Antinociceptive Interactions between the Imidazoline I2 Receptor Agonist 2-BFI and Opioids in Rats: Role of Efficacy at the μ-Opioid Receptor
Antinociceptive Interactions between the Imidazoline I2 Receptor Agonist 2-BFI and Opioids in Rats: Role of Efficacy at the μ-Opioid Receptor
复制标题
大鼠中咪唑啉 I-2 受体激动剂 2-BFI 和阿片类药物之间的镇痛相互作用：mu-阿片类药物受体功效的作用
DOI：
10.1124/jpet.116.232421
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发表时间：
2016-06-01
影响因子：
3.5
通讯作者：
Li, Jun-Xu
中科院分区：
文献类型：
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作者：
Siemian, Justin N.;Obeng, Samuel;Li, Jun-Xu
尽管据报道，在慢性疼痛动物模型中，mu-阿片类药物与咪唑啉 I-2 受体 (I2R) 配体有良好的相互作用，但之前尚未研究过 mu-阿片类药物受体配体功效对这些相互作用的依赖性。本研究系统地研究了选择性 I-2 受体配体 2-(2-苯并呋喃基)-2-咪唑啉盐酸盐 (2-BFI) 与三种不同功效的 mu-阿片受体配体之间的相互作用：芬太尼（高效）、丁丙诺啡（中低功效）和 17-环丙基甲基-3,14b二羟基-4,5α-环氧-6α-[(3'-异喹啉基)乙酰氨基]吗啡（NAQ；功效非常低）。采用von Frey机械伤害感受试验和Hargreaves热伤害感受试验检测药物组合对完全弗氏佐剂引起的大鼠炎症性疼痛的抗痛觉过敏作用。使用食物强化计划控制反应来检查每种药物组合的速率抑制效果。使用剂量添加和等辐射分析来表征每次测定中药物-药物相互作用的性质。 2-BFI和芬太尼完全逆转机械和热伤害感受，而丁丙诺啡显着逆转热伤害感受，但仅轻微逆转机械伤害感受。 NAQ 在两种伤害感受测定中均无效。当与芬太尼联合研究时，NAQ 充当竞争性拮抗剂（表观 pA(2) 值：6.19）。在伤害感受测定中，2-BFI/芬太尼混合物产生加成到下加成的镇痛相互作用，2-BFI/丁丙诺啡混合物产生超加成到下加成的相互作用，2-BFI/NAQ混合物产生超加成到加成的相互作用。所有组合对时间表控制反应的影响通常是相加的。在使用雌性大鼠的实验中发现了与这些一致的结果。这些发现表明，低效 mu-阿片受体激动剂可能比高效 m-阿片受体激动剂更有利地与 I2R 配体相互作用。
Although mu-opioids have been reported to interact favorably with imidazoline I-2 receptor (I2R) ligands in animal models of chronic pain, the dependence on the mu-opioids receptor ligand efficacy on these interactions had not been previously investigated. This study systematically examined the interactions between the selective I-2 receptor ligand 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) and three mu-opioids receptor ligands of varying efficacies: fentanyl (high efficacy), buprenorphine (medium-low efficacy), and 17-cyclopropylmethyl-3,14bdihydroxy- 4,5 alpha-epoxy-6 alpha-[(3'-isoquinolyl) acetamido] morphine (NAQ; very low efficacy). The von Frey test of mechanical nociception and Hargreaves test of thermal nociception were used to examine the antihyperalgesic effects of drug combinations in complete Freund's adjuvant-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to examine the rate-suppressing effects of each drug combination. Dose-addition and isobolographical analyses were used to characterize the nature of drug-drug interactions in each assay. 2-BFI and fentanyl fully reversed both mechanical and thermal nociception, whereas buprenorphine significantly reversed thermal but only slightly reversed mechanical nociception. NAQ was ineffective in both nociception assays. When studied in combination with fentanyl, NAQ acted as a competitive antagonist (apparent pA(2) value: 6.19). 2-BFI/fentanyl mixtures produced additive to infra-additive analgesic interactions, 2-BFI/buprenorphine mixtures produced supra-additive to infra-additive interactions, and 2-BFI/NAQ mixtures produced supra-additive to additive interactions in the nociception assays. The effects of all combinations on schedule-controlled responding were generally additive. Results consistent with these were found in experiments using female rats. These findings indicate that lower-efficacy mu-opioids receptor agonists may interact more favorably with I2R ligands than high-efficacy m-opioid receptor agonists.