Neuroscience Letters 392 (2006) 79–83 Anti-emetic activity of ghrelin in ferrets exposed to the cytotoxic anti-cancer agent cisplatin John A. Rudd a,∗ , Man P. Ngan a , Man K. Wai a , Andrew G. King b , Jason Witherington c , Paul L.R. Andrews d , Gareth J. Sanger c a Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China b Microbial, Musculoskeletal, Proliferative Disease CEDD, GlaxoSmithKline, Mail Code UP1450, 1250 S. Collegeville Road, Collegeville, PA 19426-0984, USA c Neurology and GI CEDD, GlaxoSmithKline, Harlow, Essex, CM19 4AD, UK d Division of Basic Medical Sciences, St. George’s, University of London, Cranmer Terrace, London, SW17 0RE, UK Received 15 July 2005; received in revised form 19 August 2005; accepted 31 August 2005 Abstract Emesis may be modulated via multiple mechanisms. The actions of ghrelin suggest an ability to couple an induction of hunger with preparation of the stomach for ingestion of food. Such a process might reduce any tendency to vomit, so an anti-emetic activity of ghrelin was investigated in the ferret cisplatin-induced emesis model. In controls, intra-peritoneal cisplatin (10 mg/kg) induced 41.4 ± 8.4 episodes of emesis comprising 310.4 ± 55.3 retches and 28.8 ± 6.9 vomits during the 6 h observation; the latency to onset of the first emetic episode was 108.9 ± 4.8 min. Intra- peritoneal ghrelin (1 mg/kg, split as a 30 min pre- and 30 min-post dose) did not induce a change in behaviour or modify cisplatin-induced emesis (p >0.05). Intracerebroventricular (i.c.v.) administration (third ventricle) was achieved via a pre-implanted cannula. At the first emetic episode following cisplatin, ghrelin or vehicle (20 l saline) was administered i.c.v. During the 30min following the initial episode of emesis, control animals exhibited 18.0 ± 2.6 emetic episodes comprising 160.3 ± 24.1 retches and 13.8 ± 2.7 vomits. Ghrelin 10 g i.c.v. reduced the number of retches by 61.5% (p < 0.05) and at a dose of 30 g i.c.v. ghrelin reduced the number of episodes, individual retches and vomits by 74.4 (p < 0.05), 80.4 (p < 0.01), and 72.5% (p < 0.05), respectively. At subsequent time periods there were no differences between ghrelin- or saline-treated animals (p > 0.05). An ability of ghrelin to reduce emesis is consistent with a role in modulating gastro-intestinal functions and identifies a novel approach to the treatment of emesis. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Vomiting; Anti-emetic; Ghrelin; Cisplatin; Ferret; Nucleus tractus solitarius Emesis is driven by vestibular, peripheral (e.g. vagal afferents) and central nerve pathways (e.g. brain stem and hypothalamus), and can be modulated via multiple mechanisms operating at dif- ferent loci within these systems [1,24]. As new receptors are discovered, it is important to look for any ability to interact with emetic reflex pathways. Recently, evidence has accumulated to suggest that the ghrelin receptor may have the potential for such interaction. This peptide is abundant in the stomach, where it can be released in response to several different stimuli, including the anticipation of eating [16]. Ghrelin can stimulate gastrointesti- nal motility [2,7,10,11,13,19,28,29], protect the gastric mucosa against damage caused by stress or ethanol [6,26] and in humans, ∗ Corresponding author. Tel.: +86 852 2609 6789; fax: +86 852 2603 5139. E-mail address: jar@cuhk.edu.hk (J.A. Rudd). increase appetite [31,22]. Together, these data suggest that a physiological role of ghrelin is to prepare the stomach for inges- tion of food. In rats, ghrelin receptor mRNA expression may increase in both the stomach and hypothalamus following treat- ment with the cytotoxic anti-cancer agent cisplatin, a drug which causes gastric stasis and reduces food intake; further, treatment with ghrelin stimulated food intake in the cisplatin-treated rats [20]. Rats do not have the ability to vomit but as the gastric sta- sis induced by cisplatin is amenable to treatment by agents with anti-emetic activity in species with an emetic reflex, the stasis has been argued to be an indicator of activation of pathways involved in emesis in other species [1,24]. Abdominal vagal afferents are activated by cisplatin in rats [15] and have been implicated in the mechanism(s) by which cisplatin induces eme- sis in species with an emetic reflex [24]. These observations, when coupled to the known ability of ghrelin to interact with the 0304-3940/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2005.08.062