THE ANTINOCICEPTIVE ACTIVITY OF KAPPA-OPIOID BUT NOT DELTA-OPIOID RECEPTOR AGONISTS IS MAINTAINED IN MORPHINE-TOLERANT NEUROPATHIC RATS

The antinociceptive effect of the preferential mu-opioid receptor agon ist morphine (1 mg/kg i.v.), the delta-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 K-opi oid receptor agonist U-69,593 l-N-[7-(1-pyrrolidinyl)cyclohexil]benzen eacetamide methanesulfonate) (0.25, 0.5 and 0.75 mg/kg i.v.) was evalu ated in mononeuropathic (chronic constriction of the common sciatic ne rve) 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 morph ine-pretreated rats, the antinociceptive effect of morphine on the voc alization threshold to paw pressure was greatly reduced, as compared t o the saline-pretreated group. The antinociceptive effect of DTLET and BUBUC had also disappeared in the morphine-pretreated rats. By contra st, the potent antinociceptive effect of U-69,593 was not affected by the morphine pretreatment. Furthermore, the effect of U-69,593 was rev ersed by the specific kappa-opioid receptor antagonist nor-binaltorphi mine (1 and 2 mg/kg i.v.). These results suggest that in mononeuropath ic rats, morphine pretreatment results in cross-tolerance to delta- bu t not to kappa-opioid receptor agonists.