Lubiprostone reverses the inhibitory action of morphine on mucosal secretion in human small intestine

Xiaohong Sun, Xiyu Wang, Guo Du Wang, Yun Xia, Sumei Liu, Meihua Qu, Bradley J. Needleman, Dean J. Mikami, W. Scott Melvin, Laura M. Bohn, Ryuji Ueno, Jackie D. Wood

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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 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 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.

Original languageEnglish (US)
Pages (from-to)330-338
Number of pages9
JournalDigestive Diseases and Sciences
Volume56
Issue number2
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

Keywords

  • CFTR
  • ClC-2 channels
  • Constipation
  • Enteric nervous system
  • Irritable bowel syndrome
  • Mucosal secretion
  • Opioid analgesics
  • Prostaglandins

ASJC Scopus subject areas

  • Physiology
  • Gastroenterology

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    Sun, X., Wang, X., Wang, G. D., Xia, Y., Liu, S., Qu, M., Needleman, B. J., Mikami, D. J., Scott Melvin, W., Bohn, L. M., Ueno, R., & Wood, J. D. (2011). Lubiprostone reverses the inhibitory action of morphine on mucosal secretion in human small intestine. Digestive Diseases and Sciences, 56(2), 330-338. https://doi.org/10.1007/s10620-010-1515-8