Pharmacological Properties of δ-Opioid Receptor-Mediated Behaviors: Agonist Efficacy and Receptor Reserve
Pharmacological Properties of δ-Opioid Receptor-Mediated Behaviors: Agonist Efficacy and Receptor Reserve
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δ阿片受体介导行为的药理学特性：激动剂效应和受体储备
DOI：
10.1124/jpet.119.262717
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发表时间：
2020-08-01
影响因子：
3.5
通讯作者：
Jutkiewicz, Emily M.
中科院分区：
文献类型：
--
作者：
Dripps, Isaac J.;Chen, Ruizhuo;Jutkiewicz, Emily M.
δ-阿片样受体（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，激动剂功效在产生不同5-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BU 48和完全激动剂SNC 80的作用以及δ受体消除后SNC 80效力的变化，评价δ受体介导的抗痛觉过敏、抗抑郁样作用和惊厥的疗效要求。在硝酸甘油诱导的热痛觉过敏测定中测量抗痛觉过敏。在强迫游泳试验中评价了抗抑郁样作用。在用SNC 80或δ-阿片样物质受体部分激动剂BU 48处理后，观察小鼠的惊厥。通过小鼠前脑组织中的[S-35]鸟苷5 '-O-[γ-硫代]三磷酸结合来测量配体诱导的G蛋白活化，通过[H-3]D-Pen（2，5）-脑啡肽饱和结合来测量δ受体数目。BU 48产生抗抑郁样作用和惊厥，但拮抗SNC 80诱导的抗痛觉过敏和G蛋白激活。SNC 80的效力在δ受体杂合敲除小鼠和纳曲吲哚-5 '-异硫氰酸酯处理的小鼠中向右偏移，并且效力偏移的幅度在各测定中不同，其中最大偏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。纳曲吲哚拮抗这些SNC 80诱导的行为具有相似的效力，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出疗效要求的等级顺序，其中抗痛觉过敏的要求最高，其次是抗抑郁样作用，然后是惊厥。这些发现进一步加深了我们对δ-阿片受体激动剂体内作用的药理学机制的理解。意义声明δ-阿片受体（δ-受体）激动剂在动物模型中产生抗痛觉过敏、抗抑郁样作用和惊厥。本研究评估药理学特性，特别是激动剂功效和受体储备的作用，这些δ受体介导的行为的基础。这些数据表明，δ-受体介导的行为显示出疗效要求的等级顺序，其中抗痛觉过敏的要求最高，其次是抗抑郁样作用，然后是惊厥。
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 STATEMENTdelta-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.