Opioid peptides appear to have an immunomodulatory activity. Using the chronically HIV-1-infected promonocyte clone U1, we investigated the effect of endogenous and synthetic opioid agonists on cytokine-induced HIV-1 expression. None of the endogenous or synthetic opioid agonists had an effect on constitutive HIV-1 expression. Opioid agonists such as methionine- enkephalin, dynorphin, and the κ receptor agonist, U50,488, dose-dependently suppressed (>40%) interleukin (IL)-6-induced upregulation of HIV-1 expression. Interestingly, opioid receptor antagonists (μ, δ, and κ types) also inhibited (>60%) IL-6-induced upregulation of HIV-1 expression. All opioid agonists and antagonists tested only modestly suppressed (<20%) tumor necrosis factor-α-induced upregulation of HIV-1 expression in U1 cell cultures. These data suggest that certain opioid peptides alter an IL-6- induced signal transduction pathway which triggers HIV-1 expression in the chronically infected promonocyte U1.