Study on the Receptor Subtypes Mediating the Analgesic Action of an Enkephalin Analog, Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3·AcOH (EK-399)

Abstract

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 μ and δ 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 μ-receptors, δ-receptors may be involved in its analgesic mechanism.