This study was performed to assess the interactions that occur between delta- and mu opioid receptors by studying effects of the systemically active nonpeptide delta agonist BW373U86 and the mu agonist fentanyl in mice. Concentrations of the compounds were varied, and analgesic responses were determined by 55 degrees C hot-plate assays. BW373U86 produced hot-plate antinociceptive activity along with convulsive side effects. These effects could be antagonized by the selective delta antagonist naltrindole. Fentanyl produced hot-plate antinociceptive activity with Straub tail and hyperactivity as side effects. When BW373U86 and fentanyl were coadministered, BW373U86 convulsive activity was attenuated by fentanyl in a dose-dependent manner and the fentanyl-induced Straub tail effect was antagonized by BW373U86, also in a dose-dependent manner. Hot-plate analgesic activity was additive between the two compounds. The delta antagonist naltrindole partially antagonized the ability of BW373U86 to block the fentanyl-induced Straub tail effect. The mu antagonist beta-funaltrexamine antagonized the fentanyl-induced blockade of the convulsive effects of BW373U86. These data suggest that complex inhibitory interactions take place between mu and delta receptors in mice. Future studies are clearly needed to study the neuromodulatory effects of mu and delta receptors. The widespread use of mu agonists in the clinic indicates that a large number of patients exist who could greatly benefit from the conjunctive use of delta pharmaceuticals.