MORPHINE MODULATES NF-KAPPA-B ACTIVATION IN MACROPHAGES

Chronic use of morphine affects the immune system and predisposes an i ndividual to opportunistic infections. Macrophages play an important r ole 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 treatmen t against infections such as HIV and AIDS related syndromes. Two of th e major cytokines secreted by activated macrophages are Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). Our studies show t hat morphine differentially modulates lipopolysaccharide (LPS) induced expression of IL-6 and TNF-alpha. Nanomolar concentrations of morphin e synergize with LPS and augment the secretion of both IL-6 and TNF-al pha. However, at micromolar concentrations morphine inhibits LPS induc ed synthesis of IL-6 and TNF-alpha. Expression of both these cytokine genes is dependent on the activation of a transcription factor, NF kap pa B. Interestingly, morphine treatment also modulated the activation of NF kappa B by LPS, Pretreatment with a low dose of morphine (nanomo lar) resulted in an increase in NF kappa B activation. In contrast pre treatment with a high dose of morphine (micromolar) led to a significa nt decrease in NF kappa B activation. Furthermore unlike the augmentat ion which was naloxone reversible, the inhibition of NF kappa B by mor phine was not reversed by naloxone, suggesting the involvement of a no nclassical opioid receptor. (C) 1998 Academic Press.