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

Abstract

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.

• Authors: M Gilet, H Eutamene, H Han, H W Kim, L Bueno
• Journal: Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society (Neurogastroenterol Motil) Vol. 26 Issue 12 Pg. 1761-70 (Dec 2014) ISSN: 1365-2982 [Electronic] England
• PMID: 25316608 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 John Wiley & Sons Ltd.

Chemical References

• Benzamides
• Carbamates
• Serotonin Receptor Agonists
• carbamic acid 3-(4-((4-amino-5-chloro-2-methoxybenzoylamino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl ester
• Receptors, Serotonin, 5-HT4

Topics

• Animals
• Benzamides (pharmacology)
• Carbamates (pharmacology)
• Colon (drug effects)
• Disease Models, Animal
• Female
• Hyperalgesia (etiology, physiopathology)
• Inflammation (complications)
• Male
• Manometry
• Rats
• Rats, Wistar
• Receptors, Serotonin, 5-HT4
• Serotonin Receptor Agonists (pharmacology)
• Stress, Psychological (complications)
• Visceral Pain (etiology, physiopathology)