Brief Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Mar 28, 2012; 18(12): 1391-1396
Published online Mar 28, 2012. doi: 10.3748/wjg.v18.i12.1391
Opiate-induced constipation related to activation of small intestine opioid μ2-receptors
Wency Chen, Hsien-Hui Chung, Juei-Tang Cheng
Wency Chen, Department of Internal Medicine, E-Da Hospital and I-Shou University, Kaohsiung City, Taiwan 82401, China
Hsien-Hui Chung, Juei-Tang Cheng, Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 70101, China
Juei-Tang Cheng, Institute of Medical Sciences, Chang Jung Christian University, Quei-Jen, Tainan City, Taiwan 71101, China
Author contributions: Chen C initiated this proposal and performed the experiments. Chung HH carried out all experiments together with Chen W, Cheng JT completed the preparation of the manuscript and was in charge of submission.
Supported by A grant from E-Da Hospital (in part)
Correspondence to: Juei-Tang Cheng, PhD, FCP, Professor, Institute of Medical Sciences, Chang Jung Christian University, Quei-Jen, Tainan City 71101, Taiwan, China.
Telephone: +886-6-3318516 Fax: +886-6-3317532
Received: August 11, 2011
Revised: September 24, 2011
Accepted: January 18, 2012
Published online: March 28, 2012

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+ (KATP) 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 KATP channels, relates to OIC.

Keywords: ATP-sensitive K+ channels, Isometric tension, Loperamide, Opioid μ-receptors, Small intestine