Pulmonary, gastrointestinal and urogenital pharmacology Anti-emetic and emetic effects of erythromycin in Suncus murinus: Role of vagal nerve activation, gastric motility stimulation and motilin receptors Farideh A. Javid a,1 , David C. Bulmer b,1 , John Broad b,1 , Qasim Aziz b , George E. Dukes c , Gareth J. Sanger b,n a School of Applied Sciences, Division of Pharmacy and Pharmaceuticals Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK b Neurogastroenterology group, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, UK c Academic DPU, GlaxoSmithKline, 3030 E. Cornwallis Road, Research Triangle Park, NC 27709, USA article info Article history: Received 17 September 2012 Received in revised form 6 November 2012 Accepted 20 November 2012 Available online 28 November 2012 Keywords: Erythromycin Vomiting Suncus murinus Gastric motility Vagus Motilin abstract Paradoxically, erythromycin is associated with nausea when used as an antibiotic but at lower doses erythromycin activates motilin receptors and is used to treat delayed gastric emptying and nausea. The aim of this study was to characterise pro- and anti-emetic activity of erythromycin and investigate mechanisms of action. Japanese House musk shrews (Suncus murinus) were used. Erythromycin was administered alone or prior to induction of emesis with abnormal motion or subcutaneous nicotine (10 mg/kg). The effects of erythromycin and motilin on vagal nerve activity and on cholinergically mediated contractions of the stomach (evoked by electrical field stimulation) were studied in vitro. The results showed that erythromycin (1 and 5 mg/kg) reduced vomiting caused by abnormal motion (e.g., from 10.3 71.8 to 4.0 71.1 emetic episodes at 5 mg/kg) or by nicotine (from 9.5 72.0 to 3.1 72.0 at 5 mg/kg), increasing latency of onset to emesis; lower or higher doses had no effects. When administered alone, erythromycin 100 mg/kg induced vomiting in two of four animals, whereas lower doses did not. In vitro, motilin (1, 100 nM) increased gastric vagal afferent activity without affecting jejunal afferent mesenteric nerve activity. Cholinergically mediated contractions of the stomach (prevented by tetrodotoxin 1 mM or atropine 1 mM, facilitated by L-NAME 300 mM) were facilitated by motilin (1–100 nM) and erythromycin (10–30 mM). In conclusion, low doses of erythromycin have anti-emetic activity. Potential mechanisms of action include increased gastric motility (overcoming gastric stasis) and/ or modulation of vagal nerve pathways involved in emesis, demonstrated by first- time direct recording of vagal activation by motilin. & 2012 Elsevier B.V. All rights reserved. 1. Introduction Paradoxically, when used as an antibiotic erythromycin is associated with side-effects of nausea and vomiting (Catnach and Fiarclough, 1992; Boivin et al., 2003), yet because of its ability to stimulate gastric emptying, erythromycin is used to treat conditions where nausea is a symptom (e.g., diabetic gastroparesis: Dibaise and Quigley, 1999; Gonlachanvit et al., 2003; Maganti et al., 2003; Ritz et al., 2005). These actions are usually observed at different doses. Thus, the doses used to treat patients with delayed gastric emptying (often associated with nausea; Cherian and Parkman, 2011) are lower than those given for antibiotic use (Desautels et al., 1995; Sanger, 2008), minimising nausea, stomach cramping, early satiety (Cuomo et al., 2006), tolerance to repeat dosing (Dibaise and Quigley, 1999; Gonlachanvit et al., 2003; Maganti et al., 2003; Dhir and Richter, 2004; Hunter et al., 2005; Ritz et al., 2005) and loss of therapeutic benefit (Richards et al., 1993). Erythromycin is also a motilin receptor agonist (Feighner et al., 1999) and the above paradoxical actions are potentially repro- duced in experiments with human (Broad et al., 2012) and rabbit (Dass et al., 2003; Depoortere et al., 2003; Jarvie et al., 2007; Sanger et al., 2009) isolated stomach. Here, low concentrations of motilin receptor agonists facilitate cholinergic activity to increase gastric motility, whereas higher concentrations hyper-stimulate cholinergic function and directly contract the muscle, promoting nausea by contracting the gastric fundus (Bruley Des Varannes et al., 1995) and inducing prolonged (Tack et al., 1992), non- propulsive (Coulie et al., 1998) hypermotility of the antrum. It is unlikely that erythromycin acts within the brain, where functional motilin receptors have not been identified (apart from some studies in rodents, treated with caution because of the absence of a functional motilin system in rodents; Sanger et al., 2011). However, erythromycin could influence emesis by mod- ulating vagal nerve activity (Andrews and Sanger, 2002). This is Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology 0014-2999/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2012.11.035 n Correspondence to: National Centre for Bowel Research and Surgical Innova- tion, 2 Newark Street, London, E1 2AT, UK. Tel.: þ44 2078822639. E-mail address: g.sanger@qmul.ac.uk (G.J. Sanger). 1 Joint First Authors. European Journal of Pharmacology 699 (2013) 48–54