In vivo characterization of 6β-naltrexol, an opioid ligand with less inverse agonist activity compared with naltrexone and naloxone in opioid-dependent mice
In vivo characterization of 6β-naltrexol, an opioid ligand with less inverse agonist activity compared with naltrexone and naloxone in opioid-dependent mice
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DOI：
10.1124/jpet.104.082966
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发表时间：
2005-06-01
影响因子：
3.5
通讯作者：
Bilsky, EJ
中科院分区：
文献类型：
--
作者：
Raehal, KM;Lowery, JJ;Bilsky, EJ
μ-阿片受体显示基础信号传导活性，其似乎通过暴露于阿片激动剂而增强。本研究评估了假定的“中性”拮抗剂6 β-纳洛醇与其他具有不同疗效的配体（如纳洛酮，阿片依赖状态下的反向激动剂）相比的体内药理学。使用ICR小鼠生成纳洛酮、纳洛酮、纳布啡和6 β-纳洛醇在身体依赖模型中阻断吗啡的急性抗伤害感受作用和促使阿片类戒断的完整拮抗剂剂量-反应曲线。在阻断吗啡诱导的抗伤害感受和运动活动方面，6 β-纳洛酮与纳洛酮的效力大致相等，效力比纳洛酮低4.5- 10倍，表明6 β-纳洛酮进入中枢神经系统。与纳洛酮和纳洛酮相反，在急性依赖模型中，6 β-纳洛酮在高剂量下仅引起最小程度的戒断，在慢性依赖模型中，6 β-纳洛酮在引起戒断方面的效力分别比纳洛酮和纳洛酮低77倍和30倍。6 β-纳洛酮醇在体外和体内降低了纳洛酮的反向激动剂作用，与中性拮抗剂的预期一致。因此，6 β-纳洛醇的药理作用与阿片类药物依赖状态下的纳洛酮和纳洛酮的药理作用明显不同。与中性μ阿片受体拮抗剂相关的戒断作用的减少可能在治疗阿片类药物过量和成瘾方面提供优势。
The mu-opioid receptor displays basal signaling activity, which seems to be enhanced by exposure to opioid agonists. This study assesses the in vivo pharmacology of the putative "neutral" antagonist 6 beta-naltrexol in comparison to other ligands with varying efficacy, such as naloxone, an inverse agonist in the opioid-dependent state. ICR mice were used to generate full antagonist dose-response curves for naloxone, naltrexone, nalbuphine, and 6 beta-naltrexol in blocking acute antinociceptive effects of morphine and precipitating opioid withdrawal in models of physical dependence. 6 beta-Naltrexol was roughly equipotent to naloxone and between 4.5- and 10-fold less potent than naltrexone in blocking morphine-induced antinociception and locomotor activity, showing that 6 beta-naltrexol enters the central nervous system. In contrast to naloxone and naltrexone, 6 beta-naltrexol precipitated only minimal withdrawal at high doses in an acute dependence model and was similar to 77- and 30-fold less potent than naltrexone and naloxone, respectively, in precipitating withdrawal in a chronic dependence model. 6 beta-Naltrexol reduced the inverse agonist effects of naloxone in vitro and in vivo, as expected for a neutral antagonist. Therefore, the pharmacological effects of 6 beta-naltrexol differ markedly from those of naloxone and naltrexone in the opioid-dependent state. A reduction of withdrawal effects associated with neutral mu-opioid receptor antagonists may offer advantages in treating opioid overdose and addiction.