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Published online before print March 23, 2004
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1203639

Received for publication December 17, 2003.
Revised January 28, 2004.
Accepted for publication February 16, 2004.

Article

Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation

Rajani S. Bhat , Madhu Bhaskaran , Anil Mongia , Naoko Hitosugi , and Pravin C. Singhal @

Department of Medicine, Long Island Jewish Medical Center and North Shore University Hospital, New Hyde Park, New York

@ To whom correspondence should be addressed. E-mail: singhal{at}lij.edu.


  Abstract

Occurrence of macrophage apoptosis has been implicated for the altered immune function found in an opiate milieu. In the present study, we evaluated the role of oxidative stress in morphine-induced macrophage apoptosis. Morphine promoted the apoptosis of macrophages. This effect of morphine was associated with the production of superoxide and nitric oxide (NO). Antioxidants provided protection against morphine-induced macrophage injury. In addition, diphenyleneiodonium chloride, an inhibitor of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, attenuated the proapoptotic effect of morphine. Antitransforming growth factor-{beta} (anti-TGF-{beta}) antibody and propranolol (an inhibitor of the phospholipase D pathway) inhibited morphine-induced superoxide generation as well as apoptosis. N`-Tetraacetic acid tetra (acetoxymethyl) ester, a calcium-chelating agent, inhibited morphine-induced apoptosis, whereas thapsigargin (a calcium agonist) stimulated macrophage apoptosis under basal as well as morphine-stimulated states. These studies suggest that morphine-induced macrophage apoptosis is mediated through downstream signaling involving TGF-{beta} and NO production. Moreover, there is NADPH oxidation activation involving phospholipase D and Ca2+, leading to the generation of superoxide. In in vivo studies, administration of N-acetyl cysteine and preinduction of heme oxygenase activity and epoetin {alpha} prevented morphine-induced peritoneal macrophage apoptosis, thus further confirming the role of oxidative stress in morphine-induced macrophage apoptosis.

Key Words: opiates • signal transduction • nitric oxide • reactive oxygen species




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