Neuropharmacology and analgesia Using gait analysis to assess weight bearing in rats with Freund's complete adjuvant-induced monoarthritis to improve predictivity: Interfering with the cyclooxygenase and nerve growth factor pathways Kristina Ängeby Möller a,c,n , Odd-Geir Berge a,b , Anja Finn c , Carina Stenfors a,1 , Camilla I. Svensson c a AstraZeneca R&D Södertälje, CNSP iMed Science, SE-151 85 Södertälje, Sweden b Multidisciplinary Pain Center, Uppsala University Hospital, SE-751 85 Uppsala, Sweden c Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden article info Article history: Received 24 October 2014 Received in revised form 30 January 2015 Accepted 3 February 2015 Available online 16 March 2015 Keywords: Arthritis Rat Gait analysis Weight bearing Nociception abstract Lack of predictive power for drug effects has been a major criticism against animal pain models. It is therefore important to define the utility and limitations of different models. The aim of this study was to extend previous work on gait analysis as a tool to investigate pharmacological effects in monoarthritic rats, specifically to test the hypothesis that monoarthritis induced by Freund's complete adjuvant (FCA) provides a better estimate of overall analgesic efficacy of established, and novel, clinically effective and ineffective therapeutic approaches. Male rats injected intra-articularly into one ankle joint with FCA (1.0 mg/ml) were treated with the monoclonal antibody to nerve growth factor (NGF), MEDI-578, the inhibitors of tropomyosin receptor kinases A, B and C (pan-Trk) AZ6623 or AZ7092, the transient receptor potential vanilloid 1 (TRPV1) inhibitor AZD1386, or the cyclooxygenase (COX) inhibitors naproxen, ibuprofen, valdecoxib or rofecoxib. Effects on weight bearing during locomotion were tested using video capture of print images. The apparent efficacy in this model was Trk inhibitors Zanti-NGF antibody 4COX inhibitors. The TRPV1 inhibitor was ineffective. Together with previous data, the results support using gait-related parameters in the monoarthritis model. FCA as induction agent seems to provide a good overall prediction of analgesic efficacy in disorders with inflammatory joint pain. & 2015 Elsevier B.V. All rights reserved. 1. Introduction Lack of efficacy is a major reason for failure of new treatments in clinical trials, including trials of analgesics (Kola and Landis, 2004). Several contributing factors in the chain of drug develop- ment have been identified, including low predictive power of preclinical models (Mogil and Crager, 2004; Mogil et al., 2010). Research to define the utility and limitations of experimental rodent models of pain is therefore warranted. NGF is released following tissue injury and serves as a ligand for the tropomyosin receptor kinase A (TrkA), expressed on nociceptors (Leon et al., 1994; Shu and Mendell, 2001). Experi- mental data indicate that nerve growth factor (NGF) is important in initiating and maintaining persistent pain, specifically pain associated with inflammation (Aloe et al., 1992; Andersen et al., 2008; Iannone et al., 2002; McMahon, 1996; Woolf et al., 1994), and clinical trials show that preventing the actions of NGF by anti- NGF antibodies has analgesic effect in 74–93% of patients with osteoarthritis (Lane et al., 2010; Spierings et al., 2013). Thus translation of the efficacy of NGF-interfering compounds from animal models to humans was successful. One potential pain- inducing effect of NGF is its ability to increase the expression of transient receptor potential vanilloid 1 (TRPV1) on nociceptors, and inhibition of this receptor has been suggested as a treatment of inflammatory joint pain (Gold and Gebhart, 2010; Keeble et al., 2005). However, while recent clinical trials with the TRPV1 anta- gonist AZD1386 showed a transient analgesic effect on dental extraction-evoked pain, it was without effect on pain in osteoar- thritis (Quiding et al., 2013; Svensson et al., 2010). Of note, this compound had shown efficacy in experimental rodent models of pain induced by spinal nerve ligation and plantar injection of carrageenan and Freund's complete adjuvant (FCA) with heat hypersensitivity as readout, and on capsaicin- and ultraviolet-C irradiation-induced pain in humans (Karlsten et al., 2010; Laird Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology http://dx.doi.org/10.1016/j.ejphar.2015.02.050 0014-2999/& 2015 Elsevier B.V. All rights reserved. n Corresponding author at: Department of Physiology and Pharmacology, Kar- olinska Institutet, SE-171 77 Stockholm, Sweden. Tel.: þ46 733428237. E-mail address: kristina.angeby.moller@ki.se (K. Ängeby Möller). 1 Current address: R&D CNS Research Orion Corporation Orion Pharma, Turku, Finland. European Journal of Pharmacology 756 (2015) 75–84