| Many diseases and drug treatments are associated with nausea and emesis and a reduction in appetite. Up to now, no single class of drug is effective in treating all causes of nausea and emesis. Studies in Suncus murinus have shown that the GLP-1 receptor antagonist, exendin (9-39), can reduce cisplatin-induced emesis and attenuate c-fos expression in brain areas suggested to be involved in 'nausea', emesis and feeding. The present study is to investigate the anti-emetic potential of exendin (9-39) in the ferret, a species commonly used for anti-emetic drug discovery.;Western blot revealed that GLP-1 receptors were found in gastrointestinal tissues, vagus nerve, and different brain areas. Exendin-4 and exendin (9-39) had no effect on the isolated gut contractility (P>0.05), and failed to depolarize the isolated vagus nerve (P>0.05). In the glucose tolerance test, exendin-4 (30 nmol/kg, s.c.) reduced AUC 0-120 by 36.3%, and exendin (9-39) (300 nmol/kg, s.c.) antagonized the effect of exendin-4 and also increased AUC0-120 by 31.0%, when injected alone (P<0.05).;In the first set of behavioural studies, central injection of exendin-4 induced emesis in a dose-dependent manner. The threshold dose to induce emesis was 10 nmol. Exendin-4 (30 nmol, i.c.v.) significantly induced emesis ( P<0.05). Exendin-4 (0.3-30 nmol, i.c.v.) inhibited food ( P<0.05), but not water intake, and increased the frequency of several emesis-associated behaviours (P<0.05); there was an increase of c-fos expression in hindbrain and forebrain areas (P<0.05). Area postrema (AP) ablation prevented exendin-4 (10 nmol, i.c.v.)-induced emesis (P0.05).;However, in a follow-up study, exendin-4 (10 nmol, i.c.v.) did not induce emesis but it inhibited food intake (P<0.05). C-fos expression was similar to the first study except for that there was no increase in the AP or nucleus tractus solitarius. Exendin (9-39) (100 nmol, i.c.v.) did not reverse exendin-4-induced anorexia (P>0.05) but reduced c-fos expression in the central nucleus of amygdala (P<0.05).;In telemetric studies, exendin-4 (100 nmo/kg, s.c.) induced emesis in 2/6 ferrets, decreased heart rate variability (HRV), and inhibited food intake (P<0.05) without affecting gastric myoelectric activity (GMA), blood pressure (BP), heart rate (HR), or body temperature ( P>0.05), whereas in control animals, food consumption caused a decrease of dominant frequency (DF) (P<0.05). Comparatively, exendin-4 (10 nmol, i.c.v.) induced emesis in 5/8 ferrets (P0.05), but it inhibited food intake, whereas in the control group, food consumption also caused a decrease of DF (P<0.05). Exendin-4 increased BP and HR, and decreased HRV (P0.05).;Continuous infusion of exendin (9-39) (4.2 nmol/h, i.c.v.) antagonized cisplatin (5 mg/kg)-induced acute emesis by 39.5% (P<0.05), but failed to antagonize delayed emesis or to reverse cisplatin-induced weight loss, or reductions of food and water intake (P>0.05). Paradoxically, exendin (9-39) increased BP (P<0.05), and partially reversed the cisplatin-induced hypothermia occurring during delayed phase ( P0.05).;In summary, central GLP-1 receptors may be important in emesis control and cardiovascular function in the ferret, and may represent a novel target for anti-emetic development and for vascular dysfunctions. The mechanism of exendin-4-induced anorexia remains to be determined, but may be relevant to the treatment of obesity in the absence of nausea and emesis. |
