title: Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation.
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 Ca(2+), 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.
authors.affiliation: Long Island Jewish Medical Center, 410 Lakeville Road, Suite 207, New Hyde Park, NY 11040, USA.
authors.forename: Rajani S
authors.initials: RS
authors.lastname: Bhat
authors.forename: Madhu
authors.initials: M
authors.lastname: Bhaskaran
authors.forename: Anil
authors.initials: A
authors.lastname: Mongia
authors.forename: Naoko
authors.initials: N
authors.lastname: Hitosugi
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009294:Narcotics / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D009861:Onium Compounds / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D010739:Phospholipase D / Q000037:antagonists & inhibitors; D011433:Propranolol / Q000494:pharmacology; D011994:Recombinant Proteins; D013481:Superoxides / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D014151:Anti-Anxiety Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; D009294:Narcotics; D009861:Onium Compounds; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D013481:Superoxides; D004921:Erythropoietin; D009569:Nitric Oxide; D000068817:Epoetin Alfa; D019284:Thapsigargin; C007517:diphenyleneiodonium; D009020:Morphine; D011433:Propranolol; D006419:Heme Oxygenase (Decyclizing); D019255:NADPH Oxidases; D010739:Phospholipase D; D002118:Calcium