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Morphine, but Not Trauma, Sensitizes to Systemic Acinetobacter baumannii Infection

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Abstract

Acinetobacter baumannii is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous animal studies to be immunosuppressive and to sensitize to infection. The hypotheses were tested that morphine, administered for analgesia in the battlefield, predisposes to Acinetobacter infection, and that the opioid may have an additive or synergistic effect with trauma. To test these hypotheses, an intraperitoneal infection model was established in mice using several Acinetobacter strains. Morphine administered for 48 h by implantation of a slow-release morphine pellet increased mortality compared to animals receiving a placebo pellet, an effect that was blocked by the mu-opioid receptor antagonist, naltrexone. Acinetobacter burdens in the blood, spleens, livers, and lungs of morphine-treated mice, were significantly higher than those in placebo-treated animals, confirming that mortality was due to potentiated growth of the bacteria. There were also elevated levels of pro-inflammatory cytokines in morphine-treated versus placebo-treated mice. Morphine caused a reduction in the total number of cells in the peritoneal cavity, a decrease in the percentage and total numbers of neutrophils, and a decrease in the total number of macrophages. Morphine treatment also suppressed levels of the neutrophil-inducing molecules, IL-17A and KC/CXCL1. However, IL-17A−/− mice given morphine were not sensitized to Acintobacter infection to a greater degree than similarly treated wild-type mice. Trauma alone did not sensitize to Acinetobacter infection, and there was no additive effect between morphine and trauma. These results support the hypothesis that morphine potentiates Acinetobacter infection.

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References

  • Angele MK, Chaudry IH (2005) Surgical trauma and immunosuppression: pathophysiology and potential immunomodulatory approaches. Langenbecks Arch Surg 390:333–341

    Article  PubMed  Google Scholar 

  • Asakura H, Kawamoto K, Igimi S, Yamamoto S, Makino S (2006) Enhancement of mice susceptibility to infection with Listeria monocytogenes by the treatment of morphine. Microbiol Immunol 50:543–547

    PubMed  CAS  Google Scholar 

  • Bernabeu-Wittel M, Pichardo C, Garcia-Curiel A, Pachon-Ibanez ME, Ibanez-Martinez J, Jimenez-Mejias ME, Pachon J (2005) Pharmacokinetic/pharmacodynamic assessment of the in-vivo efficacy of imipenem alone or in combination with amikacin for the treatment of experimental multiresistant Acinetobacter baumannii pneumonia. Clin Microbiol Infect 11:319–325

    Article  PubMed  CAS  Google Scholar 

  • Boucher HW, Talbo GH, Bradly JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J (2009) Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48:1–12

    Article  PubMed  Google Scholar 

  • Breslow JM, Meissler JJ, Hartzell RH, Spence PB, Truant A, Gaughan J, Eisenstein TK (2011) Innate immune responses to systemic Acinetobacter baumannii infection in mice: neutrophils, but not IL-17, mediate host resistance. Infect Immun 79:3317–3327

    Article  PubMed  CAS  Google Scholar 

  • Bryant HU, Bernton EW, Holaday JW (1988a) Morphine pellet-induced immunomodulation in mice: temporal relationships J. Pharmacol Exp Ther 245:913–920

    CAS  Google Scholar 

  • Bryant HU, Yoburn BC, Inturrisi CE, Bernton EW, Holaday JW (1988b) Morphine-induced immunomodulation is not related to serum morphine concentrations Eur. J Pharmacol 149:165–169

    CAS  Google Scholar 

  • Bussiere JL, Adler MW, Rogers TJ, Eisenstein TK (1993) Cytokine reversal of morphine-induced suppression of the antibody response. J Pharmacol Exp Ther 264:591–597

    PubMed  CAS  Google Scholar 

  • Casellas AM, Guardiola H, Renaud FL (1991) Inhibition by opioids of phagocytosis in peritoneal macrophages. Neuropeptides 18:35–40

    Article  PubMed  CAS  Google Scholar 

  • Centers for Disease Control and Prevention (2006) HIV/AIDS Surveillance Report. Cases of HIV Infection and AIDS in the United States and Dependent Areas, 2005. US Dept. of Health and Human Services:Atlanta.

