Influence of a new 5-HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and inflammation

Background: Adverse effects of previously developed 5-HT4 receptor agonists to treat functional constipation (FC) and constipation IBS (IBS-C) patients have limited their use but have given rise to new and more selective 5-HT4 receptor agonists. This work was aimed to evaluate the influence of YKP10811, a new potent 5-HT4 receptor partial agonist, on rat models of colorectal hypersensitivity to distension.

Methods: Male and female rats were submitted to colorectal distension (CRD) before and after trinitrobenzene sulfonic acid (TNBS) infusion, acute (PRS) or chronic (water avoidance -10 days - WAS) stress. Electromyographic (EMG) response of abdominal muscles to CRD (15-60 mmHg) was used to measure pain. Changes of colonic tone were also evaluated. The influence of YKP10811 was compared to that of tegaserod with or without exposure of rats to a 5-HT4 receptor antagonist in TNBS treated rats and to both tegaserod and CP-154,526, a corticotropine releasing factor-R1 antagonist in WAS. We tested a possible pharmacological tachyphylaxis of YKP10811 in TNBS-induced hypersensitivity.

Key results: YKP10811 (30 mg/kg) had no effect on basal sensitivity and tone in male and female rats but suppressed TNBS-induced hypersensitivity, an effect blocked by the 5-HT4 receptor antagonist GR113808 (10 mg/kg, SC). YKP10811 attenuated acute PRS-induced but not chronic WAS-induced colonic hypersensitivity. In addition, YKP10811 but not tegaserod reduced TNBS-induced colorectal hypersensitivity after 7 days of treatment.

Conclusions & inferences: YKP10811exhibits antinociceptive activity in inflammation and acute stress-induced colonic hypersensitivity through 5-HT4 receptors but unlike tegaserod, YKP10811 maintains its activity after repeated administrations and may represent a new candidate to treat IBS-C patients.