Pharmacological validation of a refined burrowing paradigm for prediction of analgesic efficacy in a rat model of sub-chronic knee joint inflammation.

Background: Burrowing is an evolutionarily conserved behaviour in rodents. This study validates a refined burrowing paradigm (requiring a reduced number of animals) in a rat model of sub-chronic knee joint inflammation and evaluates its sensitivity and specificity for analgesic drugs.

Methods: Knee joint inflammation in rats was induced by intra-articular injection with complete Freund's adjuvant (CFA). Burrowing performance was assessed at baseline without study drugs, and in CFA-naive and CFA-injected animals following administration of the analgesic drugs naproxen, pregabalin and morphine, each at three doses, or corresponding vehicle (nine rats per dose group). The specificity of the model was evaluated by also testing the anxiogenic drug yohimbine, the stimulant drug dexamphetamine and the anxiolytic drug chlordiazepoxide in CFA-naive and CFA-injected animals. Percentage maximum possible effect (%MPE) was determined by relating the difference between post-CFA and baseline burrowing performance in each drug dose group to that in the vehicle group in each experiment.

Results: Burrowing performance in the vehicle groups was decreased by 39.0-59.8% in CFA-injected animals compared with CFA-naive animals. CFA-induced reductions in burrowing performance were reversed by each of the three analgesic drugs tested. The highest %MPE was 75.2% with naproxen 50 mg/kg, 80.9% with pregabalin 10 mg/kg and 77.0% with morphine 1 mg/kg (all p < 0.05 vs. control). CFA-induced reductions in burrowing performance were not reversed by yohimbine, dexamphetamine or chlordiazepoxide.

Conclusions: This study provides pharmacological validation of a refined burrowing paradigm for analgesic efficacy that exhibits good predictive validity, with high sensitivity and specificity.