Possible presynaptic mechanisms involved in the naloxone-precipitated withdrawal jumping in morphine-dependent mice were studied. The withdrawal jumping precipitated by intrathecally (i.t.) administered naloxone (10 nmol) was abolished by the i.t. pretreatment with a substance P antagonist, [D-Pro4,D-Trp7,9,10]-substance P4-11 (10 nmol). The high KCl-evoked 45Ca2+ entry into synaptosomes and the release of immunoreactive substance P from slices were significantly enhanced by 10(-4) M naloxone in the morphine pelleted spinal cord, but not in the vehicle pelleted ones. These findings suggest that naloxone activates the depolarization-evoked Ca2+ entry into the nerve terminals, enhances the release of substance P from the spinal cord and the induction of withdrawal jumping in morphine-dependent mice then follows.