Differences in the characteristics of tolerance to μ-opioid receptor agonists in the colon from wild type and β-arrestin2 knockout mice
Differences in the characteristics of tolerance to μ-opioid receptor agonists in the colon from wild type and β-arrestin2 knockout mice
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DOI：
10.1016/j.ejphar.2012.04.001
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发表时间：
2012-06-15
影响因子：
5
通讯作者：
Akbarali, Hamid I.
中科院分区：
文献类型：
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作者：
Maguma, Hercules T.;Dewey, William L.;Akbarali, Hamid I.
阿片类药物使用的缺点包括镇痛耐受性和持续性便秘的发展。我们先前曾报道，吗啡耐受性的发展后，反复暴露在离体回肠，但不是离体结肠。抗伤害性耐受的细胞机制在μ阿片受体激动剂之间不同。在这项研究中，我们评估了β-arrestin 2缺失对回肠和结肠环行肌对不同阿片类药物耐受性的发展。通过评估重复体外阿片样物质暴露诱导C57 BL/6野生型（WT）和β-抑制蛋白2敲除（KO）小鼠环行肌收缩的能力来确定耐受性。每30分钟重复暴露一次，中间进行清洗，导致WT和KO小鼠的回肠对所有激动剂耐受。然而，在WT小鼠的结肠中，第4次暴露和第1次反应之间的收缩比较与DAMGO相似（100 +/-10%; N = 5），但降低至芬太尼（62 +/-13%; N = 8）和埃托啡（38 +/-4%; N = 7），表明对芬太尼和埃托啡而不是DAMGO的耐受性。相比之下，所有激动剂在KO的结肠中产生耐受性：第4次暴露时DAMGO反应降低至52 +/-10%（N = 5），芬太尼降低至20 +/-5%（N = 6），埃托啡降低至33 +/-7%（N = 6）。结肠中阿片受体激动剂之间的耐受性差异表明配体偏倚。结肠中β-arrestin 2的缺失似乎是耐受DAMGO所必需的，而不是芬太尼或埃托啡。β-arrestin 2潜在地代表了治疗阿片类药物诱导的肠功能障碍的重要靶点，并保证了对其配体偏倚的进一步探索。(C)2012爱思唯尔有限公司版权所有。
Drawbacks to opioid use include development of analgesic tolerance and persistent constipation. We previously reported that tolerance to morphine develops upon repeated exposure in the isolated ileum but not the isolated colon. The cellular mechanisms of antinociceptive tolerance vary among mu-opioid receptor agonists. In this study, we assess beta-arrestin2 deletion on the development of tolerance to different opioids in ileum and colon circular muscle. Tolerance was determined by assessing the ability of repeated in-vitro opioid exposure to induce contraction of the circular muscle from C57BL/6 wild type (WT) and beta-arrestin2 knockout (KO) mice. Repeated exposure every 30 min with in-between washes resulted in tolerance to all agonists in the ileum of both WT and KO mice. However, in the colon of WT mice, comparison of the contractions between the 4th exposure and 1st response was similar to DAMGO (100 +/- 10%; N = 5) but reduced to fentanyl (62 +/- 13%; N = 8) and etorphine (38 +/- 4%; N = 7) indicative of tolerance to fentanyl and etorphine but not DAMGO. In contrast, all agonists produced tolerance in the colon of KO: DAMGO response at the 4th exposure decreased to 52 +/- 10% (N = 5), fentanyl to 20 +/- 5% (N = 6) and etorphine 33 +/- 7% (N = 6). Differences in tolerance among opioid agonists in the colon suggest ligand bias. The deletion of beta-arrestin2 in colon appears to be necessary for tolerance to DAMGO but not fentanyl or etorphine. beta-arrestin2 potentially represents an important target for treating opioid-induced bowel dysfunction and warrants further exploration of its ligand bias. (C) 2012 Elsevier B.V. All rights reserved.