Abstract
Four groups of rats were trained to discriminate between the no-drug condition (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), μ-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 ir-opioid receptor agonist, partially substituted for EK-399, and EK-399 (0.13 mg/kg) partially substituted for EKC. NANM (0.3 ?? 10 mg/kg), a σ-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 μ-opioid receptor-mediating action and also involves, to a lesser extent, other receptor (probably δ-opioid receptor) -mediating actions.
