Pharmacological evaluation of NSAID-induced gastropathy as a “Translatable” model of referred visceral sensitivity

Abstract

AIMTo evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.METHODSGastric 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).RESULTSResults 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.CONCLUSIONTogether, 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.

Somatic pain sensitivity under the injury of gastric mucosa and small intestine induced by cold-restraint stress in rats

“…Однако имеются данные, полученные в других ульцерогенных моделях, косвенно подтверждающие это предположение. Показано, что образование геморрагических эрозий СОЖ, индуцированных ульцерогенным действием индометацина, является источником Соматическая болевая чувствительность... висцеральной боли, что подтверждается ее «отражением» в абдоминальную область у мышей (увеличением чувствительности данной области к тактильным раздражителям) (Hummel et al 2017). Патологический процесс в желудке, индуцированный йодоацетоамидом, включающий, в том числе, и образование геморрагических эрозий, вызывает увеличение амплитуды висцеромоторного ответа на действие как механического (растяжение стенки желудка), так и химического стимула (интрагастральное введение кислоты), что является признаком висцеральной гиперчувствительности (гипералгезии) (Lamb et al 2003).…”

Effects of Acetazolamide, Paracetamol, and Placebo on Postoperative Pain in Laparoscopic Cholecystectomy: A Randomized, Double-blind, Parallel-controlled Clinical Trial

“…It is possible that tissue acidosis, an important side effect of acetazolamide, be responsible for the higher frequency of diffuse abdominal pain and referred shoulder pain in group A in the recovery room. Bala et al (2015) observed that visceral pain scores were significantly lower while resting, coughing, and moving at 2, 4, 6, 12, and 4 hours postoperatively (16). The effect of a single dose of acetazolamide is known to last for 4-6 hours.…”

Activation of TRPV1 and TRPM8 Channels in the Larynx and Associated Laryngopharyngeal Regions Facilitates the Swallowing Reflex

“…AMG 9810 (2E)-N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1,1-dimethylethyl)phenyl]-2-propenamide (Enzo Life Sciences, Inc. NY, USA) and AMTB [N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride salt] (Wako Pure Chemical Industries Ltd. Osaka, Japan) were used as TRPV1 and TRPM8 antagonists, respectively. Various in vitro and in vivo studies showed the effeicacy of AMG 9810 and AMTB to block TRPV1 and TRPM8, respectively [71,72,73,74,75,76]. AMG 9810 was dissolved in small amount of DMSO and Tween 80 and diluted in normal saline.…”