Normansell & D. A. Horwitz. 1972. Depressed cell-mediated immunity in patients with primary intra-cranial tumors: characterization of a humoral immunosuppressive factor. J. Exp. Med. 136: 1631–1647. 44 Monstein, H. J., R. Folkesson & L. Terenius. 1986. Proenkephalin A-like in RNA in human leukemia leukocytes and CNS tissues. Life Sci. 39: 2237–2241. 45 Wolf, G. T. & K. A. Peterson. 1986. Beta endorphins enhances in vitro lymphokine production in patients with squamous carcinoma of the head and neck. Otolaryn. Head Neck Surg. 94: 224–229. 46 Gillies, G., S. Ratter, A. Grossman, R. Gaillard, P. J. Lowry, G. M. Besser & L. H. Rees. 1980. ACTH, LPH, and beta-endorphin secretion from perfused isolated human pituitary tumor cells in vitro. Horm. Res. 13: 280–290. 47 Asa, S. L., K. Kovacs, D. W. Killinger, N. Marcon & M. Platts. 1980. Pancreatic islet cell carcinoma producing gastrin, ACTH, alpha-endorphin, somatostatin, and calcitonin. Am. J. Gastroenterol. 74: 30–35. 48 Baker, J., I. M. Holdaway, M. Jagusch, A. R. Kerr, R. A. Donald & P. T. Pullan. 1982. Ectopic secretion of ACTH and met-enkephalin from a thymic carcinoid. J. Endocrinol. Invest. 5: 33–37. 49 Charpin, C., B. Argemi, M. Cannoni, C. Oliver, P. Gillioz, J. P. Vagneur & M. Toga. 1984. Detection immunocytochimique de calcitonine, ?ACTH, de beta MSH, de beta-endorphine, et de somtostatine dans les carcinomes medullaires de la thyrode. Ann. Pathol. 1983. 4: 27–35. 50 Roth, K. A. & J. D. Barchas. 1986. Small cell carcinoma cell lines contain opioid peptides and receptors. Cancer 57: 769–773. 51 Alumets, J., S. Falkmer, L. Grimelius, R. Hakanson, O. Ljungberg, F. Sundler & E. Wilander. 1980. Immunocytochemical demonstration of enkephalin and beta-endorphin in endocrine tumors of the rectum. Acta Pathol. Microbiol. Scand. Sect. A 88: 103–109. 52 Celio, M. R. 1979. Distribution of beta-endorphin immunoreactive cells in human fetal and adult pituitaries and in pituitary adenomas. J. Histochem. Cytochem. 27: 1215–1216. 53 Sardelli, S., F. Petraglia, F. Massolo, A. Messori, V. Santoro, F. Facchinetti & A. R. Genazzani. 1986. Changes in immunoreactive beta-endorphin, methionine-enkephalin and ACTH in bone marrow cells and fluid from leukemic children. Clin. Immunol. Immunopath. 41: 247–253. 54 Sporrong, B., J. Alumets, L. Clase, S. Falkmer, R. Hakanson, O. Ljungberg & F. Sundler 1981. Neurohormonal peptide immunoreactive cells in mucinous cystadenomas and cystadenocarcinomas of the ovary. Virchows Arch. (Pathol. Anat.) 392: 271–280. 55 Di Martino, L., A. Tarquini, I. Mitchell & N. Deshpande. 1982. Effects of opiates and naloxone on certain enzymes of carbohydrate metabolism in human breast carcinomas. Tumori 68: 397–401. 56 Laudenslager, M. L., S. M. Ryan, R. C. Drugan, R. L. Hyson & S. F. Maier. 1983. Coping and immunosuppression: inescapable but not escapable shock suppresses lymphocyte proliferation. Science 221: 568–570. 57 Stein, M., R. C. Schiavi & M. Carmerino. 1970. Influence of brain and behavior on the immune system. Science 191: 435. 58 Vogel, W. H. 1986. Effects of coping and noncoping with stressful events on the immune system. In Enkephalins and Endorphins: Stress and the Immune System. N. Plotnikoff et al., Eds. Plenum Press. New York , NY . 59 Dafney, N. 1983. Interferon modifies morphine withdrawal phenomena in rodents. Neuropharmacology 22: 647–651. 60 Solomon, G., N. Kay & J. E. Morley. 