Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation.
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.
Bhat
Rajani S
RS
Long Island Jewish Medical Center, 410 Lakeville Road, Suite 207, New Hyde Park, NY 11040, USA.
Bhaskaran
Madhu
M
Mongia
Anil
A
Hitosugi
Naoko
N
Singhal
Pravin C
PC
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
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