title: 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.
  
  
  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
  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.affiliation: Neurogastroenterology Unit INRA-Toxalim, Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Gilet
authors.forename: H
authors.initials: H
authors.lastname: Eutamene
authors.forename: H
authors.initials: H
authors.lastname: Han
authors.forename: H W
authors.initials: HW
authors.lastname: Kim
authors.forename: L
authors.initials: L
authors.lastname: Bueno
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D007249:Inflammation / Q000150:complications; D008297:Male; D008365:Manometry; D051381:Rats; D017208:Rats, Wistar; D044422:Receptors, Serotonin, 5-HT4; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013315:Stress, Psychological / Q000150:complications; D059265:Visceral Pain / Q000209:etiology / Q000503:physiopathology*
chemical_list: D001549:Benzamides; D002219:Carbamates; D017366:Serotonin Receptor Agonists; C000600155:carbamic acid 3-(4-((4-amino-5-chloro-2-methoxybenzoylamino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl ester; D044422:Receptors, Serotonin, 5-HT4
keywords: 5-HT4 receptors; YKP10811; colorectal distension; serotonin; stress; visceral pain