PT  - JOURNAL ARTICLE
AU  - Guijun Fei
AU  - Kirsten Raehal
AU  - Sumei Liu
AU  - Mei-Hua Qu
AU  - Xiaohong Sun
AU  - Guo-Du Wang
AU  - Xi-Yu Wang
AU  - Yun Xia
AU  - Cullen L. Schmid
AU  - Laura M. Bohn
AU  - Jackie D. Wood
TI  - Lubiprostone Reverses the Inhibitory Action of Morphine on Intestinal Secretion in Guinea Pig and Mouse
AID  - 10.1124/jpet.110.166116
DP  - 2010 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 333--340
VI  - 334
IP  - 1
4099  - http://jpet.aspetjournals.org/content/334/1/333.short
4100  - http://jpet.aspetjournals.org/content/334/1/333.full
SO  - J Pharmacol Exp Ther2010 Jul 01; 334
AB  - 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 IC50 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics