Circular muscle contraction in the mice rectum plays a key role in morphine-induced constipation
Circular muscle contraction in the mice rectum plays a key role in morphine-induced constipation
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DOI：
10.1111/nmo.12387
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发表时间：
2014-10-01
影响因子：
3.5
通讯作者：
Kanemasa, T.
中科院分区：
文献类型：
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作者：
Ono, H.;Nakamura, A.;Kanemasa, T.
背景虽然阿片类药物会引起肠道肌肉收缩并引发便秘，但导致便秘的肠道区域仍不清楚。我们在此报告肠道肌肉收缩对吗啡的区域特异性反应及其与体内便秘的相关性。方法对小鼠小肠和大肠区域进行组织学解剖，并使用等长传感器测量环形肌收缩反应。进行珠排出测定以评估体内便秘。主要结果 在直肠中检测到对吗啡反应最强烈的收缩。远端和横结肠也显示出强烈的收缩，而近端结肠、空肠和回肠则检测到微弱的反应。关于吗啡暴露期间肌肉收缩的可持续性，仅在直肠中检测到波延长，而其他区域的波逐渐减弱。为了确定这种差异背后的机制，我们重点关注一氧化氮合酶 (NOS)。在远端结肠中，通过应用 NOS 抑制剂（L-NAME）可以恢复吗啡暴露期间收缩的减少，而 NOS 底物（L-精氨酸）则增强收缩降解。相比之下，L-NAME 和 L-精氨酸对直肠的持续收缩影响不大。为了确认与便秘的相关性，在给予吗啡后将珠子插入横结肠、远端结肠或直肠并检查排出时间。即使将珠子插入较深的结肠区域，珠子也往往会停在直肠处。结论与推论 在体外和体内分析中，直肠对吗啡表现出最大的反应，因此它可能在阿片类药物引起的便秘中发挥关键作用。
Background Although opioids induce intestinal muscle contraction and provoke constipation, the intestinal region(s) that contribute to the constipation have remained unclear. We report here a region-specific response of intestinal muscle contraction to morphine and its correlation with in vivo constipation. Methods Regions of mice small and large intestines were dissected histologically and circular muscle contractile responses were measured using isometric transducers. Bead expulsion assays were performed to assess in vivo constipation. Key Results The strongest contraction in response to morphine was detected in the rectum. The distal and transverse colon also showed strong contractions, whereas weak responses were detected in the proximal colon, jejunum, and ileum. Regarding the sustainability of muscle contractions during morphine exposure, prolonged waves were detected only in the rectum, while the waves diminished gradually in other regions. To identify the mechanism(s) underlying this difference, we focused on nitric oxide synthase (NOS). In the distal colon, decreased contraction during morphine exposure was recovered by application of a NOS inhibitor (L-NAME), while a NOS substrate (L-arginine) enhanced contractile degradation. In contrast L-NAME and L-arginine modestly affected the sustained contraction in the rectum. To confirm the correlation with constipation, beads were inserted into the transverse colon, distal colon, or rectum after morphine administration and expulsion times were examined. Beads tended to stop at the rectum even when inserted in the deeper colonic regions. Conclusions & Inferences The rectum showed the greatest response to morphine in both in vitro and in vivo analyses, therefore itmayplay a key role for opioid-induced constipation.