Lubiprostone Reverses the Inhibitory Action of Morphine on Mucosal Secretion in Human Small Intestine

• Published in: Digestive diseases and sciences Vol. 56; no. 2; pp. 330 - 338
• Main Authors: Sun, Xiaohong, Wang, Xiyu, Wang, Guo-Du, Xia, Yun, Liu, Sumei, Qu, Meihua, Needleman, Bradley J, Mikami, Dean J, Scott Melvin, W, Bohn, Laura M, Ueno, Ryuji, Wood, Jackie D
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.02.2011; Springer US; Springer; Springer Nature B.V
• Subjects: Alprostadil - analogs & derivatives; Alprostadil - pharmacology; Analgesics, Opioid - adverse effects; Analgesics, Opioid - pharmacology; Benzoates - pharmacology; Biochemistry; Biological and medical sciences; Cadmium Chloride - pharmacology; Cathartics - pharmacology; Drug Interactions; Evaluation; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gastroenterology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatology; Humans; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestine, Small - drug effects; Intestine, Small - metabolism; Lubiprostone; Medical sciences; Medicine; Medicine & Public Health; Morphine; Morphine - adverse effects; Morphine - pharmacology; Oncology; Original Article; Other diseases. Semiology; Prostaglandins; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thiazolidines - pharmacology; Tissue Culture Techniques; Transplant Surgery; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Enteric nervous system; Prostaglandins; Mucosal secretion; Irritable bowel syndrome; Constipation; CFTR; Opioid analgesics; ClC-2 channels; Human; Prostaglandin; Secretion; Mucosa; Opiates; Metabolic diseases; Morphine; Narcotic analgesic; Small intestine; Gastroenterology; Lubiprostone; Digestive diseases; Intestinal disease; Prostaglandin derivatives
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-010-1515-8

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.