A nitro-arginine derivative of trimebutine (NO 2-Arg-Trim) attenuates pain induced by colorectal distension in conscious rats

Abstract

Irritable bowel syndrome (IBS) is characterized by dysfunction of the afferent pathways that may lead to visceral hypersensitivity. Trimebutine is a weak μ 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 (NO 2-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 NO 2-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 NO 2-Arg-Trim resulted in a dose-dependent attenuation of CRD-induced nociception and in an inhibition of CRD-induced overexpression of spinal cFOS mRNA. NO 2-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 NO 2-Arg-Trim was maintained in a rodent model of post-inflammatory allodynia. In this setting, NO 2-Arg-Trim but not trimebutine, significantly down-regulated the spinal cFOS mRNA expression and increased blood concentrations of NO 2 + NO 3. Moreover, the expression of several genes involved in inflammation and pain, as IL-1β, TNFα, COX2 and iNOS, was up-regulated in colonic tissue from post-colitis rats and NO 2-Arg-Trim, but not trimebutine, effectively reversed this effect. In summary, these data suggest that NO 2-Arg-Trim inhibits nociception induced by CRD in both healthy and post-colitis, allodynic rats. The NO 2–arginine moiety interacts with the opioid agonist trimebutine to potentiate its analgesic activity. This study provides evidence that NO 2–arginine derivative of trimebutine might have beneficial effect in the treatment of painful intestinal disorders.