The convulsive and electroencephalographic changes produced by nonpeptidic δ-opioid agonists in rats: Comparison with pentylenetetrazol

δ-Opioid agonists produce convulsions and antidepressant-like effects in rats. It has been suggested that the antidepressant-like effects are produced through a convulsant mechanism of action either through overt convulsions or nonconvulsive seizures. This study evaluated the convulsive and seizurogenic effects of nonpeptidic δ-opioid agonists at doses that previously were reported to produce antidepressant-like effects. In addition, δ-opioid agonist-induced electroencephalographic (EEG) and behavioral changes were compared with those produced by the chemical convulsant pentylenetetrazol (PTZ). For these studies, EEG changes were recorded using a telemetry system before and after injections of the δ-opioid agonists [(+)-4-[(αR)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl] -(3-methoxyphenyl)methyl]-N,N-diethylbenz (SNC80) and [(+)-4-[α(R)- α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(+3-hydroxyphenyl) methyl]-N,N-diethylbenzamide [(+)-BW373U86]. Acute administration of nonpeptidic δ-opioid agonists produced bilateral ictal and paroxysmal spike and/or sharp wave discharges. δ-Opioid agonists produced brief changes in EEG recordings, and tolerance rapidly developed to these effects; however, PTZ produced longer-lasting EEG changes that were exacerbated after repeated administration. Studies with antiepileptic drugs demonstrated that compounds used to treat absence epilepsy blocked the convulsive effects of nonpeptidic δ-opioid agonists. Overall, these data suggest that δ-opioid agonist-induced EEG changes are not required for the antidepressant-like effects of these compounds and that neural circuitry involved in absence epilepsy may be related to δ-opioid agonist-induced convulsions. In terms of therapeutic development, these data suggest that it may be possible to develop δ-opioid agonists devoid of convulsive properties.