There is evidence that suggests that endogenous opioids can modulate brain dopamine systems and the behavioral effects of drugs that are mediated by those systems. The aim of this study was to examine the role of endogenous opioids in the discriminative stimulus effects of d-amphetamine and cocaine, through the use of receptor antagonists. Two separate groups of rats were trained to discriminate 1.0mg/kg d-amphetamine or 10mg/kg cocaine from saline, in a discrete-trial, avoidance/escape procedure. Dose-response curves for d-amphetamine (0.1-1.0mg/kg, i.p.) and cocaine (1.0-10mg/kg, i.p.) were generated (using a cumulative dosing regimen) in the absence and presence of: the nonselective opioid antagonist naloxone (1.0 and 5.0mg/kg, s.c.), the delta-opioid antagonist naltrindole (10 and 30µg, i.c.; 1mg/kg, i.p.), the mu-opioid antagonist beta-funaltrexamine (30µg, i.c.), and the kappa-opioid antagonist nor-binaltorphimine (norBNI) (10 and 30µg, i.c.). The ED(50)s for d-amphetamine and cocaine alone were 0.2mg/kg (0.16-0.33) and 3.9mg/kg (2.7-5.1), respectively. None of the opioid antagonists produced significant changes in the ED(50) for d-amphetamine. NorBNI significantly increased the potency of cocaine to produce a discriminative stimulus (ED(50) 2.2mg/kg; 1.7-2.6), whereas the other antagonists were without effect. Endogenous mu- and delta-opioids do not appear to be involved in mediating the discriminative stimulus effects of d-amphetamine or cocaine; however, the endogenous kappa-opioids might have a negative modulatory effect on cocaine's interoceptive cue. The lack of effect of norBNI on the discriminative stimulus effects of d-amphetamine suggests novel differences in the mechanisms of action of d-amphetamine and cocaine.