  • Cerletti C, Keinath SH, Reidenberg MM, Adler MW (1976) Chronic morphine administration: plasma levels and withdrawal syndrome in rats. Pharmacol Biochem Behav 4:323–327

    Article  PubMed  CAS  Google Scholar 

  • Chao CC, Sharp BM, Pomeroy C, Filice GA, Peterson PK (1990) Lethality of morphine in mice infected with Toxoplasma gondii. J Pharmacol Exp Ther 252:605–609

    PubMed  CAS  Google Scholar 

  • Cheney DL, Goldstein A (1971) Tolerance to opioid narcotics: time course and reversibility of physical dependence in mice. Nature 232:477–478

    Article  PubMed  CAS  Google Scholar 

  • Clark JD, Shi X, Li X, Qiao Y, Liang DY, Angst MS, Yeomans DC (2007) Morphine reduces local cytokine expresssion and neutrophil infiltration after incision. Mol Pain 3:28–40

    Article  PubMed  Google Scholar 

  • Dijkshoorn L, Nemec A, Seifert H (2007) An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii. Nat Rev Microbiol 5:939–951

    Article  PubMed  CAS  Google Scholar 

  • Feng P, Rahim RT, Cowan A, Liu-Chen L-Y, Peng X, Gaughan J, Meissler JJ Jr, Adler MW, Eisenstein TK (2006) Effects of mu, kappa or delta opioids administered by pellet or pump on oral Salmonella infection and gastrointestinal transit. Eur J Pharmacol 534:250–257

    Article  PubMed  CAS  Google Scholar 

  • Grimm MC, Ben-Baruch A, Taub DD, Howard OMZ, Resau JH, Wang JM, Ali H, Richardson R, Snyderman R, Oppenheim JJ (1998) Opiates transdeactivate chemokine receptors: δ and μ opiate receptor-mediated heterologous desensitization. J Exp Med 188:317–325

    Article  PubMed  CAS  Google Scholar 

  • Horsburgh CR, Anderson RA, Boyko EJ (1989) Increased incidence of infections in intravenous drug use. Infect Control Hosp Epidemiol 10:211–215

    Article  PubMed  Google Scholar 

  • Hussey HH, Katz S (1950) Infections resulting from narcotic addiction. Am J Med 9:186–193

    Article  PubMed  CAS  Google Scholar 

  • Joly-Guillou M-L, Wolff M, Pocidalo J-J, Walker F, Carbon C (1997) Use of a new mouse model of Acinetobacter baumannii pneumonia to evaluate the post antibioic effect of imipenem. Antimicrob Agents Chemother 41:345–351

    PubMed  CAS  Google Scholar 

  • Kang G, Hartzell JD, Howard R, Wood-Morris RN, Johnson MD, Fraser S, Wintrob A, Wortmann G (2010) Mortality associated with Acinetobacter baumannii complex bacteremia among patients with war-related trauma. Infect Control Hosp Epidemiol 31:92–94

    Article  PubMed  Google Scholar 

  • Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Miyazaki M (2010) Immunosuppression following surgical and traumatic injury. Surg Today 40:793–808

    Article  PubMed  CAS  Google Scholar 

  • Lenz A, Franklin GA, Cheadle WG (2007) Systemic inflammation after trauma. Injury 38:1336–1345

    Article  PubMed  Google Scholar 

  • Lioy D, Sheridan PA, Hurley SD, Walton JR, Martin AM, Olschowka JA, Moynihan JA (2006) Acute morphine exposure potentiates the development of HSV-1-induced encephalitis. J Neuroimmunol 172:9–17

    Article  PubMed  CAS  Google Scholar 

  • Lockhart EL, Green AM, Flynn JL (2006) IL-17 production is dominated by γδ T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol 177:4662–4669

    PubMed  CAS  Google Scholar 

  • Louria DB, Hensle T, Rose J (1967) The major medical complications of heroin addiction. Ann Int Med 67:1–22

    PubMed  CAS  Google Scholar 

  • Ma J, Wang J, Wan J, Charboneau R, Chang Y, Barke RA, Roy S (2010) Morphine disrupts interleukin-23 (IL-23)/IL-17-mediated pulmonary mucosal host defense against Streptococcus pneumoniae infection. Infect Immun 78:830–837

    Article  PubMed  CAS  Google Scholar 

  • MacFarlane AS, Peng X, Meissler JJ Jr, Rogers TJ, Geller EB, Adler MW, Eisenstein TK (2000) Morphine increases susceptibility to oral Salmonella typhimurium infection. J Infect Dis 181:1350–1358

