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Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain.
Neurogastroenterol Motil 2010; 22(3):312-e84NM

Abstract

BACKGROUND

Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C).

METHODS

Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. KEY

RESULTS

In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice.

CONCLUSIONS

& INFERENCES These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C.

Authors+Show Affiliations

UMR INRA-Purpan Neuro-Gastroenterology and Nutrition Unit, Toulouse, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19706070

Citation

Eutamene, H, et al. "Guanylate Cyclase C-mediated Antinociceptive Effects of Linaclotide in Rodent Models of Visceral Pain." Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, vol. 22, no. 3, 2010, pp. 312-e84.
Eutamene H, Bradesi S, Larauche M, et al. Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil. 2010;22(3):312-e84.
Eutamene, H., Bradesi, S., Larauche, M., Theodorou, V., Beaufrand, C., Ohning, G., ... Bueno, L. (2010). Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, 22(3), pp. 312-e84. doi:10.1111/j.1365-2982.2009.01385.x.
Eutamene H, et al. Guanylate Cyclase C-mediated Antinociceptive Effects of Linaclotide in Rodent Models of Visceral Pain. Neurogastroenterol Motil. 2010;22(3):312-e84. PubMed PMID: 19706070.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. AU - Eutamene,H, AU - Bradesi,S, AU - Larauche,M, AU - Theodorou,V, AU - Beaufrand,C, AU - Ohning,G, AU - Fioramonti,J, AU - Cohen,M, AU - Bryant,A P, AU - Kurtz,C, AU - Currie,M G, AU - Mayer,E A, AU - Bueno,L, Y1 - 2009/08/25/ PY - 2009/8/27/entrez PY - 2009/8/27/pubmed PY - 2010/6/29/medline SP - 312 EP - e84 JF - Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society JO - Neurogastroenterol. Motil. VL - 22 IS - 3 N2 - BACKGROUND Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). METHODS Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. KEY RESULTS In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. CONCLUSIONS & INFERENCES These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C. SN - 1365-2982 UR - https://www.unboundmedicine.com/medline/citation/19706070/Guanylate_cyclase_C_mediated_antinociceptive_effects_of_linaclotide_in_rodent_models_of_visceral_pain_ L2 - https://doi.org/10.1111/j.1365-2982.2009.01385.x DB - PRIME DP - Unbound Medicine ER -