1986. Endorphins: a link between personality stress, emotions, immunity, disease? In Enkephalins and Endorphins: Stress and the Immune System. N. Plotnikoff et al., Eds. Plenum Press. New York , NY . 61 Monjan, A. A. & M. I. Collector. 1977. Stress-induced modulation of the immune response. Science 196: 307. 62 Lewis, J. W., Y. Shavit, F. C. Martin, G. W. Terman, R. P. Gale & J. C. Liebeskind. 1986. Effects of stress and morphine on natural killer cell activity and on mammary tumor development. In Enkephalins and Endorphins: Stress and the Immune System. N. Plotnikoff et al., Eds. Plenum Press. New York , NY . 63 Riley, V. 1981. Psychoneuroendocrine influences on immunocompetence and neoplasia. Science 212: 1100–1109. 64 Lymangrover, J. R., L. A. Dokas, A. Kong, R. Martin & M. Saffran. 1981. Naloxone has a direct effect on the adrenal cortex. Endocrinology 109: 1132–1137. 65 Schleifer, S. J., S. E. Keller, M. Camerino, J. C. Thornton & M. Stein. 1983. Suppression of lymphocyte stimulation following bereavement. J. Am. Med. Assoc. 250: 374–377. 66 Irwin, M., M. Daniels, E. T. Bloom & H. Weiner. 1986. Life events, depression, and natural killer cell activity. Psychopharmacol. Bull. 22: 1093–1096. 67 Messing, R. B., B. J. Vasquez, V. R. Spiehler, J. L. Martinez, Jr., R. A. Jensen, H. Rigter & J. L. McGaugh. 1980. 3H-Dihydromorphine binding in brain regions of young and aged rats. Life Sci. 26: 921–927. 68 Missale, C., S. Govoni, L. Croce, A. Bosio, P. F. Spano & M. Trabucchi. 1983. Changes of beta-endorphin and met-enkephalin content in the hypothalamus-pituitary axis induced by aging. J. Neurochem. 40: 20–24. 69 B***den, N., A. Dupont, F. Labrie, Y. Merandi, D. Rouleau, H. Vaudry & J. R. Boissier. 1981. Age-dependent changes in the beta-endorphin content of discrete rat brain nuclei. Brain Res. 208: 209–212. 70 Ogawa, N. 1985. Neuropeptides and their receptors in aged-rat brain. Acta Med. Okayama. 39: 315–319. 71 Petkov, V. V., V. D. Petkov, T. Grahorska & E. Koustantinova. 1984. Enkephalin receptor changes in rat brain during aging. Gen. Pharmacol. 15: 491–495. 72 Dupont, A., P. Savard, Y. Merand, F. Labrie & J. R. Boissier. 1981. Age-related changes in central nervous system enkephalins and substance P. Life Sci. 29: 2317–2322. 73 Jensen, R. A., R. B. Messing, V. R. Spiehler, J. L. Martinez, Jr., B. J. Vasquez & J. L. McGaugh. 1980. Memory, opiate receptors, and aging. Peptides 1: 197–201. 74 Wilkinson, C. W. & D. M. Dorsa. 1986. The effects of aging on molecular forms of beta and gamma-endorphins in rat hypothalamus. Neuroendocrinology 43: 124–131. 75 Effros, R. B. 1984. Aging and Immunity. In Stress, Immunity and Aging. E. L. Cooper, Ed. Marcel Dekker, Inc. New York , NY . 76 Kay, M. M. B. 1978. Effect of age on T-cell differentiation. Fed Proc. 37: 1241–1244. 77 Pierpaoli, W. 1981. Integrated phylogenetic and ontogenetic evolution of neuroendocrine and identity-defense, immune functions. In Psychoneuroimmunology. R. Ader, Ed. Academic Press. New York , NY . 78 Zurawski, G., M. Benedik, B. J. Kamb, J. S. Abrams, S. M. Zurawski & F. D. Lee. 1986. Activation of mouse T-helper cells induces abundant preproenkephalin in RNA synthesis. Science 232: 772. 79 McCain, H. W., I. B. Lamster & J. Bilotta. 1986. Modulation of human T-cell suppressor activity by beta endorphin and Glycyl-L- Glutamine. Int. J. Immunopharmacol. 84: 443–446. 80 Wybran, J., D. Latinne, J. Sonnet, H. Taelman, J. P. Van Vorren & N. P. Plotnikoff. 