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.