Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.).
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
J Pharmacol Exp Ther. 2020 Aug;374(2):319-330. doi: 10.1124/jpet.119.262717. Epub 2020 May 28.
δ-Opioid receptor (-receptor) agonists produce antihyperalgesia, antidepressant-like effects, and convulsions in animals. However, the role of agonist efficacy in generating different -receptor-mediated behaviors has not been thoroughly investigated. To this end, efficacy requirements for -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 -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 -opioid receptor partial agonist BU48. Ligand-induced G protein activation was measured by [S]guanosine 5'-O-[-thio]triphosphate binding in mouse forebrain tissue, and -receptor number was measured by [H]D-Pen-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 -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 -receptor. These data suggest that -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 -opioid receptor agonists. SIGNIFICANCE STATEMENT: -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.
δ-阿片受体（δ-受体）激动剂在动物中产生抗痛觉过敏、抗抑郁样作用和惊厥。然而，激动剂效力在产生不同的 δ-受体介导的行为中的作用尚未得到彻底研究。为此，通过比较部分激动剂 BU48 和完全激动剂 SNC80 的作用以及 δ-受体消除后 SNC80 效力的变化，评估了 δ-受体介导的抗痛觉过敏、抗抑郁样作用和惊厥的效力要求。在硝化甘油诱导的热痛觉过敏测定中测定抗痛觉过敏。在强迫游泳试验中评估抗抑郁样作用。在 SNC80 或 δ-阿片受体部分激动剂 BU48 处理后观察小鼠惊厥。通过在小鼠前脑组织中测量 [S]鸟苷 5'-O-[-硫]三磷酸结合来测量配体诱导的 G 蛋白激活，并且通过 [H]D-Pen-脑啡肽饱和结合来测量 δ-受体数量。BU48 产生抗抑郁样作用和惊厥，但拮抗 SNC80 诱导的抗痛觉过敏和 G 蛋白激活。在 δ-受体杂合子敲除小鼠和纳曲吲哚 5'-异硫氰酸酯处理的小鼠中，SNC80 的效力向右侧转移，并且效力转移的幅度在不同的测定中不同，最大的转移发生在热痛觉过敏测定中，其次是强迫游泳试验，然后是惊厥观察。纳曲吲哚以相似的效力拮抗这些 SNC80 诱导的行为，表明这些作用是由相同类型的 δ-受体介导的。这些数据表明，δ-受体介导的行为显示效力要求的等级顺序，抗痛觉过敏的要求最高，其次是抗抑郁样作用，然后是惊厥。这些发现进一步了解了介导 δ-阿片受体激动剂体内作用的药理学机制。
在动物模型中，δ-阿片受体（δ-受体）激动剂产生抗痛觉过敏、抗抑郁样作用和惊厥。本研究评估了药理学特性，特别是激动剂效力和受体储备在这些 δ-受体介导的行为中的作用。这些数据表明，δ-受体介导的行为显示效力要求的等级顺序，抗痛觉过敏的要求最高，其次是抗抑郁样作用，然后是惊厥。
