Distrutti Eleonora, Mencarelli Andrea, Renga Barbara, Caliendo Giuseppe, Santagada Vincenzo, Severino Beatrice, Fiorucci Stefano
S.C. di Gastroenterologia-Azienda Ospedaliera di Perugia, Ospedale Santa Maria della Misericordia, 06122 Perugia, Italy.
Pharmacol Res. 2009 May;59(5):319-29. doi: 10.1016/j.phrs.2009.01.008. Epub 2009 Jan 29.
Irritable bowel syndrome (IBS) is characterized by dysfunction of the afferent pathways that may lead to visceral hypersensitivity. Trimebutine is a weak 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-1beta, TNFalpha, 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.
肠易激综合征（IBS）的特征是传入通路功能障碍，这可能导致内脏超敏反应。曲美布汀是一种用于治疗IBS的弱阿片受体激动剂。我们报告了一种新型衍生物的作用，该衍生物是曲美布汀与硝基精氨酸成盐（NO2-Arg-Trim），在完整和结肠炎后大鼠（一种模拟IBS某些特征的动物模型）中调节对结肠扩张（CRD）的伤害感受。通过测量CRD期间的腹部退缩评分（AWR）来评估结肠敏感性和疼痛。健康大鼠分别用赋形剂、曲美布汀（10 mg/kg腹腔注射）或NO2-Arg-Trim（4、8和16 mg/kg腹腔注射）进行治疗。结肠炎后，在结肠炎诱导4周后对痛觉过敏大鼠进行研究。用NO2-Arg-Trim治疗健康大鼠导致CRD诱导的伤害感受呈剂量依赖性减弱，并抑制CRD诱导的脊髓cFOS mRNA过表达。阿片受体拮抗剂纳洛酮和一氧化氮合酶-cGMP途径抑制剂亚甲蓝可逆转NO2-Arg-Trim诱导的抗伤害感受，而L-NAME则无作用。NO2-Arg-Trim的抗伤害感受作用在炎症后痛觉过敏的啮齿动物模型中得以维持。在这种情况下，NO2-Arg-Trim而非曲美布汀显著下调脊髓cFOS mRNA表达并增加NO2 +NO3的血药浓度。此外，在结肠炎后大鼠的结肠组织中，参与炎症和疼痛的几种基因如IL-1β、TNFα、COX2和iNOS的表达上调，而NO2-Arg-Trim而非曲美布汀有效逆转了这种作用。总之，这些数据表明NO2-Arg-Trim在健康和结肠炎后痛觉过敏大鼠中均抑制CRD诱导的伤害感受。NO2-精氨酸部分与阿片类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-精氨酸衍生物可能对疼痛性肠道疾病的治疗具有有益作用。
