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 mu g) 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 rests 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)-benzeneatamide methanesulfonate hydrate (U-50,488H), another K-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 mu g), 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 K-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.