Morphine-induced antinociception in the rat: Supra-additive interactions with imidazoline I2, receptor ligands

被引:35
作者
Li, Jun-Xu [1 ]
Zhang, Yanan [2 ]
Winter, Jerrold C.
机构
[1] SUNY Buffalo, Sch Med & Biomed Sci, Dept Pharmacol & Toxicol, Buffalo, NY 14214 USA
[2] Res Triangle Inst, Res Triangle Pk, NC 27709 USA
关键词
Imidazoline I-2 receptor; Morphine; Antinociception; Writhing test; I-2-IMIDAZOLINE RECEPTORS; THERMAL NOCICEPTION; OPIOID ANALGESIA; RHESUS-MONKEYS; DIABETIC-RATS; AGMATINE; ACTIVATION; BINDING; BRAIN; DRUG;
D O I
10.1016/j.ejphar.2011.07.041
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Pain remains a significant clinical challenge and currently available analgesics are not adequate to meet clinical needs. Emerging evidence suggests the role of imidazoline I-2 receptors in pain modulation primarily from studies of the non-selective imidazoline receptor ligand, agmatine. However, little is known of the generality of the effect to selective I-2 receptor ligands. This study examined the antinociceptive effects of two selective I-2 receptor ligands 2-BFI and BU224 (>2000-fold selectivity for I-2 receptors over alpha(2) adrenoceptors) in a hypertonic (5%) saline-induced writhing test and analyzed their interaction with morphine using a dose-addition analysis. Morphine, 2-BFI and BU224 but not agmatine produced a dose-dependent antinociceptive effect. Both composite additive curve analyses and isobolographical plots revealed a supra-additive interaction between morphine and 2-BFI or BU224, whereas the interaction between 2-BFI and BU224 was additive. The antinociceptive effect of 2-BFI and BU224 was attenuated by the I-2 receptor antagonist/alpha(2) adrenoceptor antagonist idazoxan but not by the selective alpha(2) adrenoceptor antagonist yohimbine, suggesting an I-2 receptor-mediated mechanism. Agmatine enhanced the antinociceptive effect of morphine, 2-BFI and BU224 and the enhancement was prevented by yohimbine, suggesting that the effect was mediated by alpha(2) adrenoceptors. Taken together, these data represent the first report that selective I-2 receptor ligands have substantial antinociceptive activity and produce antinociceptive synergy with opioids in a rat model of acute pain. These data suggest that drugs acting on imidazoline I-2 receptors may be useful either alone or in combination with opioids for the treatment of pain. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:59 / 65
页数:7
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