Published results suggest that delta-opioid agonists can modulate the mu-mediated analgesia. In this work, the antinociceptive effects produced by the mu agonist [D-Ala2,NMe-Phe4,Gly-ol5]enkephalin or the mixed inhibitor of enkephalin-degrading enzymes RB 101 (N- [(R,S)-2-benzyl-3[(S)(2-amino-4-methyl- thio)butyldithio]-1-oxopropyl]-L-phenylalanine benzyl ester) were studied after administration of the systemically active and selective delta agonist Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu- Thr(O-tert-butyl). In the hot-plate test in mice, Tyr-D-Ser(O-tert-butyl)-Gly- Phe-Leu-Thr(O-tert-butyl) (i.v.) potentiated the antinociceptive responses elicited by [D-Ala2,NMe-Phe4,Gly-ol5]enkephalin (i.v.) or RB 101 (i.v.). These facilitatory effects were reversed not only by prior administration of the delta-selective antagonist naltrindole (0.5 mg/kg s.c.), but also unexpectedly by the selective cholecystokinin CCK-A antagonist MK-329 (20 micrograms/kg i.p.). In addition, the CCK analog [Boc- Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-Phe-NH2] (a mixed CCK-A/CCK-B agonist) increased the jump latency and this effect was blocked by MK-329 (20 micrograms/kg i.p.) and by naloxone, but not by the selective CCK-B antagonist L-365,260 (5 mg/kg i.p.). In contrast, the selective CCK-B agonist BC 264 (62 micrograms/kg i.v.) produced a hyperalgesic effect that was antagonized by L-365,260 (5 mg/kg i.p.). Taken together, these findings suggest that the potentiating effects of delta agonists on mu-mediated analgesia are due to an increase in the release of endogenous CCK interacting with CCK-A and CCK-B receptors and resulting in positive and negative regulation of the endogenous opioid system.(ABSTRACT TRUNCATED AT 250 WORDS)