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Pain related behaviour in two models of osteoarthritis in the rat knee

Fernihough, Janeta,1; Gentry, Clivea,1; Malcangio, Marziaa; Fox, Alysona; Rediske, Johnb; Pellas, Theodoreb; Kidd, Brucec; Bevan, Stuarta; Winter, Janeta,*

doi: 10.1016/j.pain.2004.08.004
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Osteoarthritis (OA) is a major healthcare burden, with increasing incidence. Pain is the predominant clinical feature, yet therapy is ineffective for many patients. While there are considerable insights into the mechanisms underlying tissue remodelling, there is poor understanding of the link between disease pathology and pain. This is in part owing to the lack of animal models that combine both osteoarthritic tissue remodelling and pain. Here, we provide an analysis of pain related behaviours in two models of OA in the rat: partial medial meniscectomy and iodoacetate injection. Histological studies demonstrated that in both models, progressive osteoarthritic joint pathology developed over the course of the next 28 days. In the ipsilateral hind limb in both models, changes in the percentage bodyweight borne were small, whereas marked mechanical hyperalgesia and tactile allodynia were seen. The responses in the iodoacetate treated animals were generally more robust, and these animals were tested for pharmacological reversal of pain related behaviour. