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Morphine modulates NF kappa B activation in macrophages
1Department of Pharmacology, Veterans Administration Medical Center, Minneapolis, Minnesota 55417. royxx002@gold.tc.umn.edu
Abstract:
Chronic use of morphine affects the immune system and predisposes an individual to opportunistic infections. Macrophages play an important role in conferring a first line of defense against invading pathogens. Understanding the mechanisms by which morphine affects the functioning of macrophages would have significant therapeutic benefit in treatment against infections such as HIV and AIDS related syndromes. Two of the major cytokines secreted by activated macrophages are Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). Our studies show that morphine differentially modulates lipopolysaccharide (LPS) induced expression of IL-6 and TNF-alpha. Nanomolar concentrations of morphine synergize with LPS and augment the secretion of both IL-6 and TNF-alpha. However, at micromolar concentrations morphine inhibits LPS induced synthesis of IL-6 and TNF-alpha. Expression of both these cytokine genes is dependent on the activation of a transcription factor, NF kappa B. Interestingly, morphine treatment also modulated the activation of NF kappa B by LPS. Pretreatment with a low dose of morphine (nanomolar) resulted in an increase in NF kappa B activation. In contrast pretreatment with a high dose of morphine (micromolar) led to a significant decrease in NF kappa B activation. Furthermore unlike the augmentation which was naloxone reversible, the inhibition of NF kappa B by morphine was not reversed by naloxone, suggesting the involvement of a nonclassical opioid receptor.
Insights
Morphine affects macrophage immune responses, increasing Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) at low doses but inhibiting them at high doses. This modulation of NF kappa B activation suggests non-opioid receptor involvement.
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Chronic morphine use impairs immune function, increasing susceptibility to opportunistic infections.
- Macrophages are critical for innate immunity, and understanding morphine's effects on them is vital for treating infections like HIV/AIDS.
Purpose of the Study:
- To investigate how morphine differentially modulates the expression of key macrophage cytokines, IL-6 and TNF-alpha.
- To elucidate the role of the transcription factor NF kappa B in morphine's effects on macrophage cytokine production.
Main Methods:
- Macrophages were stimulated with lipopolysaccharide (LPS) in the presence of varying morphine concentrations (nanomolar and micromolar).
- Expression levels of IL-6 and TNF-alpha were measured.
- Activation of the transcription factor NF kappa B was assessed.
- The effect of naloxone on morphine's actions was evaluated.
Main Results:
- Nanomolar morphine synergized with LPS to augment IL-6 and TNF-alpha secretion.
- Micromolar morphine inhibited LPS-induced IL-6 and TNF-alpha synthesis.
- Low-dose morphine increased NF kappa B activation, while high-dose morphine decreased it.
- The inhibitory effect of high-dose morphine on NF kappa B was not reversed by naloxone.
Conclusions:
- Morphine exhibits dose-dependent modulation of LPS-induced cytokine production in macrophages.
- High-dose morphine's inhibition of NF kappa B activation appears to involve non-classical opioid receptors.
- These findings have implications for managing infections in patients on chronic morphine therapy.