Abstract The antinociceptive effect of the preferential μ-opioid receptor agonist morphine (1 mg/kg i.v.), the δ-opioid receptor agonists, DTLET ([ d-Thr 2,Leu 5]enkephalin-Thr) (3 and 6 mg/kg i.v.) and BUBUC ([ d-Cys(StBu) 2,Leu 5]enkephalin-Thr(OtBu) (3 mg/kg i.v.), and the κ-opioid receptor agonist U-69,593 (trans-3,4-dichloro- N-methyl- N-[7-(1-pyrrolidinyl)cyclohexilbenzeneacetamide methanesulfonate) (0.25, 0.5 and 0.75 mg/kg i.v.) was evaluated in mononeuropathic (chronic constriction of the common sciatic nerve) rats. The rats were pretreated s.c. with 10 mg/kg of morphine, or saline, twice daily from day 12 to day 16 after the surgery. In morphine-pretreated rats, the antinociceptive effect of morphine on the vocalization threshold to paw pressure was greatly reduced, as compared to the saline-pretreated group. The antinociceptive effect of DTLET and BUBUC had also disappeared in the morphine-pretreated rats. By contrast, the potent antinociceptive effect of U-69,593 was not affected by the morphine pretreatment. Furthermore, the effect of U-69,593 was reversed by the specific κ-opioid receptor antagonist nor-binaltorphimine (1 and 2 mg/kg i.v.). These results suggest that in mononeuropathic rats, morphine pretreatment results in cross-tolerance to δ- but not to κ-opioid receptor agonists.