After implanting stimulating electrodes in the prefrontal cortex (PFC) of adult male rats, the response to PFC stimulation was studied in widely scattered neurons of the midbrain. Subsequent testing was performed to determine if the firing rates of PFC-responsive neurons could also be altered by either a noxious stimulus (foot pinch) or the microiontophoretic administration of various neurotransmitter substances (methionine-enkephalin, ME; norepinephrine, NE; acetylcholine, ACh). Numerous mesencephalic neurons were identified which altered their spontaneous firing rates in response to PFC stimulation. Following PFC stimulation, most (71%) neurons decreased their firing rates. It was also noted that most (78%) PFC-responsive neurons were also responsive to noxious stimulation. Of these neurons, 65% altered their firing rates in a similar manner in response to both PFC and noxious stimuli. The remainder of the neurons which altered their firing rates in response to both PFC and noxious stimulation responded to the two types of stimuli in opposite manners. Of this latter type, it was found that when PFC and noxious stimuli were administered concurrently, PFC stimulation abolished the response to the noxious stimulus. It was also observed that the microiontophoretic administration of either ME or NE frequently (100% and 52% respectively) mimicked the response to PFC stimulation, thereby suggesting that these neurotransmitters may be involved in mediating the PFC influence upon neurons in the midbrain.