RT Journal Article
SR Electronic
T1 Pharmacological Properties of Delta Opioid Receptor-Mediated Behaviors: Agonist Efficacy and Receptor Reserve
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.119.262717
DO 10.1124/jpet.119.262717
A1 Isaac J Dripps
A1 Ruizhuo Chen
A1 Amanda M Shafer
A1 Kathryn E Livingston
A1 Alexander Disney
A1 Stephen M Husbands
A1 John R Traynor
A1 Kenner C Rice
A1 Emily M Jutkiewicz
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/05/28/jpet.119.262717.abstract
AB Delta opioid receptor (δ-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animal models. However, the role of agonist efficacy in generating different δ-receptor-mediated behaviors has not been thoroughly investigated. To this end, efficacy requirements for δ-receptor-mediated antihyperalgesia, antidepressant-like effects, and convulsions were evaluated by comparing the effects of the partial agonist BU48 and the full agonist SNC80 as well as changes in the potency of SNC80 following δ-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 δ-opioid receptor partial agonist BU48. Ligand-induced G protein activation was measured by [35S]GTPγS binding in mouse forebrain tissue and δ-receptor number was measured by [3H]DPDPE saturation binding. BU48 produced antidepressant-like effects and convulsions but antagonized SNC80-induced antihyperalgesia. The potency of SNC80 was shifted to the right in δ-receptor heterozygous knockout mice and 5'-NTII 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. NTI antagonized these SNC80-induced behaviors with similar potencies suggesting that these effects are mediated by the same type of δ-receptor. These data suggest that δ-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 δ-opioid receptor agonists.SIGNIFICANCE STATEMENT Delta opioid receptor (δ-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 δ-receptor-mediated behaviors. These data suggest that δ-receptor-mediated behaviors display a rank order of efficacy requirement with antihyperalgesia having the highest requirement, followed by antidepressant-like effects and then convulsions.