beta-funaltrexamine and Epilepsy

There is evidence that 5-7 d after acute seizure episodes induced by kainic acid (KA) the rats develop a long-lasting increase in the susceptibility to seizures followed by spontaneous recurrent seizures (SRS). The present study was focused on the role of hippocampal mu opioid receptors (MORs) in the susceptibility of rats to seizures with the KA model of epilepsy. The rats received a convulsant dose of KA (10 mg/kg, i.p.) were continuously infused with a selective MOR agonist PL017 (2.09, 2.59, 3.29 microg/microl), or a selective MOR antagonist beta-funaltrexamine hydrochloride (beta-FNA, 0.88, 1.10, and 1.35 microg/microl) into ventral hippocampus by means of mini-osmotic pumps. Seven days later, the susceptibility of rats to seizures was checked by a subconvulsant dose of KA (5 mg/kg, i.p.). PL017 infusion shortened the latency and increased the stage of seizures induced by subconvulsant dose of KA in a dose-dependent manner. In contrast, infusion of beta-FNA exhibited a dose-dependent effect against seizures challenged by subconvulsant dose of KA. These results indicate that hippocampal MOR may exert a promoting effect on the susceptibility of rats to KA-induced seizures.

Topics: Animals; Disease Susceptibility; Dynorphins; Epilepsy; Hippocampus; Kainic Acid; Male; Naltrexone; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

In vivo and in vitro binding studies with natural thebaine and its enantiomer, (+)-thebaine were conducted to elucidate further their interactions with the opioid system. (-)-Thebaine a key intermediate in the biosynthesis of morphine in the poppy plant (Papaver somniferum) and in mammalian tissue, was poorly effective antinociceptively in mice at doses to 30 mg/kg. Its principal behavioral manifestation was lethal convulsions. Naltrindole, at doses of 1 and 10 mg/kg did not block either the convulsions or lethal effects, suggesting that the delta-opioid receptor system was not involved in this action. Surprisingly, the dextrorotatory isomer exhibited significant antinociceptive activity in the tail-flick [ED50 = 8.9 (3.4-22.1) mg/kg], hot-plate [ED50 = 22.9 (10.9-48.1) mg/kg] and phenylquinone [ED50) = 1.9 (1.6-9.5) mg/kg] assays. Studies with opioid receptor-subtype antagonists, beta-funaltrexamine, nor-binaltorphimine and naltrindole, indicated that antinociception was associated with mu- and delta-opioid receptors. Results of displacement experiments supported the in vivo data. Significant competition for [3H]diprenorphine binding with both isomers for cloned mu- and delta-opioid receptors was observed. However, (-)-thebaine was more effective at the delta-opioid receptor (Ki = 1.02+/-0.01 microM) whereas (+)-thebaine was more effective at the mu-opioid receptor ( Ki = 2.75+/-0.01 microM). Opioid-induced antinociception associated with unnatural thebaine raises the possibility of additional mu- and delta-opioid receptor sites.

Topics: Analgesics; Animals; Binding, Competitive; Cells, Cultured; Epilepsy; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Pain Measurement; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Stereoisomerism; Thebaine