Methods: Seven 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. In all of these animals pulpal inflammation was induced 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 SB705498 (bolus: 0.6 mg/ml/kg, infusion: 0.5 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 commenced 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.
Results: Stimulation of inflamed tooth pulps induced ipsilateral Fos expression caudally in subnucleus caudalis (Vc) and rostrally in subnucleus oralis (Vo). SB705498 reduced Fos expression in Vc (P = 0.04, unpaired t-test) but not in Vo (P = 0.29).
Conclusions: These results suggest that SB705498 reduces the number of trigeminal brainstem neurones activated by stimulation of the inflamed tooth pulp. Therefore SB705498 may have significant analgesic efficacy in trigeminal inflammatory pain. (Supported by GlaxoSmithKline, UK).