The novel enkephalin analog Tyr-D-Met (O)-Gly-EtPhe-NHNHCOCH3 . AcOH (EK-399) was examined for psychic dependence potential by a self-administration test in rats. Five groups of experimentally naive rats were given an intravenous dose of EK-399 (0.032, 0.064 or 0.125 mg/kg), morphine HCl (0.5 mg/kg) or cocaine HCl (0.5 mg/kg) via a cannula implanted in the jugular vein when they pressed a lever. No animals initiated self-administration of EK-399 in the first 3 or 4 weeks of the experimental period. In contrast, almost all of the animals receiving morphine or cocaine initiated a high rate of self-administration within 1 or 2 weeks. However, when the doses of EK-399 were subsequently decreased, 4 of the 10 animals increased their rate of self-administration slightly. Furthermore, an increase in the rate of EK-399 self-administration was observed in 1 of 4 rats made physically dependent on EK-399. These results suggest that EK-399 has a very weak reinforcing effect on drug-taking behavior, which is slightly enhanced by the development of physical dependence on the compound, and it may possess a low psychic dependence potential.

01 Jan 1991·Folia Pharmacologica Japonica

Evaluation of the discriminative stimulus effect of an enkephalin analog, EK-399, in the rat.

Article

Author: Nishida, Nobuyuki ; Chiba, Sukehiro ; Yasuhara, Yoshitaka

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.

01 Jan 1990·Japanese Journal of Pharmacology

Physical Dependence Potential of an Enkephalin Analog, EK-399, in Rats

Article

Author: Nishida, N

The physical dependence potential of Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399), a novel enkephalin analog with a potent analgesic effect, was assessed in rats. The animals were given EK-399 (0.008, 0.032, 0.125, or 0.5 mg/kg), morphine (0.125, 0.5, or 2 mg/kg), pethidine (2 or 8 mg/kg), or pentazocine (2 or 8 mg/kg) every hour through an implanted intravenous cannula. After 3 days of treatment, precipitated withdrawal tests were conducted: naloxone (5 mg/kg) was administered subcutaneously. Rats treated with morphine showed withdrawal signs such as hyperirritability, salivation, diarrhea, and weight loss. Rats treated with pethidine, pentazocine, or EK-399 showed similar signs, but they were less evident than those in morphine-treated rats. In abrupt withdrawal tests after 7 days of treatment, rats treated with morphine, pethidine, or pentazocine showed weight loss, whereas rats treated with EK-399 showed little or no weight loss. In substitution tests, EK-399 suppressed the withdrawal signs in morphine-dependent rats, and vice versa. These results show that EK-399 has a morphine-like physical dependence potential that is weaker than that of morphine, pethidine, or pentazocine in rats.

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