Morphine Inhibits NF-κB Nuclear Binding in Human Neutrophils and Monocytes by a Nitric Oxide–dependent Mechanism

Welters, Ingeborg; Menzebach, A.; Goumon, Yannick; Cadet, Patrick; Menges, T.; Hughes, Thomas K.; Hempelmann, G.; Stefano, George B.

doi:10.1097/00000542-200006000-00027

Cited by 90 publications

(75 citation statements)

References 38 publications

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“…A variety of different stimuli, including cytokines, oxidative stress, apoptosis-inducing stimuli and drugs used in anticancer treatment, are able to activate NF-κB (20,21). Previous studies have demonstrated that morphine directly inhibits NF-κB function via the release of nitric oxide (NO) (22,23). Similarly, in the present study, fentanyl inhibited NF-κB expression in human gastric carcinoma cells.…”

Section: Discussionsupporting

confidence: 64%

Fentanyl inhibits the progression of human gastric carcinoma MGC-803 cells by modulating NF-κB-dependent gene expression in vivo

Guan

et al. 2016

Oncology Letters

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Abstract.Fentanyl is widely used to treat acute and chronic pain. Previous in vitro studies by the present authors demonstrated that fentanyl inhibits the progression of the MGC-803 human gastric carcinoma cell line by affecting apoptosis-related genes, including nuclear factor-kappa B (NF-κB) and phosphatase and tensin homolog. In the present study, the effects of fentanyl on NF-κB-dependent gene expression were investigated in vivo. Nude mice were inoculated with an MGC-803 cell suspension, and mice that developed subcutaneous tumors measuring >1.0x1.0 cm were selected for study. Mice were administered intraperitoneal injections of fentanyl (0.05 mg/kg, group F1; 0.1 mg/kg, group F2; 0.2 mg/kg, group F3; and 0.4 mg/kg, group F4) for 14 consecutive days. Non-fentanyl-treated mice (group C) and normal saline-treated mice (group N) served as the control groups. Tumor growth was monitored by calculating the time-shift of the growth curve. Morphological changes were also observed using microscopy. The expression of NF-κB, B-cell lymphoma-2 (Bcl-2), B-cell associated X protein (Bax), vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase-9 (MMP-9) in the subcutaneous tumor tissue was also analyzed by reverse transcription-polymerase chain reaction and western blot analysis, and confirmed using immunohistochemistry. The relative tumor volumes of groups F1, F2, F3 and F4 were significantly reduced compared with groups C and N. Furthermore, subcutaneous tumor cells exhibited nuclear swelling, chromatin condensation, reduced chromatin and nuclear fragmentation in the F1, F2, F3 and F4 groups. The number of NF-κB + , Bcl-2 + , VEGF-A + and MMP-9 + subcutaneous tumor cells was reduced, whereas the number of Bax + cells was increased in the F1, F2, F3 and F4 groups. Additionally, in these groups, tumor expression of NF-κB, Bcl-2, VEGF-A and MMP-9 transcripts and proteins was downregulated, while Bax messenger RNA and protein expression levels were upregulated. The results revealed that fentanyl inhibits the growth of subcutaneous human gastric carcinoma tumors in mice. Therefore, it could be hypothesized that this antineoplastic activity may result from the inhibition of NF-κB activation, suppression of downstream VEGF-A and MMP-9 expression, and normalization of the pro-apoptotic Bax/Bcl-2 ratio. IntroductionAt present, gastric carcinoma is the fourth most common human neoplasm and the second most common cause of carcinoma-associated mortality worldwide, accounting for 986,600 novel cases and 738,000 mortalities annually (1). The incidence and mortality rates of this disease are higher in China than in other Asian countries (1). The molecular pathogenesis of gastric carcinoma has been investigated extensively with the aim of developing more effective therapeutic strategies for this type of tumor (2). Thus, there is an urgent requirement for the development of strategies to prevent and treat this disease.Fentanyl, which is the most frequently used analgesic, exhibits minimal cardiovascular effects and d...

