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Morphine inhibits AP-1 activity and CD14 expression in leukocytes by a nitric oxide and opioid receptor-dependent mechanism

Published online by Cambridge University Press:  01 November 2007

I. D. Welters ,
A. Menzebach ,
Y. Goumon ,
T. W. Langefeld ,
H. Harbach ,
J. Mühling ,
P. Cadet  and
G. B. Stefano
I. D. Welters*
Affiliation:
University of Liverpool, Division of Clinical Sciences, Liverpool, UK Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany
A. Menzebach
Affiliation:
Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany Klinik und Poliklinik für Anaesthesie und Intensivtherapie der Universität Rostock, Germany
Y. Goumon
Affiliation:
INSERM 575, IFR 37, ‘Physiopathology of the Nervous System’, Strasbourg Cedex, France
T. W. Langefeld
Affiliation:
Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany
H. Harbach
Affiliation:
Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany
J. Mühling
Affiliation:
Universitätsklinikum Giessen und Marburg, Campus Giessen, Department of Anaesthesiology, Intensive Care and Pain Therapy, Giessen, Germany
P. Cadet
Affiliation:
State University of New York at Old Westbury, Neuroscience Research Institute, Old Westbury, NY, USA
G. B. Stefano
Affiliation:
State University of New York at Old Westbury, Neuroscience Research Institute, Old Westbury, NY, USA
*
Correspondence to: Ingeborg D. Welters, School of Clinical Science, University of Liverpool, The Duncan Building, Daulby Street, Liverpool L69 3GA, UK. E-mail: I.Welters@chiru.med.uni-giessen.de; Tel: +44 151 706 4003; Fax:+44 151 706 5884
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Summary

Background

Activator protein 1 is a transcription factor involved in the regulation of proinflammatory mediators. Activation of phagocytes by lipopolysaccharide depends on the expression of CD14 on the cell surface. In this study, we investigated the effects of morphine and nitric oxide on CD14 expression and activator protein 1 activation in human blood monocytes and neutrophils as well as the leukocyte cell line HL-60.

Methods

Whole blood was incubated with morphine, the nitric oxide donor S-nitroso-N-acetyl-penicillamine, naloxone or nitric oxide synthase inhibitors Nω-nitro-l-arginine and Nω-nitro-l-arginine-methylester and stimulated with lipopolysaccharide. Activator protein 1 nuclear content was determined by flow cytometry in human blood neutrophils and monocytes. CD14 expression on neutrophils was measured after incubation with fluorescein isothiocyanate-labelled antibodies. Electric mobility shift assay served for evaluation of activator protein 1 nuclear binding in HL-60 cells.

Results

Incubation of whole blood with morphine and subsequent stimulation with lipopolysaccharide decreased activator protein 1 nuclear content. Exposure to naloxone before morphine treatment abolished morphine-induced inhibition of activator protein 1 activity in human blood monocytes and neutrophils. Nitric oxide synthase inhibitors also reversed morphine’s effects. CD14 expression on neutrophils was reduced after morphine treatment. These effects were antagonized by nitric oxide synthase inhibitors and naloxone.

Conclusion

Morphine inhibits activator protein 1 activation by a μ opioid receptor pathway coupled to nitric oxide as second messenger. The decrease in CD14 expression caused by morphine may play a role in inhibition of activator protein 1 activation following lipopolysaccharide treatment of phagocytes.

Keywords

MORPHINENITRIC OXIDEOPIOID RECEPTORSTRANSCRIPTION FACTOR AP-1LIPOPOLYSCCHARIDEL-SELECTINLEUKOCYTES
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 24 , Issue 11 , November 2007 , pp. 958 - 965
Copyright
Copyright © European Society of Anaesthesiology 2007

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