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

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.

Pharmacological characterization of the ameliorating effect on short-term memory impairment and antinociceptive effect of KT-90 in mice.

(-)-3-Acetyl-6beta-acetylthio-N-cyclopropylmethyl-normorphine (KT-90) is a synthesized compound that binds to mu-, delta- and kappa-opioid receptors in vitro. KT-90 induces analgesia in the tail-flick test and this effect is antagonized by nor-BNI, a selective kappa-opioid receptor antagonist. However, lower doses of KT-90 antagonize morphine-induced analgesia. We reported that kappa-opioid receptor agonists such as U-50,488H and dynorphin A (1-13), improved scopolamine-induced impairment of learning and memory in mice and/or rats. In this study, the effects of KT-90 were investigated in an acetic acid-induced writhing test and scopolamine-induced memory impairment test using spontaneous alternation performance in a Y-maze. Male ddY mice were treated with scopolamine (1.65 micromol/kg, s.c.) 30 min before the behavioral test. KT-90 (0.07-2.35 micromol/kg, s.c.) was injected 30 min before testing. In the writhing test, the antinociceptive effect of KT-90 (0.71 micromol/kg) was completely antagonized by a selective mu-opioid receptor antagonist, beta-funaltrexamine (10.2 nmol/mouse, i.c.v.) and partially antagonized by nor-BNI (4.9 nmol/mouse, i.c.v.), but it was not antagonized by a selective delta-opioid receptor antagonist, naltrindole (9.1 pmol/mouse, i.c.v.). KT-90 significantly improved the impairment of spontaneous alternation induced by scopolamine. The ameliorating effect of KT-90 was not antagonized by nor-BNI, but was almost completely antagonized by a selective sigma receptor antagonist, NE-100 (2.6 micromol/kg, i.p.). These results suggested that the KT-90-induced antinociceptive effect was mediated by mu- and partially by kappa-opioid receptors, and the KT-90-induced improvement in scopolamine-induced impairment of spontaneous alternation was mediated mainly via sigma receptors.