Digestive Diseases and Sciences

, Volume 56, Issue 2, pp 330–338

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
Original Article

DOI: 10.1007/s10620-010-1515-8

Cite this article as:
Sun, X., Wang, X., Wang, GD. et al. Dig Dis Sci (2011) 56: 330. doi:10.1007/s10620-010-1515-8
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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.

Keywords

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

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Xiaohong Sun
    • 4
    • 7
  • Xiyu Wang
    • 1
  • Guo-Du Wang
    • 4
  • Yun Xia
    • 1
  • Sumei Liu
    • 2
    • 4
    • 9
  • Meihua Qu
    • 4
    • 8
  • Bradley J. Needleman
    • 5
  • Dean J. Mikami
    • 5
  • W. Scott Melvin
    • 5
  • Laura M. Bohn
    • 3
    • 10
  • Ryuji Ueno
    • 6
  • Jackie D. Wood
    • 4
  1. 1.Department of AnesthesiologyThe Ohio State University College of MedicineColumbusUSA
  2. 2.Department of Internal MedicineThe Ohio State University College of MedicineColumbusUSA
  3. 3.Department of PharmacologyThe Ohio State University College of MedicineColumbusUSA
  4. 4.Department of Physiology and Cell BiologyThe Ohio State University College of MedicineColumbusUSA
  5. 5.Department of SurgeryThe Ohio State University College of MedicineColumbusUSA
  6. 6.Sucampo Pharmaceuticals, Inc.BethesdaUSA
  7. 7.Division of GastroenterologyPeking Union Medical College HospitalBeijingChina
  8. 8.Department of PharmacologyWeifang Medical UniversityWeifangChina
  9. 9.Department of Biology, College of Science and HealthUniversity of Wisconsin, La CrosseLa CrosseUSA
  10. 10.Department of Molecular TherapeuticsThe Scripps Research InstituteJupiterUSA

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