Department Translational Medicine, St. Anna University Hospital, University of Ferrara, Ferrara, Italy.
Department of Neuroscience and Rehabilitation, Section of Pharmacology, University of Ferrara, Ferrara, Italy; LTTA Laboratory for Advanced Therapies, Technopole of Ferrara, Ferrara, Italy.
Eur J Pharmacol. 2021 Jul 15;903:174132. doi: 10.1016/j.ejphar.2021.174132. Epub 2021 Apr 30.
Opioid-induced constipation is the most prevalent adverse effect of opioid drugs. Peripherally acting mu opioid receptor antagonists (PAMORAs), including naloxegol, are indicated for the treatment of opioid-induced constipation. The aim of this study was the in vitro and in vivo pharmacological characterization of naloxegol in comparison with naloxone. In vitro experiments were performed to measure calcium mobilization in cells coexpressing opioid receptors and chimeric G proteins and mu receptor interaction with G protein and β-arrestin 2 using bioluminescence resonance energy transfer. In vivo experiments were performed in mice to measure pain threshold using the tail withdrawal assay and colonic transit using the bead expulsion assay. In vitro, naloxegol behaved as a selective and competitive mu receptor antagonist similarly to naloxone, being 3-10-fold less potent. In vivo, naloxone was effective in blocking fentanyl actions when given subcutaneously (sc), but not per os (po). In contrast, naloxegol elicited very similar effects with sc or po administration counteracting in a dose dependent manner the constipating effects of fentanyl without interfering with the fentanyl mediated analgesia. Thus, a useful PAMORA action could be obtained with naloxegol both after po and sc administration.
阿片类药物引起的便秘是阿片类药物最常见的不良反应。外周作用型μ阿片受体拮抗剂（PAMORAs），包括纳洛酮，被用于治疗阿片类药物引起的便秘。本研究的目的是比较纳洛酮和纳洛格罗在体外和体内的药理学特性。在体外实验中，通过测量共表达阿片受体和嵌合 G 蛋白的细胞中钙动员和使用生物发光共振能量转移测量μ受体与 G 蛋白和β-arrestin 2 的相互作用，来评估纳洛酮和纳洛格罗的作用。在体内实验中，通过尾巴撤退试验测量疼痛阈值，通过珠子排出试验测量结肠转运。在体外，纳洛格罗与纳洛酮一样，表现为选择性和竞争性μ受体拮抗剂，效力低 3-10 倍。在体内，纳洛酮经皮下（sc）给药可有效阻断芬太尼的作用，但经口服（po）给药无效。相比之下，纳洛格罗以剂量依赖性方式发挥类似的作用，对抗芬太尼的致便秘作用，而不干扰芬太尼介导的镇痛作用。因此，纳洛格罗经 po 和 sc 给药都可获得有用的 PAMORA 作用。
