Published online Sep 7, 2017. doi: 10.3748/wjg.v23.i33.6065
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
Processing time: 217 Days and 4.2 Hours
To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.
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 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.
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.
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.