Pharmacological characterization of intraplantar Complete Freund’s Adjuvant-induced burrowing deficits

• Burrowing impairments after intraplantar CFA injection unmask spontaneous pain.
• Known analgesics (NSAIDs and an anti-NGF antibody) reinstate burrowing performance.
• Opioid efficacy is masked by sedative motor impairing side effects.
• Burrowing is not driven by an instinct to find shelter or biased by trait anxiety.
• Burrowing is an objective read-out for pain in the rat intraplantar CFA pain model.

BackgroundIt has recently been suggested that non-reflex behavioral readouts, such as burrowing, may be used to evaluate the efficacy of analgesics in rodent models of pain.ObjectiveTo confirm whether intraplantar Complete Freund’s Adjuvant (CFA)-induced pain reliably results in burrowing deficits which can be ameliorated by clinically efficacious analgesics as previously suggested.MethodsUni- or bilateral intraplantar CFA injections were performed in male Wistar Han rats. The time- and concentration-response of burrowing deficits and the ability of various analgesics to reinstate burrowing performance were studied. An anxiolytic was also tested to evaluate the motivational cue that drives this behavior.ResultsBurrowing deficits were dependent on the concentration of CFA injected, most pronounced 24 h after CFA injections and even more pronounced after bilateral compared with unilateral injections. Celecoxib and ibuprofen reversed CFA-induced burrowing deficits whereas indomethacin failed to significantly reinstate burrowing performance. Morphine and tramadol failed to reinstate burrowing performance, but sedation was observed in control rats at doses thought to be efficacious. An antibody directed against the nerve growth factor significantly improved CFA-induced burrowing deficits. Neither gabapentin nor the anxiolytic diazepam reinstated burrowing performance and the opportunity to find shelter did not modify burrowing performance.ConclusionBurrowing is an innate behavior reliably exhibited by rats. It is suppressed in a model of inflammatory pain and differently reinstated by clinically efficacious analgesics that lack motor impairing side effects, but not an anxiolytic, suggesting that this assay is suitable for the assessment of analgesic efficacy of novel drugs.