Pharmacological characterization of the ameliorating effect on learning and memory impairment and antinociceptive effect of KT-95 in mice

Behav Brain Res. 2006 Feb 28;167(2):219-25. doi: 10.1016/j.bbr.2005.09.009. Epub 2005 Oct 11.

Abstract

3-Acetoxy-6beta-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine (KT-95) is a synthesized compound that binds to mu-, delta- and kappa-opioid receptors in vitro. KT-95 induces analgesia and this effect is antagonized by nor-BNI, a selective kappa-opioid receptor antagonist. We have reported that kappa-opioid receptor agonists improve impairment of learning and memory in mice and/or rats. In this study, the effects of KT-95 were investigated in an acetic acid-induced writhing test and scopolamine-induced memory impairment test using spontaneous alternation performance in a Y-maze and a step-down type passive avoidance test. Male ddY mice were treated with KT-95 (0.24-2.35 micromol/kg, s.c.) 30 min before the behavioral test. In the writhing test, the antinociceptive effect of KT-95 (2.35 micromol/kg) was completely antagonized by nor-BNI (4.9 nmol/mouse, i.c.v.), but not by naloxone (3.05 micromol/kg, s.c.). KT-95 significantly improved the impairment of spontaneous alternation induced by scopolamine (1.65 micromol/kg, s.c.). The ameliorating effect of KT-95 was not antagonized by nor-BNI, but was almost completely antagonized by a selective sigma-receptor antagonist, N,N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine monohydrochloride (NE-100, 2.6 micromol/kg, i.p.). KT-95 also significantly improved scopolamine-induced learning and memory impairment in the passive avoidance test, although the effect was partial. Administration of KT-95 itself induced impairment of learning and memory. KT-95-induced impairment was not antagonized by naloxone, naltrindole, nor-BNI or NE-100 indicating that this impairment was not because of opioid receptor stimulation. These results suggested that although the KT-95-induced antinociceptive effect was mediated by kappa-opioid receptors, the KT-95-induced improvement in scopolamine-induced impairment of memory was mediated mainly via sigma-receptors and partially by kappa-opioid receptors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Male
  • Maze Learning / drug effects*
  • Memory / drug effects*
  • Mice
  • Morphine Derivatives / pharmacology*
  • Muscarinic Antagonists / pharmacology*
  • Nootropic Agents / pharmacology*
  • Pain Threshold / drug effects
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / physiology
  • Receptors, sigma / agonists
  • Receptors, sigma / physiology
  • Scopolamine / pharmacology*

Substances

  • KT 95
  • Morphine Derivatives
  • Muscarinic Antagonists
  • Nootropic Agents
  • Receptors, Opioid, kappa
  • Receptors, sigma
  • Scopolamine