    Article  PubMed  CAS  Google Scholar 

  • Mack VE, McCarter MD, Naama HA, Calvano SE, Daly JM (1997) Candida infection following severe trauma exacerbates Th2 cytokines and increases mortality. J Surg Res 69:399–407

    Article  PubMed  CAS  Google Scholar 

  • Mackrell PJ, Daly JM, Mestre JR, Stapleton PP, Howe LR, Subbaramaiah K, Dannerberg AJ (2001) Elevated expression of cyclooxygenase-2 contributes to immune dysfunction in a murine model of trauma. Surgery 130:826–833

    Article  PubMed  CAS  Google Scholar 

  • Martin JL, Koodie L, Krishnan AG, Charboneau R, Barke RA, Roy S (2010) Chronic morphine administration delays wound healing by inhibiting immune cell recruitment to the wound site. Amer. J Path. 176:786–799

    Google Scholar 

  • Matsuzaki G, Umemura M (2007) Interleukin-17 as an effector molecule of innate and acquired immunity against infections. Microbiol Immunol 51:1139–1147

    PubMed  CAS  Google Scholar 

  • McCarter MD, Mack VE, Daly JM, Naama HA, Calvano SE (1998) Trauma-induced alterations in macrophage function. Surgery 123:96–101

    Article  PubMed  CAS  Google Scholar 

  • McCoy CB, Metsch LR, Chitwood DD, Shapshak P, Comerford ST (1998) Parenteral transmission of HIV among injection drug users: assessing the frequency of multiperson use of needles, syringes, cookers, cotton, and water. JAIDS 18(Suppl 1):S25–S29

    PubMed  Google Scholar 

  • Meeks KD, Sieve AN, Kolls JK, Ghilardi N, Berg RE (2009) IL-23 is required for protection against systemic infection with Listeria monocytogenes. J Immunol 183:8026–8034

    Article  PubMed  CAS  Google Scholar 

  • Mojadadi S, Jamali A, Khansarinejad B, Soleimanjahi H, Bamdad T (2009) Acute morphine adminstration reduces cell-mediated immunity and induces reactivation of latent herpes simplex virus type 1 in BALB/c mice. Cell Mol Immunol 6:111–116

    Article  PubMed  CAS  Google Scholar 

  • Monroy MA, Opperman KK, Pucciarelli M, Yerrum S, Berg DA, Daly JM (2007) The PPARγ ligand 15D-PGJ2 modulates macrophage activation after injury in a murine trauma model. Shock 28:186–191

    Article  PubMed  CAS  Google Scholar 

  • Moore FA, Moore EE (1995) Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin N Amer 75:257–277

    PubMed  CAS  Google Scholar 

  • Nakae S, Komiyama Y, Nambu A, Sudo K, Iwase M, Homma I, Sekikawa K, Asano M, Iwakura Y (2002) Antigen-specific T cell sensitization is impared in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17:375–387

    Article  PubMed  CAS  Google Scholar 

  • Ni X, Gritman KR, Eisenstein TK, Adler MW, Arfors KE, Tuma RF (2000) Morphine attenuates leukocyte/endothelial interactions. Microvasc Res 60:121–130

    Article  PubMed  CAS  Google Scholar 

  • Petersen K, Riddle MS, Danko JR, Blazes DL, Hayden R, Tasker SA, Dunne JR (2007) Trauma-related infections in battlefield casualties from Iraq. Ann Surg 245:803–811

    Article  PubMed  Google Scholar 

  • Rachitskaya AV, Hansen AM, Horai R, Li Z, Villasmil R, Luger D, Nussenblatt RB, Caspi RR (2008) Cutting edge: NKT cells constitutively express IL-23 receptor and RORγt and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion. J Immunol 180:5167–5171

    PubMed  CAS  Google Scholar 

  • Renckens R, Roelofs JJ, Knapp S, deVos AF, Florquin S, van der Poll T (2006) The acute-phase response and serum amyloid A inhibit the inflammatory response to Acinetobacter baumannii pneumonia. J Infect Dis 193:187–195

    Article  PubMed  CAS  Google Scholar 

  • Riol-Blanco L, Lazarevic V, Awasthi A, Mitsdoerffer M, Wilson BS, Croxford A, Waisman A, Kuchroo VK, Glimcher LH, Oukka M (2010) IL-23 receptor regulated unconventional IL-17-producing T cells that control bacterial infection. J Immunol 184:1710–1720

