title: [Evaluation of the discriminative stimulus effect of an enkephalin analog, EK-399, in the rat].
abstract: Four groups of rats were trained to discriminate between the no-drug conditions (saline, s.c.) and the effect of s.c. injection of the novel enkephalin analog Tyr-D-Met (O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399, 1 mg/kg), morphine (3 mg/kg), ethylketocyclazocine (EKC, 0.3 mg/kg) or N-allylnormetazocine (NANM, 3 mg/kg) in a two-lever choice, water reinforced procedure. All groups of animals acquired the ability to discriminate EK-399, morphine, EKC or NANM from saline. Naloxone (0.03-0.3 mg/kg, s.c.) completely antagonized the discriminative stimulus effects of EK-399, morphine and EKC, but not that of NANM. In stimulus generalization tests, morphine (10 mg/kg) and buprenorphine (0.03 mg/kg), mu-opioid receptor agonists, completely substituted for EK-399 in groups trained with EK-399, whereas EK-399 (0.1-3 mg/kg) only partially substituted for morphine in rats trained with morphine. EKC (0.01-0.1 mg/kg), a kappa-opioid receptor agonist, partially substituted for EK-399, and EK-399 (0.1-3 mg/kg) partially substituted for EKC. NANM (0.3-10 mg/kg), a sigma-receptor agonist, partially substituted for EK-399, but EK-399 (0.1-3 mg/kg) did not substitute for NANM. These results suggest that the discriminative stimulus effect of EK-399 in rats mainly involves mu-opioid receptor-mediating action and also involves, to a lesser extent, other receptor (probably delta-opioid receptor)-mediating actions.
authors.affiliation: Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Nishida
authors.forename: Y
authors.initials: Y
authors.lastname: Yasuhara
authors.forename: S
authors.initials: S
authors.lastname: Chiba
mesh_terms: D000818:Animals; D004192:Discrimination, Psychological / Q000187:drug effects*; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016314:Ethylketocyclazocine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000145:classification / Q000378:metabolism / Q000502:physiology*
chemical_list: D004745:Enkephalins; D011957:Receptors, Opioid; D009270:Naloxone; D016314:Ethylketocyclazocine; C012134:SK&F 10047; D009020:Morphine; C057683:tyrosyl-methionyl(O)-glycyl-ethylphenylalanine-2-acetylhydrazide; D010620:Phenazocine