Pharmacological interrogation of a rodent forced ambulation model: leveraging gait impairment as a measure of pain behavior pre-clinically

Abstract

Objective: The aim of this study was to investigate whether inflammogen-induced temporal and spatial gait changes in a rodent forced-ambulation paradigm were sensitive to pharmacological intervention with both clinically validated and novel analgesics.

Methods: Using the GaitScan (CleverSys Inc., Reston, VA) treadmill system, we identified four functional endpoints inspired by clinical literature and sensitive to unilateral joint injury induced by intra-articular Complete Freund's Adjuvant (CFA). These endpoints included: range of motion, normalized stance distance, stance/swing ratio, and paw print size as a measure of guarding; collectively, these measures are proposed to serve as a high fidelity index of joint pain. We then examined the ability of known analgesic mechanisms to attenuate gait impairment as measured by this index.

Results: Clinically efficacious opioids, Nonsteroidal anti-inflammatory drugs (NSAIDs), and the yet unapproved anti-NGF antibody dose-dependently attenuated the CFA)-induced gait deficits, while a TNF-alpha fusion protein blocker had no effect on gait, but did produce a reduction in swelling. As well, the time course for gait impairment in the model appears to be distinct from the traditional endpoint of tactile hypersensitivity, offering the potential to assess a novel functional pain phenotype.

Conclusions: In response to the call for more functional pain measures, we submit this composite gait score as a novel endpoint to interrogate joint pain pre-clinically. As the etiology of human osteoarthritis (OA) remains unclear, this model/endpoint cannot attempt to improve construct validity, but may provide an additional dimension to interrogate pain-induced gait deficits.

Keywords: Complete Freund's Adjuvant; Functional pain endpoint; Gait; Joint pain.