Endogenous morphine levels are increased in sepsis: a partial implication of neutrophils

Mammalian cells synthesize morphine and the respective biosynthetic pathway has been elucidated. Human neutrophils release this alkaloid into the media after exposure to morphine precursors. However, the exact role of endogenous morphine in inflammatory processes remains unclear. We postulate that m...

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Bibliographic Details
Published in:PloS one 2010-01, Vol.5 (1), p.e8791-e8791
Main Authors: Glattard, Elise, Welters, Ingeborg D, Lavaux, Thomas, Muller, Arnaud H, Laux, Alexis, Zhang, Dan, Schmidt, Alexander R, Delalande, François, Laventie, Benoît-Joseph, Dirrig-Grosch, Sylvie, Colin, Didier A, Van Dorsselaer, Alain, Aunis, Dominique, Metz-Boutigue, Marie-Hélène, Schneider, Francis, Goumon, Yannick
Format: Article
Language:English
Subjects:
Abdominal surgery
Analgesics
Analysis
Anesthesia
Biochemistry
Blotting, Western
Calcium
Cell Biology
Cholecystectomy
Cognitive science
Confocal
Confocal microscopy
Critical Care and Emergency Medicine/Sepsis and Multiple Organ Failure
Cytokines
Cytometry
Disseminated infection
Electrophoresis, Polyacrylamide Gel
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Granulocytes
Health aspects
Hostages
Humans
Immunohistochemistry
Infection
Infections
Inflammation
Inflammatory response
Inhibition
Interleukin
Interleukin 8
Interleukin-8 - pharmacology
Interleukins
Lactoferrin
Leukocytes (neutrophilic)
Leukocytes (polymorphonuclear)
Lipopolysaccharides
Lipopolysaccharides - pharmacology
Lymphocyte Activation
Lymphocyte Activation - drug effects
Mammalian cells
Mammals
Mass spectrometry
Mass spectroscopy
Medical research
Microscopy
Microscopy, Confocal
Mitogens
Morphine
Morphine - blood
Naloxone
Narcotics
Neurosciences
Neutrophils
Neutrophils - drug effects
Neutrophils - physiology
Opioid receptors
Pain
Patients
Receptors, Opioid, mu
Receptors, Opioid, mu - metabolism
Rodents
Sepsis
Sepsis - blood
Septic shock
Spectroscopy
Systemic inflammatory response syndrome
Tandem Mass Spectrometry
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Summary:Mammalian cells synthesize morphine and the respective biosynthetic pathway has been elucidated. Human neutrophils release this alkaloid into the media after exposure to morphine precursors. However, the exact role of endogenous morphine in inflammatory processes remains unclear. We postulate that morphine is released during infection and can be determined in the serum of patients with severe infection such as sepsis. The presence and subcellular immunolocalization of endogenous morphine was investigated by ELISA, mass spectrometry analysis and laser confocal microscopy. Neutrophils were activated with Interleukin-8 (IL-8) or lipopolysaccharide (LPS). Morphine secretion was determined by a morphine-specific ELISA. mu opioid receptor expression was assessed with flow cytometry. Serum morphine concentrations of septic patients were determined with a morphine-specific ELISA and morphine identity was confirmed in human neutrophils and serum of septic patients by mass spectrometry analysis. The effects of the concentration of morphine found in serum of septic patients on LPS-induced release of IL-8 by human neutrophils were tested. We confirmed the presence of morphine in human neutrophil extracts and showed its colocalisation with lactoferrin within the secondary granules of neutrophils. Morphine secretion was quantified in the supernatant of activated human polymorphonuclear neutrophils in the presence and absence of Ca(2+). LPS and IL-8 were able to induce a significant release of morphine only in presence of Ca(2+). LPS treatment increased mu opioid receptor expression on neutrophils. Low concentration of morphine (8 nM) significantly inhibited the release of IL-8 from neutrophils when coincubated with LPS. This effect was reversed by naloxone. Patients with sepsis, severe sepsis and septic shock had significant higher circulating morphine levels compared to patients with systemic inflammatory response syndrome and healthy controls. Mass spectrometry analysis showed that endogenous morphine from serum of patient with sepsis was identical to poppy-derived morphine. Our results indicate that morphine concentrations are increased significantly in the serum of patients with systemic infection and that morphine is, at least in part, secreted from neutrophils during sepsis. Morphine concentrations equivalent to those found in the serum of septic patients significantly inhibited LPS-induced IL-8 secretion in neutrophils.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0008791