Study on the receptor subtypes mediating the analgesic action of an enkephalin analog, Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399).

The analgesic action of the enkephalin analog EK-399 (Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH) and the subtypes of the opiate receptors mediating the action were studied. The analgesic effect of subcutaneously injected EK-399 was ten times as potent as that of morphine in the rat tail flick test. EK-399 had a longer latency time and duration time than morphine. The analgesic action of EK-399 injected into the rat spinal subarachnoid space was about 800 (1800 in molar ratio) times as potent as that of morphine in the hot plate test. EK-399 had high affinities for both mu and delta opiate receptors in the rat brain receptor binding assay. The apparent pA2 values with naloxone were 7.65 for morphine and 5.98 for EK-399 in the rat tail flick test; the difference was significant. A cross tolerance between EK-399 and morphine was examined in the rat tail flick test. Although morphine tolerant rats showed no tolerance to EK-399, EK-399 tolerant rats showed a clear tolerance to morphine. These results indicate that EK-399 has a potent and long lasting analgesic effect via opiate receptors in rats. In addition to mu-receptors, delta-receptors may be involved in its analgesic mechanism.