In the course of studies investigating the effects of opioids on the immune system, we observed that implantation in mice of a 75-mg slow-release morphine pellet results in colonization of the livers, spleens, and peritoneal cavities with enteric organisms including Proteus mirabilis, Esherichia coli and enterococci 24 to 48 hr later. Further, mice given morphine were sensitized to a sublethal dose of lipopolysaccharide (endotoxin). Simultaneous implantation of a naltrexone pellet with the morphine pellet blocked colonization and endotoxin-mediated lethality. Our results suggest that morphine potentiates sepsis, a hypothesis with far-reaching implications in medical management of post-operative pain. Sepsis is a major health problem in the United States, with a minimum of 100,000 cases per year. Many of these cases occur in hospitalized patients that are post surgical. To extend our observations, we propose to l) carry out more extensive pharmacologic studies of this phenomenon including kinetics of onset of translocation of bacteria from the gastrointestinal tract; effect of dose, route, and mode of opioid delivery on induction of sepsis; comparison of effects of morphine with other opioids; and investigation of the opioid receptor type which mediates this phenomenon; 2) examine the effect of morphine and other opioids on capacity of two oral pathogens, Salmonella typhimurium and Listeria monocytogenes, and their attenuated variants, to translocate out of the gastrointestinal tract; 3) more thoroughly characterize the septic state by investigating the cytokine response and induction of inducible nitric oxide synthase (iNOS) in mesenteric lymph nodes, spleen, liver, blood, and peritoneal cavity of morphine or other opioid-treated mice using a quantitative, competitive RT-PCR technique; and 4) examine the effect of morphine or other opioids on immune responses and cellular composition in the gut-associated lymphoid tissue, including expression of cytokines and iNOS. This project deals with a major health problem and promises to cast significant insight into sepsis and the potential role of opioid receptors in this pathological state. It relates to events associated with both the therapeutic and non-therapeutic use of morphine and other opioid drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011134-05
Application #
6362829
Study Section
Special Emphasis Panel (ZDA1-MXC-A (06))
Program Officer
Sharp, Charles
Project Start
1997-04-01
Project End
2003-02-28
Budget Start
2001-03-01
Budget End
2003-02-28
Support Year
5
Fiscal Year
2001
Total Cost
$242,600
Indirect Cost
Name
Temple University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Eisenstein, Toby K; Rahim, Rahil T; Feng, Pu et al. (2006) Effects of opioid tolerance and withdrawal on the immune system. J Neuroimmune Pharmacol 1:237-49
Rahim, Rahil T; Meissler Jr, Joseph J; Adler, Martin W et al. (2005) Splenic macrophages and B cells mediate immunosuppression following abrupt withdrawal from morphine. J Leukoc Biol 78:1185-91
Rahim, Rahil T; Adler, Martin W; Meissler Jr, Joseph J et al. (2002) Abrupt or precipitated withdrawal from morphine induces immunosuppression. J Neuroimmunol 127:88-95
Peng, X; Cebra, J J; Adler, M W et al. (2001) Morphine inhibits mucosal antibody responses and TGF-beta mRNA in gut-associated lymphoid tissue following oral cholera toxin in mice. J Immunol 167:3677-81
Eisenstein, T K (2001) Implications of Salmonella-induced nitric oxide (NO) for host defense and vaccines: NO, an antimicrobial, antitumor, immunosuppressive and immunoregulatory molecule. Microbes Infect 3:1223-31
McCarthy, L; Wetzel, M; Sliker, J K et al. (2001) Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 62:111-23
Rahim, R T; Meissler Jr, J J; Cowan, A et al. (2001) Administration of mu-, kappa- or delta2-receptor agonists via osmotic minipumps suppresses murine splenic antibody responses. Int Immunopharmacol 1:2001-9
Eisenstein, L K; MacFarland, A S; Peng, X et al. (2001) Effect of opioids on oral Salmonella infection and immune function. Adv Exp Med Biol 493:169-76
MacFarlane, A S; Peng, X; Meissler Jr, J J et al. (2000) Morphine increases susceptibility to oral Salmonella typhimurium infection. J Infect Dis 181:1350-8

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