title: Morphine synergizes with lipopolysaccharide in a chronic endotoxemia model.
abstract: Emergent or elective surgical procedures may be complicated by sepsis, resulting in critical illness that can lead to organ failure and death. The opioid drug, morphine is widely used to alleviate pain in post-surgical patients; however, it is well documented that chronic treatment of mice with morphine affects the proliferation, differentiation and function of immune cells. Thus, morphine might be expected to exacerbate the effects of sepsis, which also compromises the immune system. To test this notion, we investigated the effect on several immune functions of a clinical dose of morphine (4 mg/kg) superimposed upon a lipopolysaccharide (LPS)-induced infection model. Our results show that this relatively low dose of morphine, though generally having no effects on immune parameters by itself, significantly augmented LPS responses. A clinical dose of morphine (4 mg/kg body weight) superimposed upon an animal model of sepsis resulted in a significant increase in mortality at 48 h. In the absence of the drug, most septic animals died after 96 h. Phenotypic responses such as, decreased thymic cellularity, compromised mitogenic response and inhibition of IL-2 synthesis that are evident at 48-72 h after LPS injection appear as early as 24 h in animals that receive morphine in addition to LPS. In addition, our results show that in T cells there is a shift from TH1 type cytokine elaboration to a TH2 type cytokine elaboration in animals that receive both LPS and morphine.
authors.affiliation: Department of Pharmacology, Veterans Administration Medical Center and University of Minnesota, Minneapolis 55417, USA. royxx002@gold.tc.umn.edu
authors.forename: S
authors.initials: S
authors.lastname: Roy
authors.forename: R G
authors.initials: RG
authors.lastname: Charboneau
authors.forename: R A
authors.initials: RA
authors.lastname: Barke
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004357:Drug Synergism; D019446:Endotoxemia / Q000139:chemically induced* / Q000401:mortality; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000276:immunology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000032:analysis / Q000276:immunology; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000032:analysis / Q000276:immunology; D007376:Interleukin-2 / Q000032:analysis / Q000276:immunology; D015847:Interleukin-4 / Q000032:analysis / Q000276:immunology; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009929:Organ Size; D010902:Pituitary Gland / Q000737:chemistry / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology
chemical_list: D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009294:Narcotics; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D009020:Morphine; D007371:Interferon-gamma