Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pharmacol Ther. Aug 6, 2015; 6(3): 73-83
Published online Aug 6, 2015. doi: 10.4292/wjgpt.v6.i3.73
Nociceptin effect on intestinal motility depends on opioid-receptor like-1 receptors and nitric oxide synthase co-localization
Andrei Sibaev, Jakub Fichna, Dieter Saur, Birol Yuece, Jean-Pierre Timmermans, Martin Storr
Andrei Sibaev, Birol Yuece, Martin Storr, Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, 81377 Munich, Germany
Jakub Fichna, Martin Storr, Division of Gastroenterology, University of Calgary, Calgary T2N 2T9, Canada
Jakub Fichna, Department of Biochemistry, Medical University of Lodz, 92215 Lodz, Poland
Dieter Saur, Department of Internal Medicine II, Technical University Munich, 81675 Munich, Germany
Jean-Pierre Timmermans, Laboratory of Cell Biology and Histology, University of Antwerp, B-2020 Antwerp, Belgium
Author contributions: Sibaev A, Fichna J, Saur D, Yuece B, Timmermans JP and Storr M contributed to study concept and design; Sibaev A, Fichna J, Saur D and Timmermans JP contributed to acquisition of data; all authors contributed to analysis and interpretation of data; Storr M contributed to drafting of the manuscript; all authors contributed to critical revision of the manuscript for important intellectual content; Sibaev A and Fichna J contributed to statistical analysis; Timmermans JP and Storr M contributed to study supervision.
Supported by The Deutsche Forschungsgemeinschaft (STO 645/2-1 to Storr M and YU132/2-1 to Yuece B), the Society of Gastroenterology in Bavaria (to Storr M), the Förderprogramm für Forschung und Lehre of the Ludwig Maximilians University Munich to Yuece B, the University of Calgary Research Grant Committee (to Storr M), the Iuventus Plus program of the Polish Ministry of Science and Higher Education (#0107/IP1/2013/72 to Fichna J) and the grants from the Medical University of Lodz (#503/1-156-04/503-01 to Fichna J) and National Science Centre (#UMO-2013/11/B/NZ7/01301 to Fichna J).
Institutional review board statement: The study was reviewed and approved by the University of Calgary, Calgary, Canada Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Calgary, Calgary, Canada (IACUC protocol number: M07071/2010).
Conflict-of-interest statement: Authors declare no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Martin Storr, MD, PhD, Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Marchioninistrasse 15, 81377 Munich, Germany. martin.storr@med.uni-muenchen.de
Telephone: +49-89-70950 Fax: +49-89-70955281
Received: November 18, 2014
Peer-review started: November 18, 2014
First decision: December 12, 2014
Revised: April 26, 2015
Accepted: May 16, 2015
Article in press: May 18, 2015
Published online: August 6, 2015
Processing time: 263 Days and 9.2 Hours
Abstract

AIM: To study the effect of the opioid-receptor like-1 (ORL1) agonist nociceptin on gastrointestinal (GI) myenteric neurotransmission and motility.

METHODS: Reverse transcriptase - polymerase chain reaction and immunohistochemistry were used to localize nociceptin and ORL1 in mouse tissues. Intracellular electrophysiological recordings of excitatory and inhibitory junction potentials (EJP, IJP) were made in a chambered organ bath. Intestinal motility was measured in vivo.

RESULTS: Nociceptin accelerated whole and upper GI transit, but slowed colonic expulsion in vivo in an ORL1-dependent manner, as shown using [Nphe1]NOC and AS ODN pretreatment. ORL1 and nociceptin immunoreactivity were found on enteric neurons. Nociceptin reduced the EJP and the nitric oxide-sensitive slow IJP in an ORL1-dependent manner, whereas the fast IJP was unchanged. Nociceptin further reduced the spatial spreading of the EJP up to 2 cm.

CONCLUSION: Compounds acting at ORL1 are good candidates for the future treatment of disorders associated with increased colonic transit, such as diarrhea or diarrhea-predominant irritable bowel syndrome.

Keywords: Nociceptin, Gastrointestinal transit, Opioid-receptor like-1, Electrophysiology, Expression

Core tip: Here we aimed to study the effect of the endogenous opioid-receptor like-1 (ORL1) agonist nociceptin on gastrointestinal (GI) myenteric neurotransmission and motility. We observed that nociceptin reduces excitatory and inhibitory neurotransmission in motorneurons and interneurons and the overall effect on the GI tract may depend on co-localization of ORL1 receptors with nitric oxide synthase. Since ORL1 activation, unlike other opioid receptor-active drugs, is not associated with central side effects, compounds acting at the ORL1 may be good candidates for the future treatment of disorders associated with increased colonic transit, such as diarrhea or diarrhea-predominant irritable bowel syndrome.