The acute effects of opioid drugs are generally hypothesized to be mediated by multiple receptors, for which three types of binding sites have been established. In order to evaluate the selective participation of each type of opioid receptor in opiate withdrawal, the opiate withdrawal syndrome, precipitated by the intraventricular acute administration of mu-, delta- and kappa-selective opioid antagonists was investigated. After implantation of the cannula into the lateral ventricle, rats were made physically dependent by subcutaneous insertion of two 75-mg pellets of morphine (base). D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) (5-5000 ng), a mu-selective opioid antagonist, naltrindole (62-2000 ng), a delta-selective antagonist or nor-binaltorphimine (nor-BNI) (600-20,000 ng), a kappa-selective antagonist, were administered 72 hr after implantation of the pellets. All three drugs elicited some signs of morphine withdrawal but they differed in both their potency and their efficacy. The most efficacious and the most potent was CTAP, eliciting 8 of the 14 withdrawal signs at doses of 5-5000 ng. Nor-BNI was less efficacious and less potent, eliciting a significant increase in 5 of the 14 withdrawal signs in a dose range of 600-20,000 ng. Naltrindole was the least potent and least efficacious of the three drugs, eliciting a significant increase of only 2 withdrawal signs after intraventricular administration of 2000 ng. In a second experiment, the withdrawal syndrome was precipitated by the combined administration of CTAP+naltrindole or CTAP+nor-BNI. The severity of withdrawal, obtained with these two combinations, was similar to that observed with CTAP alone. These results support the importance of the mu receptor in the expression of central opiate dependence and suggest a minor role for delta and kappa receptors.