RE 101 (N-[(R, S)-2-benzyl-3-[(S)-2-amino-4-methylthiobutyldithio]-1-oxopropyl]-L-phenylalaninebenzyl ester), a systemically active inhibitor of enkephalin catabolism, has been shown to elicit antidepressant-like effects in mice, both in the forced-swimming and in the conditioned suppression of the mobility tests. The same type of response has been also observed following administration of the cholecystokinin CCKB receptor antagonist L-365,260 ((3R)-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-3-methylphenylurea). Interestingly, the delta-opioid receptor antagonist naltrindole (17-cyclopropylmethyl-6,7-dehydro-4,5 alpha-epoxy-3,14-dihydroxy-6,7,2'-3'-indolomorphinan) blocks the effect of both RE 101 and L-365,260 in the conditioned suppression of the motility test. In this work we have investigated the involvement of the opioid system in the antidepressant response to the CCKB receptor antagonist L-365,260 in the forced-swimming test in mice. The effect of L-365,260 was decreased by the delta-opioid receptor antagonist naltrindole. Furthermore, the CCKB receptor agonist, BC 264 (Boc-Tyr(OSO3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2), blocked the antidepressant-like effect of RE 101 while CCK-8 (H-Asp-Tyr(OSO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2) enhanced the effect of this drug, probably through stimulation of central CCKA receptors, since the CCKA receptor antagonist devazepide ((3S)-(-)-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide) abolished the CCK-8-induced potentiation of the RE 101 effect. In addition, RE 101 enhanced the effect of L-365,260. Such an effect was blocked by the delta-opioid receptor antagonist naltrindole. These data further support the involvement of opioid receptors in the antidepressant-type effect induced by CCKB receptor blockers and support the hypothesis of a regulatory role of CCK in the activity of the endogenous opioid system. As in other experimental paradigms, CCKA and CCKB receptor stimulation appears to have opposite effects in modulating opioidergic activity.