Unrestricted Weight Bearing as a Method for Assessment of Nociceptive Behavior in a Model of Tibiofemoral Osteoarthritis in Rats

Abstract

Background: Novel preclinical models for prediction of osteoarthritis-like pain are necessary for the elucidation of osteoarthritis (OA) pathology and for assessment of novel analgesics. A widely used behavioral test in rat models of tibiofemoral OA is hind limb weight bearing (WB). However, this method evaluates WB in an unnaturally restricted manner. The aim of this study was therefore to characterize the Tekscan Pressure Measurement System as a means to assess OA-like tibiofemoral pain in rats by determination of plantar pressure distribution in a more natural and unrestricted position, defined as unrestricted WB. Methods: Intra-articular injections of 1 mg monosodium iodoacetate (MIA) or saline were administrated in the left hind knee of 84 male Sprague Dawley rats. Changes in unrestricted WB between ipsilateral and contralateral hindlimbs were determined. Morphine (5 mg/kg administered subcutaneously) and naproxen (60 mg/kg per-oral) were examined for their ability to reverse WB changes. Results: Changes in hind limb unrestricted WB were observed 14 (P < 0.05), 21 (P < 0.001) and 28 (P < 0.001) days post intra-articular injections of MIA compared to control. These alterations were attenuated by morphine 1 hour post administration compared to baseline but were not affected by naproxen. Conclusion: This study indicated that unrestricted WB assessed by the Tekscan system can be utilized as a clinically relevant method to assess aberrations in WB induced by intra-articular MIA injections in rodents. Therefore, this system may be useful for understanding the mechanisms of OA pain in humans and may also assist in the discovery of novel pharmacological agents.

Efficacy of CR4056, a first-in-class imidazoline-2 analgesic drug, in comparison with naproxen in two rat models of osteoarthritis

“…Acute naproxen was previously found to alleviate the joint discomfort following MIA injection in the rat 28. Other authors suggest a specific role for NSAIDs only during the first week post-MIA injection 36,29. In our hands, 10 mg/kg naproxen evidenced a robust efficacy to reverse allodynia both after acute administration and after 7 days of repeated treatment, comparable to that of 6 mg/kg CR4056.…”

“… 28 Other authors suggest a specific role for NSAIDs only during the first week post-MIA injection. 36 , 29 In our hands, 10 mg/kg naproxen evidenced a robust efficacy to reverse allodynia both after acute administration and after 7 days of repeated treatment, comparable to that of 6 mg/kg CR4056. Conversely, when testing naproxen for anti-hyperalgesic efficacy after acute administration, we found only a trend of efficacy that did not reach statistical significance, contrary to CR4056.…”

Gait Analysis Methods for Rodent Models of Osteoarthritis

“…In addition to these spatial data, paw print characteristics may also indicate limb injury in rodent OA models, where the spacing of toes and paw print lengths can be used to form functionality indices for the sciatic, tibial, and peroneal nerves [29–32]. In addition, paw print area or intensity differences between limbs may indicate dynamic weight-bearing imbalances due to a musculoskeletal pathology [23, 26•, 33, 34]. …”

Measuring and realizing the translational significance of preclinical in vivo studies of painful osteoarthritis

“…In fact, alterations in weight-bearing symmetry can persist even after the pain is reduced with interventions such as total knee arthroplasty in OA patients 40,41 . By way of translation, a preclinical assessment of the effect of PF-04457845 on MIA-induced deficits in dynamic or static weightbearing would have been beneficial as such deficits are often very difficult to reverse 42 . An assessment using this endpoint would have had the potential to provide better guidance as to clinical trial design, target population and/or the overall utility of this molecule in OA in general.…”