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Influence of a new 5-HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and inflammation.
Neurogastroenterol Motil 2014; 26(12):1761-70NM

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+Show Affiliations

Neurogastroenterology Unit INRA-Toxalim, Toulouse, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25316608

Citation

Gilet, M, et al. "Influence of a New 5-HT4 Receptor Partial Agonist, YKP10811, On Visceral Hypersensitivity in Rats Triggered By Stress and Inflammation." Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, vol. 26, no. 12, 2014, pp. 1761-70.
Gilet M, Eutamene H, Han H, et al. Influence of a new 5-HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and inflammation. Neurogastroenterol Motil. 2014;26(12):1761-70.
Gilet, M., Eutamene, H., Han, H., Kim, H. W., & Bueno, L. (2014). Influence of a new 5-HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and inflammation. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, 26(12), pp. 1761-70. doi:10.1111/nmo.12458.
Gilet M, et al. Influence of a New 5-HT4 Receptor Partial Agonist, YKP10811, On Visceral Hypersensitivity in Rats Triggered By Stress and Inflammation. Neurogastroenterol Motil. 2014;26(12):1761-70. PubMed PMID: 25316608.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Influence of a new 5-HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and inflammation. AU - Gilet,M, AU - Eutamene,H, AU - Han,H, AU - Kim,H W, AU - Bueno,L, Y1 - 2014/10/15/ PY - 2014/05/13/received PY - 2014/09/18/accepted PY - 2014/10/16/entrez PY - 2014/10/16/pubmed PY - 2015/8/12/medline KW - 5-HT4 receptors KW - YKP10811 KW - colorectal distension KW - serotonin KW - stress KW - visceral pain SP - 1761 EP - 70 JF - Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society JO - Neurogastroenterol. Motil. VL - 26 IS - 12 N2 - 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. SN - 1365-2982 UR - https://www.unboundmedicine.com/medline/citation/25316608/Influence_of_a_new_5_HT4_receptor_partial_agonist_YKP10811_on_visceral_hypersensitivity_in_rats_triggered_by_stress_and_inflammation_ L2 - https://doi.org/10.1111/nmo.12458 DB - PRIME DP - Unbound Medicine ER -