Systemic administration of dynorphin A-(1-13) markedly improves cycloheximide-induced amnesia in mice.
The effects of systemic or intracerebroventricular injection of dynorphin A-(1-13), a kappa-selective opioid receptor agonist, on cycloheximide-induced amnesia were investigated by using a step-down-type passive avoidance task in mice. The intracerebroventricular injection of dynorphin A-(1-13) (0.3-3 micrograms) before training significantly prolonged step-down latency. The systemic administration of dynorphin A-(1-13) (1, 3 and/or 10 mg/kg, i.p.) before training or retention tests markedly inhibited the cycloheximide (30 mg/kg, s.c.)-induced shortening of step-down latency, indicating antiamnesic effects of dynorphin A-(1-13). One and 3 mg/kg doses of ((+/-)trans-3, 4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, methanesulfonate hydrate (U-50,488H), another kappa-selective opioid receptor agonist, significantly inhibited the shortening. The anti-amnesic effects of dynorphin A-(1-13) (3 and 10 mg/kg, i.p.) were almost completely antagonized by intracerebroventricular administration of the quaternary derivative of the opioid receptor antagonist naltrexone methobromide (0.3 microgram), but not by systemic administration of the opioid receptor antagonist (1 mg/kg, s.c.), demonstrating central mediation of the anti-amnesic effects of dynorphin A-(1-13). Furthermore, the kappa-selective opioid receptor antagonist, nor-binaltorphimine (2 mg/kg, s.c.), almost completely antagonized the effects of dynorphin A-(1-13) (3 and 10 mg/kg, i.p.). These results suggest that dynorphin A-(1-13) produces anti-amnesic effects through the blood-brain barrier.
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
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Ukai
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Shan-Wu
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Kobayashi
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Kameyama
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000647:Amnesia / Q000139:chemically induced / Q000517:prevention & control*; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D003513:Cycloheximide / Q000037:antagonists & inhibitors*; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000502:physiology
D000700:Analgesics; D009292:Narcotic Antagonists; D011500:Protein Synthesis Inhibitors; D011759:Pyrrolidines; D000644:Quaternary Ammonium Compounds; D017473:Receptors, Opioid, kappa; C032257:methylnaltrexone; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins; D003513:Cycloheximide