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

Eur J Pharmacol. 1996 Nov 14;315(2):119-25. doi: 10.1016/s0014-2999(96)00622-x.


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 mumol/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 kappa-opioid receptors, we attempted to block its action using a selective kappa-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 mumol/kg s.c.) also blocked the ameliorating effect of U-50488H. U-50488H (0.21-2.15 mumol/kg s.c.) did not facilitate the acquisition of memory in normal mice. These results suggest that U-50488H modulates the kappa-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Amnesia / chemically induced*
  • Amnesia / drug therapy*
  • Analgesics / antagonists & inhibitors
  • Analgesics / therapeutic use*
  • Animals
  • Avoidance Learning / drug effects*
  • Carbon Monoxide Poisoning / drug therapy*
  • Electric Stimulation
  • Male
  • Mice
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Pyrrolidines / antagonists & inhibitors
  • Pyrrolidines / therapeutic use*


  • Analgesics
  • Narcotic Antagonists
  • Pyrrolidines
  • norbinaltorphimine
  • Naltrexone
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer