title: Lubiprostone reverses the inhibitory action of morphine on mucosal secretion in human small intestine.
abstract: OBJECTIVE
  Treatments with morphine or opioid agonists cause constipation. Lubiprostone is approved for treatment of adult idiopathic constipation and constipation-predominant IBS in adult women. We tested whether lubiprostone can reverse morphine-suppression of mucosal secretion in human intestine and explored the mechanism of action.
  
  
  METHODS
  Fresh segments of jejunum discarded during Roux-En-Y gastric bypass surgeries were used. Changes in short-circuit current (ΔIsc) were recorded in Ussing flux chambers as a marker for electrogenic chloride secretion during pharmacological interactions between morphine, prostaglandin receptor antagonists, chloride channel blockers and lubiprostone.
  
  
  RESULTS
  Morphine suppressed basal Isc. Lubiprostone reversed morphine suppression of basal Isc. Lubiprostone, applied to the mucosa in concentrations ranging from 3 nM to 30 μM, evoked increases in Isc in concentration-dependent manner when applied to the mucosal side of muscle-stripped preparations. Blockade of enteric nerves did not change stimulation of Isc by lubiprostone. Removal of chloride or application of bumetanide or NPPB suppressed or abolished responses to lubiprostone. Antagonists acting at CFTR channels and prostaglandin EP(4) receptors, but not at E(1), EP(1-3) receptors, partially suppressed stimulation of Isc by lubiprostone.
  
  
  CONCLUSIONS
  Antisecretory action of morphine results from suppression of excitability of secretomotor neurons in the enteric nervous system. Lubiprostone, which does not affect enteric neurons directly, bypasses the action of morphine by directly opening mucosal chloride channels.
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, OH 43210, USA. sunxiaoh1968@yahoo.com.cn
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Sun
authors.forename: Xiyu
authors.initials: X
authors.lastname: Wang
authors.forename: Guo-Du
authors.initials: GD
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Xia
authors.forename: Sumei
authors.initials: S
authors.lastname: Liu
authors.forename: Meihua
authors.initials: M
authors.lastname: Qu
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Needleman
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Mikami
authors.forename: W Scott
authors.initials: WS
authors.lastname: Melvin
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ueno
authors.forename: Jackie D
authors.initials: JD
authors.lastname: Wood
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D019256:Cadmium Chloride / Q000494:pharmacology; D002400:Cathartics / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D000068238:Lubiprostone; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D053778:Thiazolidines / Q000494:pharmacology; D046509:Tissue Culture Techniques
chemical_list: C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D000701:Analgesics, Opioid; D001565:Benzoates; D002400:Cathartics; D053778:Thiazolidines; D000068238:Lubiprostone; D009020:Morphine; D000527:Alprostadil; D019256:Cadmium Chloride