阿片类药物引起的便秘与小肠阿片 μ2 受体的激活有关。
Opiate-induced constipation related to activation of small intestine opioid μ2-receptors.
机构信息
Department of Internal Medicine, E-Da Hospital and I-Shou University, Kaohsiung City, Taiwan 82401, China.
出版信息
World J Gastroenterol. 2012 Mar 28;18(12):1391-6. doi: 10.3748/wjg.v18.i12.1391.
AIM
To investigate the role of opioid μ-receptor subtype in opiate-induced constipation (OIC).
METHODS
The effect of loperamide on intestinal transit was investigated in mice. Ileum strips were isolated from 12-wk-old male BALB/c mice for identification of isometric tension. The ileum strips were precontracted with 1 μmol/L acetylcholine (ACh). Then, decrease in muscle tone (relaxation) was characterized after cumulative administration of 0.1-10 μmol/L loperamide into the organ bath, for a concentration-dependent study. Specific blockers or antagonists were used for pretreatment to compare the changes in loperamide-induced relaxation.
RESULTS
In addition to the delay in intestinal transit, loperamide produced a marked relaxation in isolated ileum precontracted with ACh, in a dose-dependent manner. This relaxation was abolished by cyprodime, a selective opioid μ-receptor antagonist, but not modified by naloxonazine at a dose sufficient to block opioid μ-1 receptors. Also, treatment with opioid μ-1 receptor agonist failed to modify the muscle tone. Moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K+ (K(ATP)) channels, and by protein kinase A (PKA) inhibitor, but was enhanced by an inhibitor of phosphodiesterase for cyclic adenosine monophosphate (cAMP).
CONCLUSION
Loperamide induces intestinal relaxation by activation of opioid μ-2 receptors via the cAMP-PKA pathway to open K(ATP) channels, relates to OIC.
目的
探讨阿片 μ 受体亚型在阿片类药物诱导性便秘（OIC）中的作用。
方法
观察洛哌丁胺对小鼠肠道转运的影响。从小鼠回肠分离 12 周龄雄性 BALB/c 小鼠的回肠条，用于鉴定等长张力。用 1 μmol/L 乙酰胆碱（ACh）预收缩回肠条。然后，在器官浴中累积给予 0.1-10 μmol/L 洛哌丁胺，观察其对肌肉张力（松弛）的影响，进行浓度依赖性研究。使用特定的阻滞剂或拮抗剂进行预处理，以比较洛哌丁胺诱导的松弛变化。
结果
除了延迟肠道转运外，洛哌丁胺还以剂量依赖的方式使预先用 ACh 收缩的离体回肠产生明显的松弛。这种松弛被环丙吗啡，一种选择性阿片 μ 受体拮抗剂所消除，但纳洛酮嗪在足以阻断阿片 μ-1 受体的剂量下没有改变。此外，阿片 μ-1 受体激动剂的治疗未能改变肌肉张力。此外，洛哌丁胺的松弛作用被足以阻断三磷酸腺苷敏感性钾（K(ATP)）通道的格列本脲和蛋白激酶 A（PKA）抑制剂减弱，但被环腺苷酸（cAMP）磷酸二酯酶抑制剂增强。
结论
洛哌丁胺通过 cAMP-PKA 途径激活阿片 μ-2 受体诱导肠道松弛，从而打开 K(ATP)通道，与 OIC 有关。
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