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Section: Discussionsupporting

confidence: 64%

Fentanyl inhibits the progression of human gastric carcinoma MGC-803 cells by modulating NF-κB-dependent gene expression in vivo

Guan

et al. 2016

Oncology Letters

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“…88 It has been demonstrated that high concentrations of NO can inhibit NF-kB activation in macrophage cell lines 91 and human macrophages, 120 monocytes 121 and neutrophils. 121,122 NO may inhibit NF-kB DNA binding through S-nitrosation of the p50 subunit of the transcription factor, as has been demon-strated in isolated NF-kB protein 123 and in human respiratory cells and murine macrophages. 124 Alternatively, transcriptional induction and stabilisation of the inhibitory molecule IkB, that keeps NF-kB sequestered in the cytoplasm, may account for the inhibition of NF-kB activity.…”

Section: Proapoptotic Mechanismsmentioning

confidence: 93%

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

et al. 2003

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Apoptosis of inflammatory cells is a critical event in the resolution of inflammation, as failure to undergo this form of cell death leads to increased tissue damage and exacerbation of the inflammatory response. Many factors are able to influence the rate of apoptosis in neutrophils, eosinophils, monocytes and macrophages. Among these is the signalling molecule nitric oxide (NO), which possesses both anti-and proapoptotic properties, depending on the concentration and flux of NO, and also the source from which NO is derived. This review summarises the differential effects of NO on inflammatory cell apoptosis and outlines potential mechanisms that have been proposed to explain such actions.

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“…Thus, a reduction in the production of these cytokines and mediators could affect the generation of a fever response. Interestingly, chronic opiate exposure has been shown to inhibit nuclear factor kappa B (NFκB) (e.g., Wang et al, 2005;Welters et al, 2000), a transcription factor involved in the downstream effects of IL-1β (Nadjar et al, 2003) and the production of PGE 2 (Pistritto et al, 1999). There is some precedent for effects downstream of IL-1 affecting fever responding following developmental insults.…”

Section: Discussionmentioning

confidence: 99%

Prenatal opiate exposure attenuates LPS-induced fever in adult rats: Role of interleukin-1β

Hamilton¹,

Franklin²,

Roy³

et al. 2007

Brain Research

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Much is known about the immunomodulatory effects of opiate exposure and withdrawal in adult rats. However, little research has delved into understanding the immunological consequences of prenatal opiate exposure and postnatal withdrawal. The purpose of the current study was to measure changes in responding to immune stimulation in adult rats following prenatal opiate exposure. Further, we sought to characterize the role of interleukin (IL)-1β in these changes. Following prenatal exposure to the long-acting opiate l-alpha-acetylmethadol (LAAM), adult male and female rats were assessed for their fever response to lipopolysaccharide (LPS). Blood and tissue samples were collected to measure circulating IL-1β and IL-1β protein in the hypothalamus and spleen. Prenatal LAAM exposure resulted in a blunted fever response to LPS injection without any changes in basal body temperature or in response to saline injection. Circulating IL-1β was not affected by prenatal LAAM exposure, nor was IL-1β protein in the spleen. Interestingly, mature IL-1β protein was elevated in the hypothalamus of prenatally LAAM-treated rats. These results indicate that prenatal opiate exposure blunts the fever response of adult offspring. Direct action of IL-1β is likely not the cause of the dysfunction reported here. However, alterations in signaling mechanisms downstream from IL-1β may play a role in the altered fever response in adult rats treated prenatally with opiates.

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Morphine Inhibits NF-κB Nuclear Binding in Human Neutrophils and Monocytes by a Nitric Oxide–dependent Mechanism

Abstract: Morphine causes immunosuppression, at least in part, via the NO-stimulated depression of NF-kappaB nuclear binding.

Cited by 90 publications

References 38 publications

Fentanyl inhibits the progression of human gastric carcinoma MGC-803 cells by modulating NF-κB-dependent gene expression in vivo

Fentanyl inhibits the progression of human gastric carcinoma MGC-803 cells by modulating NF-κB-dependent gene expression in vivo

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

Prenatal opiate exposure attenuates LPS-induced fever in adult rats: Role of interleukin-1β

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