Behavioral effects of nonpeptidic delta-opioid receptor agonists

In the search for narcotic analgesic agents without the unwanted complications of μ-opioid receptor agonists, research has focused on the δ-opioid receptor as a target for antinociceptive agents. In the past decade, nonpeptidic δ-opioid receptor agonists such as BW373U86 and SNC80 have been developed and shown to produce antinociception in some pain models. However, when administered to mice, these agents also produce a characteristic brief, nonlethal convulsion that is mediated via the delta opioid receptor. The aim of the present studies was to further characterize the behavioral effects of nonpeptidic δ-opioid receptor agonists.; The first experiments compared previously identified effects mediated through the δ-opioid receptor to those produced by BU48, a novel buprenorphine analog. BU48 produced δ-opioid-mediated convulsions characteristic of BW373U86 and other nonpeptidic δ-receptor agonists without any evidence for δ-opioid-mediated antinociception. It was hypothesized that the differential activity of BU48 in vivo was due to a potentially higher efficacy requirement for the production of δ-mediated antinociception when compared to the convulsant effect of nonpeptidic δ-opioid agonists. Antagonist and tolerance studies with BW373U86 were consistent with this hypothesis and suggested that the receptor reserve for δ-mediated convulsant activity may be greater than that for δ-mediated antinociceptive activity.; Further studies have characterized a previous claim that nonpeptidic δ-opioid receptor agonists may produce antidepressant-like effects. (+)BW373U86 and SNC80 both produced a δ-mediated antidepressant-like effect in the rat forced swim assay. The role of δ-mediated convulsant activity in the production of antidepressant-like activity was then examined. As was seen with mice, a characteristic δ-mediated convulsion was seen upon administration of δ-opioid receptor agonists to rats. Separation of the convulsant and the antidepressant-like activity of (+)BW373U86 demonstrated that the convulsant activity was not necessary for the expression of the antidepressant-like effects of these compounds although both effects were mediated through the δ-opioid receptor.; In summary, the studies described in this thesis have produced intriguing insights into previously-described and novel behavioral effects mediated through the δ-opioid receptor.