Comparison of Receptor Mechanisms and Efficacy Requirements for δ-Agonist-Induced Convulsive Activity and Antinociception in Mice

Abstract

␦-Opioid receptor-selective agonists produce antinociception and convulsions in several species, including mice. This article examines two hypotheses in mice: 1) that antinociception and convulsive activity are mediated through the same type of ␦-receptor and 2) that greater ␦-agonist efficacy is required for antinociception than for convulsive activity. ␦-Mediated antinociception was evaluated in the acetic acid-induced abdominal constriction assay, which involves a low-intensity noxious stimulus; convulsive activity was indicated as a mild tonic-clonic convulsive episode followed by a period of catalepsy. In ␦-opioid receptor knockout mice [DOR-1(Ϫ/Ϫ)], the nonpeptidicfailed to produce convulsive behavior demonstrating the absolute involvement of DOR-1 in this effect. In NIH Swiss mice expressing ␦-opioid receptors, BW373U86 produced both antinociception and convulsive activity. These effects were antagonized by the putative ␦ 1 -receptor-selective antagonist 7-benzylidenenaltrexone and the putative ␦ 2 -receptor-selective antagonist naltriben. Tolerance developed to both the convulsive and antinociceptive effects of BW373U86. Tolerance to the convulsive, but not the antinociceptive, effects of BW373U86 was largely prevented when the antagonist naltrindole was given 20 min after each dose of the agonist in a 3-day treatment paradigm. The convulsive action of BW373U86 was also less sensitive than the antinociceptive action to treatment with the irreversible ␦-antagonist naltrindole isothiocyanate. Collectively, these data suggest that the convulsive and antinociceptive activities of ␦-agonists are mediated through the same receptor but that the receptor reserve for ␦-mediated convulsive activity is greater than for ␦-mediated antinociceptive activity.

Electroencephalographic and convulsant effects of the delta opioid agonist SNC80 in rhesus monkeys

“…These results confirm and extend other studies to suggest that SNC80 and other piperazinyl benzamides (e.g. BW373U86) may produce behavioral convulsions in mice (Comer et al, 1993;Bilsky et al, 1995;Hong et al, 1998;Broom et al, 2002b), rats (Broom et al, 2002a;Jutkiewicz et al, 2006), squirrel monkeys (Dykstra et al, 1993;Allen et al, 2002) and rhesus monkeys (Negus et al, 1994). However, the convulsant effects of SNC80 were not replicated in this monkey during a second test with 10 mg/kg SNC80 one year later, and a lower dose of 3.2 mg/kg SNC80 also failed to produce either EEG seizures or behavioral convulsions in this monkey.…”

“…Preclinical studies conducted with these and other related drugs suggest that delta agonists may have clinical utility as analgesics, antidepressants, cardioprotective agents, and modulators of immune function Calderon et al, 1994;Brandt et al, 2001a;Gross et al, 2004;Ossipov et al, 2004;Weber and Gomez-Flores, 2004). However, it was recognized at an early stage that piperazinyl benzamide delta agonists such as BW373U86 and SNC80 also produced convulsions in mice and rats (Comer et al, 1993;Bilsky et al, 1995;Hong et al, 1998;Broom et al, 2002a;Broom et al, 2002b;. These convulsions in rodents are typically brief and non-lethal (but see (Hong et al, 1998), but they are also delta-receptor mediated and produced at doses similar to those that produce potentially useful effects such as antinociception.…”

Separation of the convulsions and antidepressant-like effects produced by the delta-opioid agonist SNC80 in rats

“…With long infusion durations, delta-opioid receptors can become desensitized and, perhaps, down-regulated. This hypothesis would suggest that there is a small receptor reserve for delta-opioid agonist-induced convulsions (Broom et al 2002c). As demonstrated by the convulsive threshold data in Table 3, previous SNC80 exposure decreased the number of rats convulsing, increased the total amount of drug infused, and increased the threshold dose required for convulsions.…”

Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats

“…In conclusion, there is mounting evidence demonstrating antidepressant-like behavioral effects of several types of delta opioid receptor agonists, in several animal models, suggesting that activation of the delta receptor consistently produces effects similar to clinically prescribed antidepressants (Broom et al, 2002a;Saitoh et al, 2004;Jutkiewicz et al, 2004;present study). In addition, the ability of delta opioid receptor agonists to increase BDNF mRNA expression suggests that these compounds could be important in treating depression, but also in treating patients suffering stroke, head trauma, or possibly other neurodegenerative disorders.…”

“…Most behavioral and physiological effects of delta agonists have been demonstrated to occur with both the peptidic and nonpeptidic agonists; however, there are a few exceptions. The nonpeptidic delta agonists produce convulsions in mice (Comer et al, 1993;Hong et al, 1998;Broom et al, 2002a), rats (Broom et al, 2002c), and nonhuman primates (Dykstra et al, 1993;Pakarinen et al, 1995;Negus et al, 1994). On the other hand, peptidic agonists have not been reported to produce convulsions in any species; however, they do produce wet dog shakes, unstable movement, and epileptic discharges as measured by electroencephalogram (EEG) (Haffmans and Dzoljic, 1983).…”