Abstract

The morphine-like discriminative stimulus effects of opioid peptides with selectivity for the mu- or delta-opioid receptors were examined in rats trained to discriminate 3.0 mg/kg of morphine (s.c.) from saline in a two-choice discrete-trial avoidance paradigm. The mu-selective peptides D-Ala2-NMePhe4-Gly5(ol)enkephalin, FK 33,824 and morphiceptin, the delta-selective peptides D-Ala2-D-Leu5enkephalin and metkephamid and beta-endorphin (mu- and delta-selective) produced morphine-like stimulus effects after administration into the lateral ventricle. Generalization with the morphine cue was dose-dependent and occurred over a wide range of doses (0.01-30 micrograms), depending upon peptide. On a molar basis, the order of relative potency of the peptides as morphine-like discriminative stimuli was: D-Ala2-NMePhe4-Gly5(ol)enkephalin = FK 33,824 greater than beta-endorphin greater than D-Ala2-D-Leu5enkephalin = metkephamid greater than morphiceptin. The discriminative effects of D-Ala2-NMePhe4-Gly5(ol)enkephalin, D-Ala2-D-Leu5enkephalin and beta-endorphin were antagonized by low doses of s.c. naltrexone (0.01-1.0 mg/kg). Furthermore, the stimulus effects of s.c. morphine were antagonized by 24-hr pretreatment of rats with the irreversible mu-antagonist beta-funaltrexamine (5.0 micrograms i.c.v.). Based upon the order of relative potency of the peptides and the relative potency for antagonism of their discriminative effects by naltrexone and beta-funaltrexamine, mu-opioid receptors in the brain appear to be an important element in the genesis of morphine-like discriminative effects by opioid peptides.