Small doses of endotoxin evoked a dramatic biphasic response of opioid peptide secretion into blood in sheep. The first phase began within minutes and coincided with a brief hypertensive response to endotoxin well before the appearance of fever or hypotension. The ratio of beta-endorphin to beta-lipotropin fell abruptly at the onset of the second phase of release, suggesting early depletion of a pool rich in beta-endorphin and subsequent emergence of a pool rich in unprocessed precursor. The concentration of cerebrospinal fluid opioids increased tenfold during the second phase. Naloxone administration augmented endotoxin-induced opioid secretion in both early and late phases, suggesting a short-loop feedback regulation of stress-induced endorphin secretion.