Naloxone, the opioid receptor antagonist, attenuates the effects of amphetamine in a wide range of behavioral paradigms. To determine the role of the opioid receptor subtypes in this phenomenon, subtype-selective opioid receptor antagonists were administered intracisternally to rats either as a 15-min [naloxone methiodide (NX.M) and naltrindole (NTI)] or a 24-hr [beta-funaltrexamine (beta-FNA) and norbinaltorphimine (nBNI)] pretreatment. Cumulative dose-response curves to amphetamine were constructed (saline, 0.1, 0.4, 1.6 and 6.4 mg/kg s.c.) with dosing every 30 min. Motor activity (gross and fine movements) was recorded for 20 min, commencing 10 min postinjection. Amphetamine dose-dependently increased both fine and gross movements. NX.M (30 micrograms) and NTI (10 and 30 micrograms) attenuated the gross activity response to amphetamine but did not alter the increase in fine movements. Lower doses of NX.M (2.0 and 10 micrograms) potentiated the fine activity response to amphetamine without any effect on the gross movements. Pretreatment with beta-FNA (1.25-20 micrograms), nBNI (10 and 30 micrograms) or NX.M (5.0 mg/kg s.c.) did not influence the response to amphetamine. However, beta-FNA and nBNI blocked the antinociceptive effects of morphine and spiradoline, respectively, indicating that these antagonists were tested under appropriate conditions for opioid receptor blockade. These data indicate a central site of action for the opioid antagonist-amphetamine interaction. The ability of NX.M (i.c.) and NTI, but not beta-FNA or nBNI, to influence the motor activity response to amphetamine implicates delta receptors in the opioid-mediated modulation of the behavioral stimulant effects of amphetamine.