Analgesia produced by E-2078, a systemically active dynorphin analog, in mice.

E-2078 is a very stable dynorphin analog that has the same affinity and selectivity for opioid receptors as dynorphin-A by in vitro bioassay. In the present study, we have characterized the receptor selectivity of E-2078 in mu-, delta- and kappa-representative binding assays, and have evaluated the analgesic effect of systemically administered E-2078 by the tail pinch, tail flick and formalin tests in mice. E-2078 possessed a higher affinity for kappa-receptors than for mu- or delta-receptors in the receptor-binding assay. Dose-related, long-lasting analgesia was produced by s.c. injection of E-2078, and its peak effect was observed 2 hr after s.c. administration in all the analgesic tests. This analgesic effect was produced at doses that did not affect rotarod latency. Post-treatment with naloxone dose-dependently reversed the analgesic effects of both E-2078 and morphine, but E-2078-induced analgesia was relatively resistant to naloxone antagonism. Pre-treatment with the kappa-antagonist, nor-binaltorphimine, antagonized the analgesic effect of E-2078 but had little effect on the analgesic action of morphine. These data indicate that E-2078 is a systemically active analgesic and suggest that the activation of kappa-opioid receptors contributes to analgesia.