Convulsive Behavior of Nonpeptide δ-Opioid Ligands:Comparison of SNC80 and BW373U86 in Mice

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Abstract
BW373U86 is a systematically active δ-opioid receptor selective nonpeptide agonist. This compound shows convulsive properties in mice at doses that are antinociceptive. SNC80, the methyl ether of the (+) isomer of BW373U86, has a greater selectivity and specificity for the δ-opioid receptor than BW373U86. To examine whether this compound also produces convulsive behaviors at antinociceptive doses, we compared the behavioral properties of SNC80 and BW373U86 in male mice. Both compounds consistently produced a mild convulsion at a dose of 10 mg/kg IP. These convulsive episodes were dose-dependently shifted by the δ-opioid-selective antagonist, naltrindole, and were completely suppressed by the benzodiazepine, midazolam. Antinociception in the acetic acid writhing assay was observed at the same doses that caused convulsions. In contrast to BW373U86, SNC80 at a dose of 320 mg/kg produced a more violent convulsion that always resulted in death, when the milder convulsion was blocked with naltrindole or midazolam. This lethal convulsion was not blocked by either naltrindole or midazolam. Pretreatment of mice with 100 mg/kg of SNC80 or BW373U86 produced tolerance to the mild convulsive effects of subsequent administrations of either agonist, with the mice recovering to an apparently normal state after 8–16 days. Tolerance was not prevented by midazolam, indicating that the convulsive episode itself was not necessary for the manifestation of tolerance. Tolerance over a similar time course was also observed to the antinociceptive effects of SNC80. The findings are consistent with a similar δ-mediated mechanism being responsible for both the convulsive and antinociceptive properties of both SNC80 and BW373U86.

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