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- Title
Lubiprostone reverses the inhibitory action of morphine on mucosal secretion in human small intestine.
- Authors
Sun, Xiaohong; Wang, Xiyu; Wang, Guo-Du; Xia, Yun; Liu, Sumei; Qu, Meihua; Needleman, Bradley; Mikami, Dean; Scott Melvin, W.; Bohn, Laura; Ueno, Ryuji; Wood, Jackie; Needleman, Bradley J; Mikami, Dean J; Melvin, W Scott; Bohn, Laura M; Wood, Jackie D
- Abstract
<bold>Background and Aims: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
CONSTIPATION; THERAPEUTICS; ENTERIC nervous system; IRRITABLE colon; MORPHINE; OPIOIDS; BIOCHEMICAL mechanism of action; GASTRIC bypass; PROSTAGLANDINS; CYSTIC fibrosis; CHLORIDE channels; ANALGESICS; ANTI-infective agents; DRUG interactions; INTESTINAL mucosa; SMALL intestine; LAXATIVES; RESEARCH methodology; NARCOTICS; RESEARCH funding; THIAZOLES; TISSUE culture; VASODILATORS; CADMIUM chloride; PHARMACODYNAMICS
- Publication
Digestive Diseases & Sciences, 2011, Vol 56, Issue 2, p330
- ISSN
0163-2116
- Publication type
journal article
- DOI
10.1007/s10620-010-1515-8