    Article  PubMed  CAS  Google Scholar 

  • Rogers TJ, Bednar F, Kaminsky DE, Davey PC, Meissler JJ Jr, Eisenstein TK (2005) Laboratory model systems of drug abuse and their relevance to HIV infection and dementia. In: Gendelman HE, Grant I, Everall IP, Lipton SA, Swindells S (eds) The neurology of AIDS. Oxford University Press, Oxford, pp 310–320

    Google Scholar 

  • Roumen RM, Hendriks T, van der Ven-Jongekrijg J, Nieuwenhiujzen GAP, Sauerwein RW, van der Meer JW, Goris RJA (1993) Cytokine patterns in patients after major surgery, hemorrhagic shock, and severe blunt trauma. Ann Surg 6:769–776

    Article  Google Scholar 

  • Russo TA, Beanan JM, Olson R, MacDonald U, Luke NR, Gill SR, Campagnari AA (2008) Rat pneumonia and soft-tissue infection models for the study of Acinetobacter baumannii biology. Infect Immun 76:3577–3586

    Article  PubMed  CAS  Google Scholar 

  • Scott PT (2004) Acinetobacter baumannii infections among patients at military medical facilities treating injured U.S. service members, 2002–2004 Morbidity and Mortality Weekly. Report 53:1064–1065

    Google Scholar 

  • Scott P, Deye G, Srinivasan A, Murray C, Moran K, Hulten E, Fishbain J, Craft D, Riddell S, Lindler L, Mancuso J, Milstrey E, Bautista CT, Patel J, Ewell A, Hamilton T, Geddy C, Tenney M, Christopher G, Peterson K, Endy T, Petruccelli B (2007) An outbreak of multidrug-resistant Acinetobacter baumannii-calcoaceticus complex infection in the US military health care system associated with military operations in Iraq. Clin Infect Dis 44:1577–1584

    Article  PubMed  CAS  Google Scholar 

  • Shavit Y, Terman GW, Lewis JW, Zane CJ, Gale RP, Liebeskind JC (1986) Effects of footshock stress and morphine on natural killer lymphocytes in rats: studies of tolerance and cross-tolerance. Brain Res 372:382–385

    Article  PubMed  CAS  Google Scholar 

  • Shibata K, Yamata H, Hara H, Kishihara K, Yoshikai Y (2007) Resident Vγ1+ γδ T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production. J Immunol 178:4466–4472

    PubMed  CAS  Google Scholar 

  • Shirzad H, Shahrani M, Rafieian-Kopaei M (2009) Comparison of morphine and tramadol effects on phagocytic activity of mice peritoneal phagocytes in vivo. Int Immunopharm 9:968–970

    Article  CAS  Google Scholar 

  • Singal P, Kinhikar AG, Singh S, Singh PP (2002) Neuroimmunomodulatory effects of morphine in Leishmania donovani-infected hamsters. Neuroimmunomod 10:261–269

    Article  Google Scholar 

  • Singh PP, Singal P (2007) Morphine-induced neuroimmunomodulation in murine visceral leishmaniasis: the role(s) of cytokines and nitric oxide. J Neuroimm Pharmacol 2:338–351

    Article  Google Scholar 

  • Singh PP, Singh S, Dutta GP, Srimal RC (1993) Immunomodulation by morphine in Plasmodium berghei-infected mice. Life Sci 54:331–339

    Article  Google Scholar 

  • Singhal PC, Bhaskaran M, Patel J, Patel K, Kasinath BS, Duraisamy S, Franki N, Reddy K, Kapasi AA (2002) Role of P38 mitogen-activated protein kinase phophorylation and Fas-Fas ligand interaction in morphine-induced macrophage apoptosis. J Immunol 168:4025–4033

    PubMed  CAS  Google Scholar 

  • Szabo I, Rojavin M, Bussiere JL, Eisenstein TK, Adler MW, Rogers TJ (1993) Suppression of peritoneal macrophage phagocytosis of Candida albicans by opioids. J Pharmacol Exp Ther 267:703–706

    PubMed  CAS  Google Scholar 

  • Szabo I, Wetzel MA, Zhang N, Steele AD, Kaminsky DE, Chen C, Liu-Chen L-Y, Bednar F, Henderson EE, Howard OMZ, Oppenheim JJ, Rogers TJ (2003) Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization. J Leukoc Biol 74:1074–1082

    Article  PubMed  CAS  Google Scholar 

  • Towner KJ (2009) Acinetobacter: an old friend but a new enemy. J Hosp Infect 73:355–363

    Article  PubMed  CAS  Google Scholar 

  • Tubaro E, Borelli G, Croce C, Cavallo G, Santiangeli C (1983) Effect of morphine on resistance to infection. J Infect Dis 148:656–666

    Article  PubMed  CAS  Google Scholar 

  • Van Faassen H, KuoLee R, Harris G, Zhao X, Conlan JW, Chen W (2007) Neutrophils play an important role in host resistance to respiratory infection with Acinetobacter baumannii in mice. Infect Immun 75:5597–5608

    Article  PubMed  Google Scholar 

  • Vassou D, Badogeorgou E, Kampa M, Dimitriou H, Hatzoglou A, Castanas E (2008) Opioids modulate constitutive B-lymphocyte secretion. Int Immunopharm 8:634–644

    Article  CAS  Google Scholar 

  • Vincent JL, Bello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, Gomersall C, Sakr Y, Reinhart K (2009) International study of the prevalence and outcomes of infection in Intensive Care Units. JAMA 302:2323–2329

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Barke RA, Charboneau R, Roy S (2005) Morphine impairs host innate immune response and increases susceptibility to Streptococcus pneumoniae lung infection. J Immunol 174:426–434

    PubMed  CAS  Google Scholar 

  • Wang J, Barke RA, Charboneau R, Schwendener R, Roy S (2008) Morphine induces defects in early response of alveolar macrophages to Streptococcus pneumoniae by modulating TLR9-NFkB signaling. J Immunol 180:3594–3600

    PubMed  CAS  Google Scholar 

  • Weber RJ, Pert A (1989) The periaqueductal gray matter mediates opiate-induced immunosuppression. Science 245:188–190

    Article  PubMed  CAS  Google Scholar 

  • Wendt C, Dietze B, Dietz E, Ruden H (1997) Survival of Acinetobacter baumannii on dry surfaces. J Clin Microbiol 35:1394–1397

    PubMed  CAS  Google Scholar 

  • Wisplinghoff H, Bischoff T, Tallent M, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39:309–317

    Article  PubMed  Google Scholar 

  • Witowski J, Ksiazek K, Jorres A (2004) Interleukin-17: a mediator of inflammatory responses. Cell Mol Life Sci 61:567–572

    Article  PubMed  CAS  Google Scholar 

  • Yin D, Mufson A, Wang R, Shi Y (1999) Fas-mediated cell death promoted by opioids. Nature 397:218

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Col. Craft for providing the Acinetobacter strains. We are grateful to Dr. Iwakura for giving us permission to obtain the IL-17a −/− mice, and to Dr. Kolls for supplying us with breeding stock of the IL-17a −/− mice.

Disclosure

There is no financial or other relationship that might lead to a conflict of interest in regard to the data being reported.

These studies were supported by USAMRMC grant W81XWH-06-1-0147, NIDA grant DA13429, and NIDA Training Grant T32DA07237.

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  1. Jessica M. Breslow

    Present address: Department of Infectious Diseases, University of Kentucky Chandler Medical Center, Lexington, KY, 40536, USA

Authors and Affiliations

  1. Center for Substance Abuse Research, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA, 19140, USA

    Jessica M. Breslow, Joseph J. Meissler, Martin W. Adler & Toby K. Eisenstein

  2. Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA

    Jessica M. Breslow, Joseph J. Meissler & Toby K. Eisenstein

  3. Department of Surgery, Temple University School of Medicine, Philadelphia, PA, USA

    M. Alexandra Monroy & John M. Daly

  4. Biostatistics Consulting Center, Temple University School of Medicine, Philadelphia, PA, USA

    John Gaughan

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Correspondence to Toby K. Eisenstein.

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Breslow, J.M., Monroy, M.A., Daly, J.M. et al. Morphine, but Not Trauma, Sensitizes to Systemic Acinetobacter baumannii Infection. J Neuroimmune Pharmacol 6, 551–565 (2011). https://doi.org/10.1007/s11481-011-9303-6

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