Prostaglandins contribute substantially to neuronal sensitisation at both peripheral and central sites. The effects of prostaglandin E₂ (PGE₂) are mediated by G-protein-coupled EP (EP1-EP4) receptors. Activation of EP1 receptors increases intracellular calcium concentration and is crucial in the late phase of carrageenan-induced mechanical hyperalgesia (Nakayama et al. 2002). An EP1 receptor antagonist could block the positive feedback cascade mediated by PGE₂, resulting in inhibition of inflammation-induced hyperalgesia. Therefore selective EP1 antagonists are potential analgesics for inflammatory pain (Giblin et al. 2007). We have previously carried out detailed characterisation and identification of Fos expression within the trigeminal nucleus after tooth pulp stimulation in ferrets (Worsley et al. 2007). The aim of this study was to assess the ability of the EP1 receptor antagonist GW848687X (GlaxoSmithKline) to modify central neurone activation in response to stimulation of inflamed ferret tooth pulp. Eleven adult ferrets were prepared under anaesthesia (ketamine 25 mg/kg, xylazine 2 mg/kg, IM.) to allow tooth pulp stimulation, recording from the digastric muscle and intravenous injections at a subsequent experiment. Pulpal inflammation was induced in all animals by introducing human caries into a deep buccal cavity. Five days later, animals were re-anaesthetised (alphaxalone/alphadalone, induction: 6 mg/kg, maintenance: 6-8 mg/kg/h, IV) and the jaw opening reflex (JOR) threshold was measured. Animals were treated intravenously with either GW848687X (bolus 10 mg/ml/kg, infusion 10 mg/10 ml/kg over 1 h, n = 4 and bolus 5 mg/ml/kg, infusion 5 mg/10 ml/kg over 1 h, n = 4) or vehicle (2% dimethyl sulfoxide and 5% glucose containing 10% hydroxypropyl-β-cyclodextrin, n = 3). Fifteen minutes after the initial bolus, tooth pulp stimulation was initiated at 10 times the threshold of the JOR for 90 minutes. All animals were perfused with fixative 120 minutes from the start of the stimulation and brainstems processed for Fos immunohistochemistry. Stimulation of inflamed tooth pulps induced ipsilateral Fos expression caudally in subnucleus caudalis (Vc) and rostrally in subnucleus oralis (Vo). Both doses of GW848687X reduced Fos expression in Vc (10 mg P = 0.0003, 5 mg P = 0.002, unpaired t-test with Bonferonni’s correction) and Vo (10 mg P = 0.02, 5 mg P = 0.02). These results suggest that GW848687X reduces the number of trigeminal brainstem neurones activated by stimulation of the inflamed tooth pulp. Therefore GW848687X may have significant analgesic efficacy in trigeminal inflammatory pain.