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The kappa-receptor selectivity of nor-binaltorphimine (nor-BNI), a highly selective kappa-opioid receptor antagonist in vitro, was examined in vivo by measuring the time course of the antagonistic action of nor-BNI (5 and 20 mg/kg, s.c.) against the responses to U-50488H (10 mg/kg, s.c.), morphine (10 mg/kg, s.c.) and fentanyl (50 micrograms/kg, s.c.) in mice. In the tail pinch test, nor-BNI partially antagonized morphine and fentanyl analgesia, but not U-50488H analgesia in the first 30 min after s.c. administration. However, the kappa-antagonistic action gradually increased, reaching a plateau at 2 hr. This antagonistic action was maintained for at least 4 days. In contrast, the mu-antagonistic action declined to the control level at 2 or 4 hr after nor-BNI administration. In the acetic acid-induced writhing test, nor-BNI also exerted a more potent and selective kappa-antagonistic action at 24 hr than at 1 hr after its s.c. administration. Nor-BNI also showed a long-lasting kappa-antagonism against the hyperthermic response induced by U-50488H (5 mg/kg, s.c.). Thus, we found that nor-BNI is a slow-onset, long-lasting, selective kappa-antagonist in vivo.

In its pattern of sensitivity to anticonvulsants, kainic acid (KA) showed little resemblance to pentylenetetrazol (PTZ), 3-mercaptopropionic acid (3-MP), bicuculline, picrotoxin or bemegride. That KA may have an action on the gamma-aminobutyrate system is suggested by the following: it is strongly antagonized by aminooxyacetic acid; ethosuximide is ineffective against KA as it is against 3-MP; and a subconvulsive dose of KA potentiated 3-MP but not PTZ. However, KA is to some extent comparable to PTZ in that it is antagonized by trimethadione, phenobarbital and chlordiazepoxide more effectively than is 3-MP. The convulsive action of KA is potentiated by the glutamate antagonists l-glutamate diethyl ester (GDEE) and l-nuciferine. GDEE also slightly potentiated bicuculline, but not other convulsants tested; it slightly antagonized PTZ. Nuciferine potentiated all except PTZ and bemegride. The failure of these agents to antagonize KA-induced seizures is consistent with the view that KA and glutamate act at separate excitatory receptor sites. The potentiation might possibly be due to a blocking of glutamergic activation of neurons that are inhibitory.