Central GLP-1 receptors are involved in the emetic reflex of Suncus murinus (house musk shrew)

Abstract

Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gastrointestinal hormone produced by intestinal L cells. Studies in rodents and ferrets demonstrated that GLP-1 containing neurons connect the brainstem emetic centres with forebrain areas involved in nausea and feeding. The aim of the present study was to investigate the potential role of GLP-1 receptors in emesis control in Suncus murinus, a species commonly used in emesis research. The distribution of GLP-1 receptors in S.murinus brain was identified using immunohistochemistry. In behavioural studies, animals were pretreated with the GLP-1 receptor antagonist, exendin (9–39) (30 nmol, i.c.v), or vehicle (5μL), and they were then injected with the GLP-1 receptor agonist, exendin-4 (3 nmol, i.c.v.), or several well-known emetic treatments including cisplatin (100μmol kg^-1, i.p.), (–)-nicotine tartrate (10μmol kg^-1, s.c.), or copper sulphatepentahydrate (500μmol kg^-1, p.o.). For studies involving exendin-4 and cisplatin, c-fos expression in the CNS was also examined. GLP-1 receptor immunoreactive neurons were found to be widely distributed in the hypothalamus and caudal medulla oblongata, especially the ventromedial and dorsomedial hypothalamus, and the area postrema. Exendin (9–39) antagonised emesis induced by exendin-4 (78% reduction during 60 min observation time; P< 0.05) and cisplatin (74% reduction during the first 30 min; P< 0.05). Cisplatin also increased c-fos expression in the dorsal vagal complex (P< 0.05), whereas exendin-4 increased c-fos expression in both the dorsal vagal complex (P< 0.001) and the hypothalamus, including paraventricular (P< 0.01), ventromedial (P< 0.001), dorsomedial (P< 0.01) and lateral hypothalamic nuclei (P< 0.01), where high densities of GLP-1 receptors were expressed; these increases were prevented by exendin (9–39) (P< 0.05). Conversely, exendin (9–39) failed to significantly reduce emesis induced by nicotine or copper sulphate (P> 0.05). In conclusion, GLP-1 receptors appear differentially involved in the control of drug-induced emesis. It is likely that GLP-1 receptors in the central nervous system may be involved in emesis induced by cisplatin.