U-50488H, a selective κ-opioid receptor agonist, improves carbon monoxide-induced delayed amnesia in mice

Abstract

The effects of trans-(±)-3,4-dichloro- N-methyl- N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulfonate salt (U-50488H) on carbon monoxide (CO)-induced amnesia in mice were investigated using spontaneous alternation and step-down type passive avoidance tasks. The lower percentage alternation and shorter median step-down latency in the retention test of the CO-exposed group indicated that memory deficiency occurred in mice when behavioral testing commenced 5–7 days after CO exposure. Administration of U-50488H (0.21 and 0.64 μmol/kg s.c.) 25 min before spontaneous alternation performance or the first training session of the passive avoidance task improved the CO-induced impairment of alternation performance and passive avoidance tasks. To determine whether the effect of U-50488H was mediated via κ-opioid receptors, we attempted to block its action using a selective κ-opioid receptor antagonist (nor-binaltorphimine). Nor-binaltorphimine (5.44 nmol/mouse i.c.v.) blocked the effect of U-50488H on CO-induced delayed amnesia. Furthermore, a low dose of scopolamine (0.41 μmol/kg s.c.) also blocked the ameliorating effect of U-50488H. U-50488H (0.21–2.15 μmol/kg s.c.) did not facilitate the acquisition of memory in normal mice. These results suggest that U-50488H modulates the κ-opioid receptor-mediated opioid neuronal system and activates the cholinergic neuronal system, and that it ameliorates the disruptive effect of CO on acquisition and/or consolidation of memory.