Laboratory data indicate that
morphine decreases the numbier of peritoneal and alveolar macrophages (Mphi) 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, Mphi by programming their death. We studied the effect of
morphine on Mphi apoptosis in vivo as well as in vitro. Peritoneal Mphi harvested from
morphine-treated rats showed DNA fragmentation.
Morphine enhanced murine Mphi (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 Mphi.
Morphine also enhanced Mphi
mRNA expression of inducible
NO synthase (iNOS). Since
morphine-induced Mphi apoptosis was inhibited by
L-NAME and
L-NMMA, it appears that
morphine-induced Mphi apoptosis may be mediated through the generation of NO.
Morphine promoted the synthesis of Bax and p53
proteins by Mphi. Moreover, IL-converting
enzyme (ICE)-1 inhibitor attenuated
morphine-induced Mphi 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 Mphi apoptosis in patients with
opiate addiction.