Heroin treatment or abusive drug addiction influences many physiological functions, including the reactions of the immune system. Although suppression of various manifestations of the immune system after heroin (or morphine) administration has been reported, we show here that production of proinflammatory cytokines and nitric oxide (NO) was enhanced and allotransplantation reactions were accelerated significantly in heroin-treated recipients. Mice were treated by a subcutaneous administration of heroin (diacetylmorphine) given in one or repeated daily doses. The ability of spleen cells from treated mice to respond in vitro to alloantigens and to produce IL-2, IL-4, IL-10 and IFN-gamma, and the production of IL-1beta, IL-12 and NO by peritoneal macrophages, were tested. Within 2 h after heroin administration, proliferative responses to alloantigens and the production of IL-1beta, IFN-gamma, IL-12 and NO were enhanced significantly. In contrast, the production of anti-inflammatory cytokines IL-4 and IL-10 was at the same time rather decreased. As a consequence, skin allografts in heroin-treated mice were rejected more promptly than in untreated or vehicle-treated recipients. Similarly, the growth of allogeneic tumours induced by high doses of tumour cells was suppressed significantly in heroin-treated mice. The enhancing effects of heroin on the production of proinflammatory cytokines were antagonized by naltrexone, a specific inhibitor of classic opioid receptors. These results show that heroin treatment augments production of proinflammatory cytokines and accelerates allotransplantation reactions. The observations thus illustrate the complexity of the effects of heroin on the immune system and should be taken into account during medical treatment of opiate addicts and in the use of morphine to decrease pain in various clinical situations.

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague Czech Republic

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Pacifici R, Di Carlo S, Bacosi A, Pichini S, Zuccaro P. Pharmacokinetics and cytokine production in heroin and morphine-treated mice. Int J Immunopharmacol. 2000;22:603–14. PubMed

Pacifici R, Minetti M, Zuccaro P, Pietraforte D. Morphine affects cytostatic activity of macrophages by the modulation of nitric oxide release. Int J Immunopharmacol. 1995;17:771–7. PubMed

Peng X, Mosser DM, Adler MW, Rogers TJ, Meisser JJ, Eisenstein TK. Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages. J Leukoc Biol. 2000;68:723–8. PubMed

Nelson CJ, How T, Lysle DT. Enhancement of the contact hypersensitivity reaction by acute morphine administration at the elicitation phase. Clin Immunol. 1999;93:176–83. PubMed

Zubelewicz B, Braczkowski R, Renshaw D, Harbuz MS. Central injection of morphine stimulates plasma corticosterone and interleukin (IL) -6 and IL-6 R mRNAs in the pituitary and adrenals in adjuvant-induced arthritis. J Biol Regul Homeost Agents. 1999;13:103–9. PubMed

Houghtling RA, Mellon RD, Tan RJ, Bayer BM. Acute effects of morphine on blood lymphocyte proliferation and plasma IL-6 levels. Ann N Y Acad Sci. 2000;917:771–7. PubMed

Roy S, Cain KJ, Chapin RB, Charboneau RG, Barke RA. Morphine modulated NF kappa B activation in macrophages. Biochem Biophys Res Commun. 1998;245:392–6. PubMed

Kapasi AA, Gibbons N, Mattana J, Singhal PC. Morphine stimulates mesangial cell TNF-alfa and nitrite production. Inflammation. 2000;24:463–76. PubMed

Bayer BM, Gastonguay MR, Hernandez MC. Distinction between the in vitro and in vivo inhibiotory effects of morphine on lymphocyte proliferation based on agonist sensitivity and naltrexone reversibility. Immunopharmacology. 1992;23:117–24. PubMed

Bryant HU, Bernton EW, Holaday JW. Immunosuppressive effects of chronic morphine treatment in mice. Life Sci. 1987;41:1731–8. PubMed

Lysle DT, Coussons ME, Watts VJ, Bennett EH, Dykstra LA. Morphine-induced alterations of immune status: dose dependency, compartment specificity and antagonism by naltrexone. J Pharmacol Exp Ther. 1993;265:1071–8. PubMed

Krulová M, Zajícová A, Frič J, Holáň V. Alloantigen-induced, T-cell-dependent production of nitric oxide by macrophages infiltrating skin allografts in mice. Transpl Int. 2002;15:108–16. PubMed

