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Lubiprostone reverses the inhibitory action of morphine on intestinal secretion in guinea pig and mouse

Academic Article
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Overview

authors

  • Fei, G. J.
  • Raehal, K.
  • Liu, S. M.
  • Qu, M. H.
  • Sun, X. H.
  • Wang, G. D.
  • Wang, X. Y.
  • Xia, Y.
  • Schmid, C. L.
  • Bohn, Laura
  • Wood, J. D.

publication date

  • July 2010

journal

  • Journal of Pharmacology and Experimental Therapeutics  Journal

abstract

  • Lubiprostone activates ClC-2 chloride channels in epithelia. It is approved for treatment of chronic idiopathic constipation in adults and constipation-predominate irritable bowel syndrome in women. We tested a hypothesis that lubiprostone can reverse the constipating action of morphine and investigated the mechanism of action. Short-circuit current (Isc) was recorded in Ussing chambers as a marker for chloride secretion during pharmacological interactions between morphine and lubiprostone. Measurements of fecal wet weight were used to obtain information on morphine-lubiprostone interactions in conscious mice. Morphine decreased basal Isc, with an IC(50) of 96.1 nM. The action of dimethylphenylpiperazinium (DMPP), a nicotinic receptor agonist that stimulates neurogenic Isc, was suppressed by morphine. Lubiprostone applied after pretreatment with morphine reversed morphine suppression of both basal Isc and DMPP-evoked chloride secretion. Electrical field stimulation (EFS) of submucosal neurons evoked biphasic increases in Isc. Morphine abolished the first phase and marginally suppressed the second phase. Lubiprostone reversed, in concentration-dependent manner, the action of morphine on the first and second phases of the EFS-evoked responses. Subcutaneous lubiprostone increased fecal wet weight and numbers of pellets expelled. Morphine significantly reduced fecal wet weight and number of pellets. Injection of lubiprostone, 30-min after morphine, reversed morphine-induced suppression of fecal wet weight. We conclude that inhibitory action of morphine on chloride secretion reflects suppression of excitability of cholinergic secretomotor neurons in the enteric nervous system. Lubiprostone, which does not directly affect enteric neurons, bypasses the neurogenic constipating effects of morphine by directly opening chloride channels in the mucosal epithelium.

subject areas

  • Alprostadil
  • Animals
  • Chloride Channels
  • Chlorine
  • Constipation
  • Dose-Response Relationship, Drug
  • Feces
  • Guinea Pigs
  • In Vitro Techniques
  • Intestinal Mucosa
  • Intestines
  • Ion Channel Gating
  • Lubiprostone
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morphine
  • Neurons
  • Prostaglandins
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Identity

PubMed Central ID

  • PMC2912047

International Standard Serial Number (ISSN)

  • 0022-3565

Digital Object Identifier (DOI)

  • 10.1124/jpet.110.166116

PubMed ID

  • 20406855
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Additional Document Info

start page

  • 333

end page

  • 340

volume

  • 334

issue

  • 1

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