Neuropharmacology and Analgesia Pharmacological modulation of movement-evoked pain in a rat model of osteoarthritis Prasant Chandran a, ⁎, Madhavi Pai a , Eric A. Blomme b , Gin C. Hsieh a , Michael W. Decker a , Prisca Honore a a Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Dept. R4N5, Bldg. AP9A-LL,100 Abbott Park Road, Abbott Park, Illinois 60064-6115, USA b Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA abstract article info Article history: Received 25 November 2008 Received in revised form 23 March 2009 Accepted 7 April 2009 Available online 16 April 2009 Keywords: Animal model Osteoarthritis Pain This study was conducted to characterize movement-induced pain in a rat model of knee joint osteoarthritis and validate this behavioral assessment by evaluating the effects of clinically used analgesic compounds. Unilateral intra-articular administration of a chondrocyte glycolytic inhibitor monoiodoacetate, was used to induce knee joint osteoarthritis in Sprague–Dawley rats. In this osteoarthritis model, histologically erosive disintegration of the articular surfaces of the ipsilateral joint are observed which closely mimic the clinical picture of osteoarthritis. Movement-induced pain behavior was measured using hind limb compressive grip force evaluation. The animals exhibited pain behaviors epitomized by a long-lasting decrement in bilateral compressive hind limb grip force following unilateral knee injury. The effects of clinically used reference analgesics were evaluated 20 days following i.a. injection of monoiodoacetate. Full analgesic activity was observed for tramadol, celecoxib and diclofenac; moderate effects for indomethacin, duloxetine and gabapentin but weak or no effects for acetaminophen, ibuprofen and lamotrigine. As morphine reduced grip force in naïve rats, its analgesic effects could not be accurately evaluated in this model. Finally, the effects of celecoxib were maintained following chronic dosing. The results indicate that this in vivo model utilizing a movement-induced pain behavior spawned by knee joint osteoarthritis may provide a valuable tool in examining the role of potential analgesic targets in osteoarthritic pain. As the model is clinically relevant, it will further enhance the mechanistic understanding of chronic arthritic joint pain and help in developing newer and better therapeutic strategies to manage osteoarthritis pain. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Osteoarthritis is by far the most common type of degenerative arthritis and afflicts millions of people worldwide including an estimated 20 million people in the US (Lawrence et al., 1998). Pain worsened by weight bearing activity is one of the cardinal symptoms of osteoarthritis and is the leading cause of disability and quality of life impairment due to functional limitations (O'Reilly et al., 1998; American College of Rheumatology Subcommittee on Osteoarthritis Guidelines, 2000). In the US, the percentage of people with osteoarthritis-induced functional limitation is projected to increase from 2.8 in 1990 to 3.6% of the population in 2020 (Yasmin et al., 2000). Therefore, pain management is a challenging but critical cornerstone for the pharmacotherapy of osteoarthritis, which in effect facilitates maintaining or improving joint mobility and minimizing functional impairment. Relief from chronic joint pain secondary to osteoarthritis is often refractory to currently available pharmacological interventions including non-steroidal anti-inflammatory drugs and opioid formula- tions, posing a challenge for the clinicians (Kidd, 2006). Osteoarthritis pain is complex as its etiology is often from multiple sources and can be either inflammatory or non-inflammatory in origin (Pinals, 1996). Clinically, the patients afflicted with osteoarthritis describe their joint pain as being a deep and dull ache that is exacerbated with motion or activity. Movement-induced pain is a characteristic early symptom however, with the progression of the disease, a continuous aching pain or pain at rest is the main clinical presentation (Sinkov and Cymet, 2003). Recent clinical studies have reported a difference in pharmacological profile for relief of pain at rest versus movement- induced pain in osteoarthritic patients (Petrella et al., 2002). There- fore, a thorough understanding of the mechanisms of actions of currently used analgesics and their utility in treating the different qualities of pain is vital. Evaluation of hind limb compressive grip force in animal models of osteoarthritis may reproduce clinically observed symptoms of move- ment-induced pain in osteoarthritis patients. There have been reports of several animal models of osteoarthritis evaluating the pathogenesis and potential therapeutic modulation of the disease (Bendele, 2001). Intra-articular administration (i.a.) of sodium monoiodoacetate in rodents causes a disruption of the articular cartilage by inhibiting chondrocyte metabolism (Guingamp et al., 1997; van der Kraan et al., European Journal of Pharmacology 613 (2009) 39–45 ⁎ Corresponding author. Tel.: +1847 936 3537; fax: +1 847 938 0072. E-mail address: Prasant.Chandran@abbott.com (P. Chandran). 0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.04.009 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar