A nitro-arginine derivative of trimebutine (NO2-Arg-Trim) attenuates pain induced by colorectal distension in conscious rats
A nitro-arginine derivative of trimebutine (NO2-Arg-Trim) attenuates pain induced by colorectal distension in conscious rats
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DOI：
10.1016/j.phrs.2009.01.008
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发表时间：
2009-05-01
影响因子：
9.3
通讯作者：
Fiorucci, Stefano
中科院分区：
文献类型：
--
作者：
Distrutti, Eleonora;Mencarelli, Andrea;Fiorucci, Stefano
肠易激综合征（IBS）的特征是传入通路功能障碍，可能导致内脏高敏感性。曲美布汀是一种用于治疗IBS的弱β阿片受体激动剂。我们报告了一种新的衍生物的影响，其中曲美布汀已成盐与硝基精氨酸（NO2-Arg-Trim），在调制伤害性感受结肠直肠扩张（CRD）在完整的和结肠炎后大鼠，动物模型，模仿IBS的一些功能。通过测量CRD期间的腹部退缩评分（AWR）来评估结直肠敏感性和疼痛。将健康大鼠用载体、曲美布汀（10 mg/kg i. p.）或NO2-Arg-Trim（4、8和16 mg/kg i. p.）。结肠炎后，在结肠炎诱导后4周研究异常性疼痛大鼠。用NO2-Arg-Trim处理健康大鼠导致CRD诱导的伤害性感受的剂量依赖性衰减和CRD诱导的脊髓cFOS mRNA过表达的抑制。NO2-Arg-Trim诱导的抗伤害作用可被阿片受体拮抗剂纳洛酮和NO还原酶-cGMP通路抑制剂亚甲蓝逆转，而L-NAME则无此作用。NO2-Arg-Trim的抗伤害感受作用在炎症后异常性疼痛的啮齿动物模型中得以维持。在这种情况下，NO2-Arg-Trim，而不是曲美布汀，显着下调脊髓cFOS mRNA的表达和增加NO2 + NO3的血液浓度。此外，参与炎症和疼痛的几个基因的表达，如IL-1 β，TNF α，COX 2和iNOS，在结肠炎后大鼠的结肠组织中上调，NO2-Arg-Trim，而不是曲美布汀，有效地逆转了这种作用。总之，这些数据表明，NO2-Arg-Trim抑制健康和结肠炎后异常性疼痛大鼠中CRD诱导的伤害感受。NO2-精氨酸部分与阿片激动剂曲美布汀相互作用，以增强其镇痛活性。本研究提供了证据表明，曲美布汀的NO2-精氨酸衍生物可能在治疗疼痛性肠道疾病中具有有益作用。(C)2009爱思唯尔有限公司版权所有。
Irritable bowel syndrome (IBS) is characterized by dysfunction of the afferent pathways that may lead to visceral hypersensitivity. Trimebutine is a weak p, opioid receptor agonist used in the treatment of IBS. We report on the effects of a novel derivative in which trimebutine has been salified with nitro-arginine (NO2-Arg-Trim), in modulating nociception to colorectal distension (CRD) in intact and post-colitis rats, an animal model that mimics some features of IBS. Colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal score (AWR) during CRD. Healthy rats were treated with vehicle, trimebutine (10 mg/kg i.p.) or NO2-Arg-Trim (4, 8 and 16 mg/kg i.p.). Post-colitis, allodynic rats were investigated 4 weeks after colitis induction. Treating healthy rats with NO2-Arg-Trim resulted in a dose-dependent attenuation of CRD-induced nociception and in an inhibition of CRD-induced overexpression of spinal cFOS mRNA. NO2-Arg-Trim-induced antinociception was reversed by the opioid receptor antagonist naloxone and by the NO synthase-cGMP pathway inhibitor methylene blue, while L-NAME had no effect. The antinociceptive effect of NO2-Arg-Trim was maintained in a rodent model of post-inflammatory allodynia. In this setting, NO2-Arg-Trim but not trimebutine, significantly down-regulated the spinal cFOS mRNA expression and increased blood concentrations of NO2 + NO3. Moreover, the expression of several genes involved in inflammation and pain, as IL-1 beta, TNF alpha, COX2 and iNOS, was up-regulated in colonic tissue from post-colitis rats and NO2-Arg-Trim, but not trimebutine, effectively reversed this effect. In summary, these data suggest that NO2-Arg-Trim inhibits nociception induced by CRD in both healthy and post-colitis, allodynic rats. The NO2-arginine moiety interacts with the opioid agonist trimebutine to potentiate its analgesic activity. This study provides evidence that NO2-arginine derivative of trimebutine might have beneficial effect in the treatment of painful intestinal disorders. (C) 2009 Elsevier Ltd. All rights reserved.