title: Analgesia produced by E-2078, a systemically active dynorphin analog, in mice.
abstract: 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.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakazawa
authors.forename: Y
authors.initials: Y
authors.lastname: Furuya
authors.forename: T
authors.initials: T
authors.lastname: Kaneko
authors.forename: K
authors.initials: K
authors.lastname: Yamatsu
authors.forename: H
authors.initials: H
authors.lastname: Yoshino
authors.forename: S
authors.initials: S
authors.lastname: Tachibana
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002047:Buprenorphine / Q000494:pharmacology; D004347:Drug Interactions; D004399:Dynorphins / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism
chemical_list: D000700:Analgesics; D010446:Peptide Fragments; D011759:Pyrrolidines; D011957:Receptors, Opioid; C061285:E 2078; D009270:Naloxone; D002047:Buprenorphine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins; D009020:Morphine