ARTHRITIS & RHEUMATISM Vol. 56, No. 12, December 2007, pp 4015–4023 DOI 10.1002/art.23063 © 2007, American College of Rheumatology Collagen-Induced Arthritis as a Model of Hyperalgesia Functional and Cellular Analysis of the Analgesic Actions of Tumor Necrosis Factor Blockade Julia J. Inglis, 1 Clare A. Notley, 1 David Essex, 1 Alex W. Wilson, 2 Marc Feldmann, 1 Praveen Anand, 1 and Richard Williams 1 Objective. There is a disparity in the animal models used to study pain in rheumatoid arthritis (RA), which tends to be acute in nature, and models used to assess the pathogenesis of RA. The latter models, like human RA, are lymphocyte-driven and polyarthritic. We assessed pain behavior and mechanisms in collagen- induced arthritis (CIA), the model of preclinical arthri- tis used most commonly in the field of immunology. We then validated the model using anti–tumor necrosis factor (anti-TNF) therapy, which has analgesic effects in models of inflammation as well as in human RA. Methods. CIA was induced in DBA/1 mice by immunization with type II collagen at the base of the tail. Swelling and mechanical and thermal hyperalgesia were assessed before and for 28 days after the onset of arthritis. Spontaneous behavior was assessed using an automated activity monitor. Glial activity was assessed by glial fibrillary acidic protein expression, and nerve damage was evaluated by activating transcription factor 3 expression. The actions of anti-TNF therapy on noci- ception were then evaluated. Results. Arthritis resulted in a decrease in the threshold for thermal and mechanical stimuli, begin- ning on the day of onset. Decreased spontaneous activity was also observed. A significant increase in the number of hyperplasic spinal cord astrocytes was observed be- ginning 10 days after the onset of arthritis. Anti-TNF therapy was profoundly analgesic, with an efficacy sim- ilar to that of cyclooxygenase 2 inhibition, and reduced astrocyte activity in CIA. Conclusion. This study shows that the CIA model is suitable for testing not only antiinflammatory but also analgesic drugs for potential use in RA, and highlights the importance of using appropriate disease models to assess relevant pain pathways. Several animal models are used for the study of inflammation and inflammatory pain. The most com- monly used models for the study of inflammatory pain involve injecting mediators of inflammation into the footpad or knee (1). This results in a monarthritis, in which the contralateral limb can be used as an internal control. However, the inflammation in these models is acute and often self limiting in nature, differing from that in arthritis, and does not involve B lymphocytes or T lymphocytes, which are known to be key in the pathogenesis of rheumatoid arthritis (RA). Antigen- induced arthritis, in which mice are immunized with methylated bovine serum albumin, has been used to study pain in arthritis (2). This model is T cell dependent but, unlike RA, is not major histocompatibility complex restricted or B cell dependent. Streptococcal cell wall– induced arthritis has also been used for the study of arthritic pain. However, this model more closely resem- bles reactive arthritis than human RA. In contrast to models used to study pain, the animal model that is currently most widely used to study the pathogenesis and treatment of RA is collagen- induced arthritis (CIA) in male DBA/1 mice (3). CIA is induced by immunization with type II collagen in Freund’s complete adjuvant (CFA), which induces an Supported by GlaxoSmithKline and the Arthritis Research Campaign. 1 Julia J. Inglis, PhD, Clare A. Notley, PhD, David Essex, MSc, Marc Feldmann, PhD, Praveen Anand, MD, Richard Williams, PhD: Imperial College London, London, UK; 2 Alex W. Wilson, PhD: GlaxoSmithKline Research & Development Limited, Essex, UK. Address correspondence and reprint requests to Julia J. Ing- lis, PhD, Kennedy Institute of Rheumatology, Imperial College Lon- don, London W6 8LH, UK. E-mail: j.inglis@imperial.ac.uk. Submitted for publication January 31, 2007; accepted in revised form August 20, 2007. 4015