Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2017; 23(33): 6065-6076
Published online Sep 7, 2017. doi: 10.3748/wjg.v23.i33.6065
Pharmacological evaluation of NSAID-induced gastropathy as a "Translatable" model of referred visceral hypersensitivity
Michele Hummel, Terri Knappenberger, Meghan Reilly, Garth T Whiteside
Michele Hummel, Terri Knappenberger, Meghan Reilly, Garth T Whiteside, Purdue Pharma L.P., Discovery Research, Cranbury, NJ 08512, United States
Author contributions: Hummel M and Whiteside GT equally conceptualized study design, analysis, and interpretation of study results; Hummel M wrote the manuscript; Knappenberger T collected and analyzed the data; Reilly M collected rotarod data and prepared the figures depicting the data.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Purdue Institutional Animal Care and Use Committee (IACUC Protocol number: 2014-100) in accordance with the NIH Guide for the Care and Use of Laboratory Animals and the Ethical Guidelines of the International Association for the Study of Pain (www.iasp-pain.org) and are reported in accordance with the ARRIVE guidelines (www.nc3rs.org.uk). All efforts were made to minimize the number of animals used and to avoid any undue pain.
Conflict-of-interest statement: There are no conflicts of interests with any of the authors.
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: Michele Hummel, PhD, Trevena, Inc., 1018 West 8th Avenue, Suite A, King of Prussia, PA 19406. United States. mhummel@trevena.com
Telephone: +1-610-3548840 ext. 346 Fax: +1-610-3548850
Received: February 2, 2017
Peer-review started: February 8, 2017
First decision: May 12, 2017
Revised: May 31, 2017
Accepted: July 12, 2017
Article in press: July 12, 2017
Published online: September 7, 2017
Abstract
AIM

To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.

METHODS

Gastric ulcer pain was induced by the oral administration of indomethacin to male, CD1 mice (n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential (TRP), sodium and acid-sensing ion channels (ASICs) as well as opioid receptors and guanylate cyclase C (GC-C).

RESULTS

Results showed that two opioids and a GC-C agonist, morphine, asimadoline and linaclotide, respectively, the TRP antagonists, AMG9810 and HC-030031 and the sodium channel blocker, carbamazepine, elicited a dose- and/or time-dependent attenuation of referred visceral hypersensitivity, while the ASIC blocker, amiloride, was ineffective at all doses tested.

CONCLUSION

Together, these findings implicate opioid receptors, GC-C, and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly, these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.

Keywords: Visceral hypersensitivity, Pain, Translation, Guanylate cyclase C, Non-steroidal anti-inflammatory drugs, Transient receptor potential channel

Core tip: Recently, standard animal models of pain have been vehemently challenged for their inability to successfully predict human clinical outcomes. Further, few animal models have been represented with reasonable translational value for conditions presenting with visceral pain. Non-steroidal anti-inflammatory drug -induced gastropathy represents a translatable model of visceral hypersensitivity in which several pain targets have demonstrated reliable sensitivity when assayed. Further, this model is robust enough that proper pharmacological evaluation can be conducted. Overall, this model has the potential to efficiently triage molecules with pain-attenuating properties for their utility in gastrointestinal disorders that include pain as a hallmark symptom.