An animal model of chronic inflammatory pain: Pharmacological and temporal differentiation from acute models Alex W. Wilson a, * , Stephen J. Medhurst a , Claire I. Dixon a , Nick C. Bontoft a , Lisa A. Winyard a , Kim T. Brackenborough a , Jorge De Alba a , Christopher J. Clarke a , Martin J. Gunthorpe a , Gareth A. Hicks a , Chas Bountra a , Daniel S. McQueen b , Iain P. Chessell a a Department of Pain Research, Neurology and Gastrointestinal CEDD, GlaxoSmithKline Research and Development Ltd., Third Avenue, Harlow, Essex CM19 5AW, UK b Division of Neuroscience, University of Edinburgh College of Medicine and Vet Medicine, 1 George Square, Edinburgh EH8 9JZ, UK Received 4 November 2004; accepted 8 August 2005 Available online 30 September 2005 Abstract Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal mod- els focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3 mg/kg, t.i.d.), dexamethasone (1 mg/kg, b.i.d.), ibuprofen (30 mg/kg, t.i.d.), etoricoxib (5 mg/kg, b.i.d.) and rofecoxib (0.3–10 mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plan- tar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treat- ment of chronic inflammatory pain states in the clinic. Ó 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Chronic inflammation pain; Hypersensitivity; NR2B antagonist; iNOS inhibitor; Joint 1. Introduction Rheumatoid and osteoarthritis comprise the two most common forms of arthritis, with over seven million sufferers in the UK alone (Arthritis Research Campaign, 2004). Although arthritis is defined as inflammation of the joint, the primary feature with which patients pres- ent in the clinic is chronic pain. Currently available ther- apies used in osteoarthritis (OA) and rheumatoid arthritis (RA) fail to adequately alleviate pain in many patients, and side effects of the treatments often limit 1090-3801/$32 Ó 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2005.08.003 * Corresponding author. Tel.: +44 1279 622079; fax: +44 1279 622211. E-mail address: Alex_W_Wilson@gsk.com (A.W. Wilson). www.EuropeanJournalPain.com European Journal of Pain 10 (2006) 537–549