Morphine Modulates NFκB Activation in Macrophages

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-α). Our studies show that morphine differentially modulates lipopolysaccharide (LPS) induced expression of IL-6 and TNF-α. Nanomolar concentrations of morphine synergize with LPS and augment the secretion of both IL-6 and TNF-α. However, at micromolar concentrations morphine inhibits LPS induced synthesis of IL-6 and TNF-α. Expression of both these cytokine genes is dependent on the activation of a transcription factor, NFκB. Interestingly, morphine treatment also modulated the activation of NFκB by LPS. Pretreatment with a low dose of morphine (nanomolar) resulted in an increase in NFκB activation. In contrast pretreatment with a high dose of morphine (micromolar) led to a significant decrease in NFκB activation. Furthermore unlike the augmentation which was naloxone reversible, the inhibition of NFκB by morphine was not reversed by naloxone, suggesting the involvement of a nonclassical opioid receptor.