A single dose precipitated withdrawal paradigm was used to test the hypothesis that nonspecific morphine (M) effects mediate withdrawal. Naloxone (Nal) was given i.p. to Swiss-Texas outbred mice 15 min after M (50 mg/kg), and typical withdrawal reactions occurred rapidly. The Nal dose-response curve, based on tallies of stereotypical jumping, was Gaussian and peaked at 125 mg/kg. As a further test of the hypothesis, another group of mice received the Nal 2 min before M, and these also underwent withdrawal; this dose-response curve was similar but was shifted to the right, with a peak effective dose at 175 mg/kg. Control tests showed that both drugs had to be present in an appropriate balance of doses for withdrawal signs to occur. These results are consistent with a model which predicts that withdrawal can occur whenever M concentration is above a certain threshold and when stereospecific opiate receptors are inactivated, either by tolerance development or by Nal blockade.