Ito A, Minagava M, Tomiyama K, Ito M, Kawai K. Cytotoxic pathways in the skin allograft rejection by CD4+ T cells. Transplantation. 1999;68:97–100. PubMed

Yamamoto M, Einaga-Naito K, Kuriyama M, Kawada Y, Yoshida R. Cellular basis of skin allograft rejecion. Specific lysis of allogeneic skin components by non-T cells. Transplantation. 1998;65:818–25. PubMed

Billingham RE, Brent L, Medawar PB. Quantitative studies on tissue transplantation immunity. The survival times of skin homografts exchanged between members of different inbred strains of mice. Proc Roy Soc Lond. 1954;143:43–55. PubMed

Bubeník J, Indrová M, Němečková Š, et al. Solubilized tumour-associated antigens of methylcholanthrene-induced sarcomas. Comparative studies by in vitro sensitization of lymph-node cells, macrophage electrophoretic mobility assay and transplantation tests. Int J Cancer. 1987;21:348–55. PubMed

Holáň V, Zajícová A, Krulová M, Plšková J, Frič J, Filipec M. Induction of specific transplantation immunity by oral immunization with allogeneic cells. Immunology. 2000;101:404–11. PubMed PMC

Holáň V, Kuffová L, Zajícová A, et al. Urocanic acid enhances IL-10 production in activated CD4+ T cells. J Immunol. 1998;161:3237–41. PubMed

Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982;126:131–8. PubMed

Govitrapong P, Suttitum T, Kotchabhakdi N, Uneklabh T. Alterations of immune functions in heroin addicts and heroin withdrawal subjects. J Pharmacol Exp Ther. 1998;286:883–9. PubMed

Bhargava HN, Thomas PT, Thorat S, House RV. Effect of morphine tolerance and abstinence on cellular immune function. Brain Res. 1994;642:1–10. PubMed

MacFarlane AS, Peng X, Meissler JJ, Jr, et al. Morphine increases susceptibility to oral Salmonella typhimurium infection. J Infect Dis. 2000;181:1350–8. PubMed

Roy S, Barke RA, Loh HH. Mu-opioid receptor-knockout mice. role of mu-opioid receptor in morphine mediated immune functions. Mol Brain Res. 1998;61:190–4. PubMed

Carr DJ, Bost KL, Blalock JE. The production of antibodies which recognize opiate receptors on murine leukocytes. Life Sci. 1988;42:2615–24. PubMed

Houghtling RA, Bayer BM. Rapid elevation of plasma interleukin-6 by morphine is dependent on autonomic stimulation of adrenal gland. J Pharmacol Exp Ther. 2002;300:213–9. PubMed

Wang J, Charboneau R, Balasubramanian S, Barke RA, Loh HH, Roy S. The immunosuppressive effects of chronic morphine treatment are partially dependent on corticosterone and mediated by the mu-opioid receptor. J Leukoc Biol. 2002;71:782–90. PubMed

House SD, Mao X, Wu G, Espinelli D, Li WX, Chang SL. Chronic morphine potentiates the inflammatory response by disrupting interleukin-1beta modulation of the hypothalamic–pituitary–adrenal axis. J Neuroimmunol. 2001;118:277–85. PubMed

Zagon IS, McLaughlin PJ. Heroin prolongs survival time and retards tumor growth in mice with neuroblastoma. Brain Res Bull. 1981;7:25–32. PubMed

Kim MH, Hahm TS. Plasma levels of interleukin-6 and interleukin-10 are affected by ketorolac as an adjunct to patient-controlled morphine after abdominal hysterectomy. Clin J Pain. 2001;17:72–7. PubMed

Nathan C. Natural resistance and nitric oxide. Cell. 1995;82:873–6. PubMed

Holáň V, Krulová M, Zajícová A, Pindjáková J. Nitric oxide as a regulatory and effector molecule in the immune system. Molec Immunol. 2002;38:989–95. PubMed

Wang J, Charboneau R, Balasubramanian S, Barke RA, Loh HH, Roy S. Morphine modulates lymph node-derived T lymphocyte function. role of caspase-3, -8, and nitric oxide. J Leukoc Biol. 2001;70:527–36. PubMed

Fecho K, Maslonek KA, Coussons-Read ME, Dykstra LA, Lysle DT. Macrophage-derived nitric oxide is involved in the depressed concanavalin A responsiveness of splenic lymphocytes from rats administered morphine in vivo. J Immunol. 1994;152:1545–52. PubMed

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