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Morphine Enhances Macrophage Apoptosis^{1 ,2}

Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11040. The Long Island Campus for Albert Einstein College of Medicine, Bronx, NY 10461.

Laboratory data indicate that morphine decreases the number of peritoneal and alveolar macrophages (M) and compromises their phagocytic capability for immune complexes and bacteria. We hypothesize that morphine decreases the number of, as well as compromises the phagocytic capability of, M by programming their death. We studied the effect of morphine on M apoptosis in vivo as well as in vitro. Peritoneal M harvested from morphine-treated rats showed DNA fragmentation. Morphine enhanced murine M (J 774.16) apoptosis in a dose-dependent manner. Human monocytes treated with morphine showed a classic ladder pattern in gel electrophoretic and end-labeling studies. Morphine promoted nitric oxide (NO) production both under basal and LPS-activated states. N^G-nitro-L-arginine methyl ester (L-NAME) and N^G-monomethyl-L-arginine monoacetate (L-NMMA), inhibitors of NO synthase, attenuated the morphine-induced generation of NO by M. Morphine also enhanced M mRNA expression of inducible NO synthase (iNOS). Since morphine-induced M apoptosis was inhibited by L-NAME and L-NMMA, it appears that morphine-induced M apoptosis may be mediated through the generation of NO. Morphine promoted the synthesis of Bax and p53 proteins by M. Moreover, IL-converting enzyme (ICE)-1 inhibitor attenuated morphine-induced M apoptosis. These studies suggest that morphine activates the induction phase of the apoptotic pathway through accumulation of p53. The effector phase of morphine-induced apoptosis appears to proceed through the accumulation of Bax and activation of ICE-1. The present study provides a basis for a hypothesis that morphine may be directly compromising immune function by promoting M apoptosis in patients with opiate addiction.

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