Behavioral studies support the importance of the medial prefrontal cortex in the circuitry of drug-reinforced behavior, yet the neurophysiological correlates of this phenomenon remain unclear. The present study evaluates opioid neuropharmacology in the medial prefrontal cortex of the anesthetized rat. The effects of both systemic and local application of mu agonists on individual neurons in the medial prefrontal cortex were examined. Systemic morphine was found to inhibit (63%), excite (4%) or have no effect on (33%) spontaneous firing. The inhibitory response was reversed by systemic naloxone in 77% of the cases. Electrophoretic application of a mu-selective agonist, [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin, had mixed effects on cell activity. While most cells exhibited no change in firing rate (53%), 38% showed inhibition of spontaneous activity. The [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin-evoked inhibitory responses were antagonized by electrophoresis of naloxone (86%). These results indicate that the medial prefrontal cortex might directly mediate some portion of the overall response to opiates in reinforcement or self-administration paradigms. The naloxone-reversible inhibition of firing seen following both systemic and local application of predominantly mu-selective agonists argues for a direct involvement of medial prefrontal cortical neurons in opiate-induced effects. However, the smaller percentage of cells inhibited by local versus systemic application of mu agonists also supports an influence of other brain circuitry in this response.