Pharmacological Properties of δ-Opioid Receptor-Mediated Behaviors: Agonist Efficacy and Receptor Reserve

delta-Opioid receptor (delta-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animals. However, the role of agonist efficacy in generating different 5-receptor-mediated behaviors has not been thoroughly investigated. To this end, efficacy requirements for delta-receptor-mediated antihyperalgesia, antidepressant-like effects, and convulsions were evaluated by comparing the effects of the partial agonist BU48 and the full agonist SNC80 and changes in the potency of SNC80 after delta-receptor elimination. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. An antidepressant-like effect was evaluated in the forced swim test. Mice were observed for convulsions after treatment with SNC80 or the delta-opioid receptor partial agonist BU48. Ligand-induced G protein activation was measured by [S-35]guanosine 5'-O-[gamma-thio] triphosphate binding in mouse forebrain tissue, and delta-receptor number was measured by [H-3]D-Pen(2,5)-enkephalin saturation binding. BU48 produced antidepressant-like effects and convulsions but antagonized SNC80-induced antihyperalgesia and G protein activation. The potency of SNC80 was shifted to the right in delta-receptor heterozygous knockout mice and naltrindole-5'-isothiocyanate-treated mice, and the magnitude of potency shift differed across assays, with the largest shift occurring in the thermal hyperalgesia assay, followed by the forced swim test and then convulsion observation. Naltrindole antagonized these SNC80-induced behaviors with similar potencies, suggesting that these effects are mediated by the same type of delta-receptor. These data suggest that delta-receptor-mediated behaviors display a rank order of efficacy requirement, with antihyperalgesia having the highest requirement, followed by antidepressant-like effects and then convulsions. These findings further our understanding of the pharmacological mechanisms mediating the in vivo effects of delta-opioid receptor agonists. SIGNIFICANCE STATEMENT delta-Opioid receptor (delta-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animal models. This study evaluates pharmacological properties, specifically the role of agonist efficacy and receptor reserve, underlying these delta-receptor-mediated behaviors. These data suggest that delta-receptor-mediated behaviors display a rank order of efficacy requirement, with antihyperalgesia having the highest requirement, followed by antidepressant-like effects and then convulsions.