title: Pharmacological interrogation of a rodent forced ambulation model: leveraging gait impairment as a measure of pain behavior pre-clinically.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Neuroscience Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Adams
authors.affiliation: Neuroscience Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: W
authors.initials: W
authors.lastname: Guo
authors.affiliation: Neuroscience Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Gors
authors.affiliation: Neuroscience Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA. Electronic address: k.knopp@lilly.com.
authors.forename: K L
authors.initials: KL
authors.lastname: Knopp
mesh_terms: D000700:Analgesics; D000818:Animals; D005684:Gait; D010146:Pain; D012377:Rodentia
chemical_list: D000700:Analgesics
keywords: Complete Freund's Adjuvant; Functional pain endpoint; Gait; Joint pain