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Morphine enhances macrophage apoptosis
P C Singhal1, P Sharma, A A Kapasi
1Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11040, USA.
Abstract:
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.
Insights
Morphine triggers programmed cell death (apoptosis) in macrophages, impairing immune function. This mechanism involves nitric oxide production and key proteins like p53 and Bax, potentially explaining immune compromise in opiate addiction.
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Morphine is known to reduce macrophage numbers and phagocytic capacity.
- The precise mechanisms by which morphine affects macrophage function are not fully understood.
Purpose of the Study:
- To investigate the effect of morphine on macrophage apoptosis.
- To elucidate the molecular pathways involved in morphine-induced macrophage apoptosis.
Main Methods:
- In vivo and in vitro studies using rat and murine macrophages, as well as human monocytes.
- Assays for DNA fragmentation, apoptosis, nitric oxide (NO) production, and protein/mRNA expression (p53, Bax, iNOS).
- Use of NO synthase inhibitors (L-NAME, L-NMMA) and an ICE-1 inhibitor.
Main Results:
- Morphine induced DNA fragmentation and apoptosis in macrophages in a dose-dependent manner.
- Morphine increased nitric oxide (NO) production and inducible NO synthase (iNOS) expression.
- Apoptosis was attenuated by NO synthase inhibitors, suggesting NO mediation.
- Morphine promoted p53 and Bax protein synthesis, and apoptosis was inhibited by an ICE-1 inhibitor.
- These findings indicate a pathway involving p53, Bax, and ICE-1 in morphine-induced apoptosis.
Conclusions:
- Morphine induces macrophage apoptosis through a pathway involving nitric oxide generation.
- The induction phase involves p53 accumulation, and the effector phase involves Bax and ICE-1 activation.
- Morphine may compromise immune function in patients by promoting macrophage apoptosis.