The Effect of CB2 Agonist GW833972A on Trigeminal Fos Expression

Objectives: Recent studies demonstrate that selective CB2 receptor agonists have antihyperalgesic effects in models of inflammatory and neuropathic pain, thus indicating a potential role in the treatment of chronic pain. The aim of this study was to assess the ability of the CB2 agonist GW833972A (GlaxoSmithKline) to modify central neurone activation in response to both non-inflamed and inflamed ferret tooth pulp stimulation. Methods: Fourteen adult ferrets were prepared under anaesthesia (ketamine 25 mg/kg, xylazine 2 mg/kg: i.m.) to allow tooth pulp stimulation, recording from the digastric muscle and i.v. injections at a subsequent experiment. In seven 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 i.v.) and the jaw opening reflex (JOR) threshold was measured. Animals were treated with either GW833972A (i.v. bolus: 1 mg/kg, i.v. infusion: 1 mg/kg administered at 10 ml/kg/hr over 1 hour; non-inflamed n = 4, inflamed n = 4) or N-methyl-pyrrolidinone (NMP) based vehicle (non-inflamed n = 3, inflamed n = 3). Fifteen minutes after the initial bolus the teeth were stimulated at 10 times the threshold of the JOR for 90 minutes. At 120 minutes from the start of the experiment all animals were perfused with fixative and brainstems processed for Fos immunohistochemistry. Results: Stimulation of non-inflamed and inflamed tooth pulps induces ipsilateral Fos expression caudally in subnucleus caudalis (Vc) and rostrally in subnucleus oralis. GW833972A reduces Fos expression in Vc in both non-inflamed (P = 0.0002, unpaired t-test) and inflamed animals (P = 0.01). Conclusions: These results suggest that GW833972A reduces the number of trigeminal brainstem neurones activated by electrical tooth pulp stimulation caudally but not rostrally in all animals. Therefore GW833972A may have analgesic efficacy in dental pain. (Supported by GlaxoSmithKline, UK).