caa a22 4500 445797231 CHVBK 20180317145129.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s10620-010-1515-8 doi (NATIONALLICENCE)springer-10.1007/s10620-010-1515-8 Lubiprostone Reverses the Inhibitory Action of Morphine on Mucosal Secretion in Human Small Intestine [Elektronische Daten] [Xiaohong Sun, Xiyu Wang, Guo-Du Wang, Yun Xia, Sumei Liu, Meihua Qu, Bradley Needleman, Dean Mikami, W. Scott Melvin, Laura Bohn, Ryuji Ueno, Jackie Wood] Background and Aims: 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 3nM to 30μM, 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 EP4 receptors, but not at E1, EP1-3 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. Springer Science+Business Media, LLC, 2010 Constipation nationallicence Opioid analgesics nationallicence Mucosal secretion nationallicence Enteric nervous system nationallicence Prostaglandins nationallicence Irritable bowel syndrome nationallicence CFTR nationallicence ClC-2 channels nationallicence Sun Xiaohong Department of Physiology and Cell Biology, The Ohio State University College of Medicine, 304 Hamilton Hall, 1645 Neil Avenue, 43210, Columbus, OH, USA aut Wang Xiyu Department of Anesthesiology, The Ohio State University College of Medicine, Columbus, OH, USA aut Wang Guo-Du Department of Physiology and Cell Biology, The Ohio State University College of Medicine, 304 Hamilton Hall, 1645 Neil Avenue, 43210, Columbus, OH, USA aut Xia Yun Department of Anesthesiology, The Ohio State University College of Medicine, Columbus, OH, USA aut Liu Sumei Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA aut Qu Meihua Department of Physiology and Cell Biology, The Ohio State University College of Medicine, 304 Hamilton Hall, 1645 Neil Avenue, 43210, Columbus, OH, USA aut Needleman Bradley Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA aut Mikami Dean Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA aut Scott Melvin W. Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA aut Bohn Laura Department of Pharmacology, The Ohio State University College of Medicine, Columbus, OH, USA aut Ueno Ryuji Sucampo Pharmaceuticals, Inc., Bethesda, MD, USA aut Wood Jackie Department of Physiology and Cell Biology, The Ohio State University College of Medicine, 304 Hamilton Hall, 1645 Neil Avenue, 43210, Columbus, OH, USA aut Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/2(2011-02-01), 330-338 0163-2116 56:2<330 2011 56 10620 https://doi.org/10.1007/s10620-010-1515-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10620-010-1515-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sun Xiaohong Department of Physiology and Cell Biology, The Ohio State University College of Medicine, 304 Hamilton Hall, 1645 Neil Avenue, 43210, Columbus, OH, USA aut NATIONALLICENCE 700 1- Wang Xiyu Department of Anesthesiology, The Ohio State University College of Medicine, Columbus, OH, USA aut NATIONALLICENCE 700 1- Wang Guo-Du Department of Physiology and Cell Biology, The Ohio State University College of Medicine, 304 Hamilton Hall, 1645 Neil Avenue, 43210, Columbus, OH, USA aut NATIONALLICENCE 700 1- Xia Yun Department of Anesthesiology, The Ohio State University College of Medicine, Columbus, OH, USA aut NATIONALLICENCE 700 1- Liu Sumei Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA aut NATIONALLICENCE 700 1- Qu Meihua Department of Physiology and Cell Biology, The Ohio State University College of Medicine, 304 Hamilton Hall, 1645 Neil Avenue, 43210, Columbus, OH, USA aut NATIONALLICENCE 700 1- Needleman Bradley Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA aut NATIONALLICENCE 700 1- Mikami Dean Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA aut NATIONALLICENCE 700 1- Scott Melvin W. Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA aut NATIONALLICENCE 700 1- Bohn Laura Department of Pharmacology, The Ohio State University College of Medicine, Columbus, OH, USA aut NATIONALLICENCE 700 1- Ueno Ryuji Sucampo Pharmaceuticals, Inc., Bethesda, MD, USA aut NATIONALLICENCE 700 1- Wood Jackie Department of Physiology and Cell Biology, The Ohio State University College of Medicine, 304 Hamilton Hall, 1645 Neil Avenue, 43210, Columbus, OH, USA aut NATIONALLICENCE 773 0- Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/2(2011-02-01), 330-338 0163-2116 56:2<330 2011 56 10620 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer