title: Toll-like receptor 4 contributes to the inhibitory effect of morphine on colonic motility in vitro and in vivo.
abstract: Opioids rank among the most potent analgesic drugs but gastrointestinal side effects, especially constipation, limit their therapeutic utility. The adverse effects of opioids have been attributed to stimulation of opioid receptors, but emerging evidence suggests that opioids interact with the innate immune receptor Toll-like receptor 4 (TLR4) and its signalling pathway. As TLR4 signalling affects gastrointestinal motility, we examined the involvement of TLR4 in morphine-induced depression of peristaltic motility in the guinea-pig intestine in vitro and male C57BL/6N mice in vivo. While the TLR4 antagonist TAK-242 (0.1 μM and 1 μM) did not alter the morphine-induced inhibition of peristalsis in the isolated guinea-pig small intestine, the morphine-induced decrease in pellet propulsion velocity in colonic segments was attenuated by TAK-242 (0.1 μM). The ability of TAK-242 (4 mg/kg) to mitigate the morphine-induced suppression of colonic motility was replicated in mice in vivo by measuring the expulsion time of beads inserted in the distal colon. The inhibition of upper gastrointestinal transit of mice by morphine was not affected by pre-treatment with TAK-242 (4 mg/kg) in vivo. This is the first report that morphine-induced inhibition of colonic peristalsis is alleviated by TLR4 antagonism. We therefore conclude that TLR4 may contribute to opioid-induced constipation.
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Aitak
authors.initials: A
authors.lastname: Farzi
authors.affiliation: 1] Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria [2] Department of Pathophysiology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Halicka
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Mayerhofer
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Fröhlich
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 29, 8036 Graz, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Tatzl
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Holzer
mesh_terms: D000818:Animals; D003106:Colon / Q000378:metabolism*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009020:Morphine