Separation of emetic and anorexic responses of exendin-4, a GLP-1 receptor agonist in Suncus murinus (house musk shrew).

Abstract

The use of glucagon-like peptide-1 (7-36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Therefore, the present studies investigated the potential of GLP-1 receptor ligands to modulate emesis and feeding in Suncus murinus. Exendin-4, a selective GLP-1 receptor agonist, was administered subcutaneously (1-30 nmol/kg) or intracerebroventricularly (0.03-3 nmol) after 12-h of fasting. In other studies, animals were pretreated with the GLP-1 receptor antagonist, exendin (9-39), or saline (5 μl) 15 min prior to exendin-4 (3 nmol, i.c.v.). Behaviour of animals and food and water intake were then recorded for 1-2 h; c-Fos expression was also assessed in the brains of animals in the i.c.v. studies. The subcutaneous administration of exendin-4 reduced food and water intake (p < 0.001) and induced emesis in 40% of animals (p > 0.05). The intracerebroventricular administration of exendin-4 also prevented feeding, and induced emesis (p < 0.01). In these studies, exendin (9-39) (30 nmol, i.c.v.) antagonised emesis induced by exendin-4 and the increased c-Fos expressions in the brainstem and hypothalamus (p < 0.05), but it was ineffective in reversing the exendin-4-induced inhibition of food and water intake (p > 0.05). These data suggest that exendin-4 exerts its emetic effects in the brainstem and/or hypothalamus via GLP-1 receptors. The action of exendin-4 to suppress feeding may involve non-classical GLP-1 receptors or other mechanisms.

• Authors: Sze Wa Chan, Ge Lin, David Tai Wai Yew, Chi Kong Yeung, John A Rudd
• Journal: Neuropharmacology (Neuropharmacology) Vol. 70 Pg. 141-7 (Jul 2013) ISSN: 1873-7064 [Electronic] England
• PMID: 23357334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Appetite Depressants
• Emetics
• Glucagon-Like Peptide-1 Receptor
• Peptide Fragments
• Peptides
• Proto-Oncogene Proteins c-fos
• Receptors, Glucagon
• Venoms
• exendin (9-39)
• Exenatide

Topics

• Animals
• Appetite Depressants (pharmacology)
• Brain Stem (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Drinking (drug effects)
• Drug Interactions
• Eating (drug effects)
• Emetics (pharmacology)
• Exenatide
• Female
• Glucagon-Like Peptide-1 Receptor
• Hypothalamus (drug effects, metabolism)
• Injections, Intraventricular
• Injections, Subcutaneous
• Motor Activity (drug effects)
• Peptide Fragments (pharmacology)
• Peptides (administration & dosage, antagonists & inhibitors, pharmacology)
• Proto-Oncogene Proteins c-fos (metabolism)
• Receptors, Glucagon (agonists, antagonists & inhibitors)
• Shrews
• Venoms (administration & dosage, pharmacology)