Peripheral administration of naloxone is known to produce a conditioned place aversion and to block cocaine-induced conditioned place preference. The ventral pallidum receives a dense enkephalinergic projection from the nucleus accumbens and is implicated as a locus mediating the rewarding and reinforcing effects of psychostimulant and opiate drugs. We sought to provide evidence for the involvement of pallidal opioid receptors in modulating affective state using the place-conditioning paradigm. Microinjection of naloxone (0.01-10 microg) into the ventral pallidum once a day for 3 days dose-dependently produced a conditioned place aversion when tested in the drug-free state 24 h after the last naloxone injection. This effect was reproduced using the mu-opioid receptor selective agonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP, 1 microg). Locomotor activity was reduced following injection of the highest dose of naloxone (10 microg) but elevated following CTOP (1 microg). Daily injection of cocaine (10 mg/kg) for 3 days produced a conditioned place preference 24 h later. This effect of cocaine was attenuated by concomitant intra-ventral pallidal injection of naloxone at a dose (0.01 microg) that had no significant aversive property when injected alone. In contrast, the locomotor activation induced by peripheral cocaine injection was unaffected by naloxone injection into the ventral pallidum. The data implicate endogenous opioid peptide systems within the ventral pallidum as regulators of hedonic status.