The effect of pertussis toxin pretreatment on electrophysiological responses to selective delta- and mu-opioid receptor agonists was examined in rat hippocampal brain slices. The evoked population spike response in the CA1 region following activation of the Schaffer collateral and commissural afferents was increased following perfusion with the delta-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE), and with the mu-selective agonist [D-Ala2,NMe-Phe4,Gly(O)5ol]enkephalin (DAGO). Both effects were significantly reduced or abolished in brain slices obtained from animals that had been pretreated with pertussis toxin 2-3 days earlier. These findings suggest that the excitatory responses to opioid agonists in hippocampus are the result of interactions with receptors that are coupled via pertussis toxin sensitive GTP-binding proteins to their respective effector mechanisms.