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.