title: Opiate-induced constipation related to activation of small intestine opioid μ2-receptors.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  Loperamide induces intestinal relaxation by activation of opioid μ-2 receptors via the cAMP-PKA pathway to open K(ATP) channels, relates to OIC.
authors.affiliation: Department of Internal Medicine, E-Da Hospital and I-Shou University, Kaohsiung City, Taiwan 82401, China.
authors.forename: Wency
authors.initials: W
authors.lastname: Chen
authors.forename: Hsien-Hui
authors.initials: HH
authors.lastname: Chung
authors.forename: Juei-Tang
authors.initials: JT
authors.lastname: Cheng
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology; D003248:Constipation / Q000139:chemically induced* / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005772:Gastrointestinal Transit / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009019:Morphinans / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D000930:Antidiarrheals; D009019:Morphinans; D017450:Receptors, Opioid, mu; C058450:cyprodime; D009270:Naloxone; D008139:Loperamide; C034643:naloxonazine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000109:Acetylcholine; D005905:Glyburide