GLP-1 receptors in nausea and emesis

Abstract

Glucagon-like peptide-1 (7–36) amide (GLP-1) is released from the gut as an incretin hormone to facilitate glucose-stimulated insulin secretion. The use of GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus, however, is commonly associated with nausea and vomiting. Studies in rodents and ferrets have shown that GLP-1 containing neurons connect brainstem emetic centres with forebrain areas potentially involved in nausea and feeding. Previously, we identified the distribution of GLP-1 immunoreactive fibres and GLP-1 receptor immunoreactivity in the hypothalamus and brainstem of Suncus murinus. In anesthetized animals, subcutaneous (1 – 30 nmol/kg) and intracerebroventricular (0.3–3 nmol) administration of the GLP1 receptor agonist, exendin-4, reduced blood glucose levels dose-dependently. In conscious freely moving animals, exendin-4 induced emesis (P<0.01) with associated increases in c-fos expression in the amygdala (P<0.01), hypothalamus (P<0.01) and brainstem (P<0.001). The GLP-1 receptor antagonist, exendin (9-39) (30 nmol, i.c.v.), antagonized emesis induced by exendin-4, and also to the chemotherapeutic drug, cisplatin (30 mg/kg, i.p.; P<0.05). In ferrets, exendin-4 over similar dose ranges also reduced blood glucose levels (threshold 30 nmol/kg; P<0.05) and induced emesis (10 nmol, i.c.v.; P<0.05). GLP-1 receptors appear to be important in emesis control and GLP-1 receptor antagonists may represent a novel class of anti-emetic. These studies were supported by the Research Grants Council of Hong Kong (CUHK 4739/09).