The β-chemokine RANTES has recently been implicated in the neuropathogenesis of the human immunodefiency virus. Based upon previous studies of the effects of morphine on microglial cell production of cytokines and chemotaxis towards the activated complement component C5a, we tested the hypothesis that this opiate would alter the production of and migration towards RANTES by human microglia. Treatment of highly purified microglial cell cultures with morphine (10-8-10-6 M) potently inhibited RANTES production by lipopolysaccharide- and interleukin-1β-stimulated cells. Using a chemotaxis chamber to assess directed migration towards RANTES, treatment of microglial cells with morphine (10-10-10-6 M) was found to suppress chemotaxis. The inhibitory effects of morphine on RANTES production and on chemotaxis were blocked by naloxone and β-funaltrexamine, indicating that morphine mediated its suppressive effects via activation of microglial p-opioid receptors. Morphine's inhibitory effect on chemotaxis did not appear to be associated with an alteration in RANTES-induced [Ca2+](i) mobilization. While the clinical significance of these in-vitro findings is unknown, they suggest that μ-opioid receptor agonists could alter certain neurodegenerative and inflammatory processes within the brain.