Purdue Pharma L.P., Discovery Research, Cranbury, NJ 08512, United States.
World J Gastroenterol. 2017 Sep 7;23(33):6065-6076. doi: 10.3748/wjg.v23.i33.6065.
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 ( = 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.
评估非甾体抗炎药（NSAIDs）诱导的胃病是否是内脏感觉过敏的临床预测模型。
通过给雄性 CD1 小鼠口服吲哚美辛诱导胃溃疡疼痛，然后通过测量对触诊的腹部超敏反应来评估。随后研究了多种与疼痛有关的药理学机制。这些机制包括：瞬时受体电位（TRP）、钠和酸感应离子通道（ASICs）以及阿片受体和鸟苷酸环化酶 C（GC-C）。
结果表明，两种阿片类药物和一种 GC-C 激动剂，即吗啡、asimadoline 和利那洛肽，分别是 TRP 拮抗剂 AMG9810 和 HC-030031 和钠通道阻滞剂卡马西平，都能剂量和/或时间依赖性地减轻内脏超敏反应，而 ASIC 阻滞剂阿米洛利在所有测试剂量下均无效。
这些发现表明，阿片受体、GC-C 以及钠和 TRP 通道的激活可能与内脏超敏反应有关。更重要的是，这些发现还验证了 NSAIDs 诱导的胃病作为一种敏感且具有临床预测性的小鼠模型，适合评估具有潜在镇痛特性的新型分子。
