title: Spinal kappa receptor-mediated analgesia of E-2078, a systemically active dynorphin analog, in mice.
abstract: E-2078 ([N-methyl-Tyr1, N-methyl-Arg7, D-Leu8]dynorphin A (1-8) ethylamide) is a systematically active dynorphin analog. We examined the sites of action of analgesia induced by systemic application of E-2078 compared with morphine in mice. When administered either intracerebroventricularly or intrathecally, E-2078 produced maximal dose-dependent analgesia in the tail-pinch, tail-flick and formalin tests. Its peak effect was observed 15 min after both injections, contrasted with a slow peak (120 min) by subcutaneous injection. The intrathecal site was relatively more sensitive than the intracerebroventricular site and many times more sensitive than the subcutaneous route. In contrast, morphine was equipotent when given intracerebroventricularly and intrathecally. When E-2078 was administered subcutaneously and naloxone or nor-binaltorphine were given either intracerebroventricularly or intrathecally, the analgesic action of E-2078 was most potently and totally reversed by intrathecal injection of nor-binaltorphimine. Intracerebroventricular and intrathecal injections of naloxone were equally effective for antagonism of morphine-analgesia. These data indicate that systemically administered E-2078 produces analgesia via central actions, in which the activation of the spinal kappa receptors is most important.
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
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013116:Spinal Cord / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D000700:Analgesics; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C061285:E 2078; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D004399:Dynorphins; D009020:Morphine