This study evaluated the antinociceptive effects produced when different combinations of supraspinal mu- and delta-opioid agonists were co-administered with spinal mu-, delta-, and kappa-opioid agonists. Using the Randall-Selitto paw-withdrawal test, in the rat, changes in nociceptive thresholds were measured following co-administration of sequentially increasing i.c.v. doses of either DAMGO or DPDPE with a low-antinociceptive dose of intrathecal DAMGO, DPDPE, or U50,488H. Antinociceptive synergy (i.e. a more than additive antinociceptive effect) was demonstrated with all of the combinations tested except for supraspinal DPDPE co-administered with spinal DAMGO. The results of this study provide support for the suggestion that supraspinal and spinal antinociceptive mechanisms share, in part, common neural circuits. Marked differences in the overall magnitude of the antinociceptive effects produced by the various combinations of opioid agonists were demonstrated through a secondary analysis of the data. When sequentially increasing i.c.v. doses of DAMGO were administered, significantly larger increases in nociceptive thresholds were observed with co-administration of intrathecal injections of low antinociceptive doses of either DAMGO or U50,488H compared to DPDPE. In contrast, when DPDPE was administered supraspinally, the largest increases in nociceptive thresholds were demonstrated with co-administration of DPDPE at the spinal site. The results of the secondary analysis provide support for the hypothesis that descending antinociceptive control systems activated by supraspinal administration of selective mu- and delta-opioid agonists interact, differently, with spinal mu-, delta-, and kappa-opioidergic mechanisms.