1986. Immunorestorative effect of methionine-enkephalin in ARC and AIDS patients. Int. Conf. Acq. Immunodef. Syndrome. Paris , France . 81 Youkilis, E., J. Chapman, E. Woods & N. P. Plotnikoff. 1985. In vivo immunostimulation and increased in vitro production of interleukin 1 (IL-1) activity by metenkephalin. Int. J. Immunopharmacol. 7: 79. 82 Brown, S. L. & E. E. Van Epps 1985. Beta endorphin (BE), methionine enkephalin (ME), and corticotrophin (ACTH) modulate the production of gamma interferon (INF) in vitro. Fed Proc. 44: 949. 83 Rosenberg, S. A. & M. T. Lotzel. 1986. Cancer immunotherapy using interleukin-2 and interleukin-2-activated lymphocytes. Annu. Rev. Immunol. 4: 681–711. Citing Literature Volume521, Issue1Neuroimmunomodulation: Interventions in Aging and Cancer–First Stromboli Conference on Aging & CancerMarch 1988Pages 312-322 ReferencesRelatedInformation

Clinical studies of the immunological effects of methionine enkephalin in normal volunteers, cancer, and AIDS patients are summarized. The major immunology changes seen were increases in T cell subsets, natural killer activity, as well as mitogen blastogenesis. Clinically, the cancer and ARC patients did not develop infections.

A review of the literature in the field of psychoneuroimmunology was reported by Robert Ader [1]. Basically, three research approaches have been used to demonstrate a relationship between central sites within the brain that have modulatory influences on the immune system. These include: (1) both the electrical stimulation and surgical lesioning of nuclei in the hypothalamus; (2) traditional behavioral conditioning; and (3) behavioral stress studies. The mechanisms of action for the psychoneuroimmunologic response appear to be focused in three areas: (1) the autonomic nervous system, where direct anatomical connections from the brain to the immune system have been recently demonstrated; (2) the endocrine system where the individual hormones have direct and indirect effects on the immune system; and (3) enkephalins-endorphins in the brain, pituitary, and adrenals that also have direct and indirect effects on the immune system. Examples of drug effects on the above complex systems will be centered on morphine and the enkephalins-endorphins with reference to drugs of abuse, food additives, and cosmetics.

Methionine-enkephalin (Met-Enk) and ZnCl 2 in combination enhances active T cell rosette formation of human peripheral blood lymphocytes to a greater degree than either of the agents used separately. Enhancement of rosette formation by Met-Enk plus ZnCl 2 was not inhibited by the opiate receptor antagonist naloxone but was completely blocked by the zinc chelator 1, 10-phenathroline. The results suggest a relationship between zinc and Met-Enk and that zinc may be a modulator of enkephalin binding and function in the immune system as well as the nervous system.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNew azacannabinoids highly active in the central nervous systemCheuk Man Lee, Harold E. Zaugg, Raymond J. Michaels, Anthony T. Dren, Nicholas P. Plotnikoff, and Patrick R. YoungCite this: J. Med. Chem. 1983, 26, 2, 278–280Publication Date (Print):February 1, 1983Publication History Published online1 May 2002Published inissue 1 February 1983https://pubs.acs.org/doi/10.1021/jm00356a031https://doi.org/10.1021/jm00356a031research-articleACS PublicationsRequest reuse permissionsArticle Views72Altmetric-Citations4LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts