To investigate the effect of opiates on human immunodeficiency virus type 1 (HIV-1)-related neuronal apoptosis, primary human fetal neuronal/glial cell cultures were exposed to gp120(IIIB) in the absence and the presence of morphine. Although morphine by itself had little effect on neuronal survival, the combination of morphine (>/=10(-7) mol/L) and gp120(IIIB) (1 nmol/L) significantly increased neuronal apoptosis. The mechanism whereby morphine potentiates gp120(IIIB)-induced neuronal apoptosis appears to involve activation of the p38 mitogen-activated protein kinase intracellular signaling pathway and microglial cells dispersed within the neuronal/glial cell cultures. These results provide additional insight into the molecular basis whereby opiate abuse could promote HIV-1-associated dementia.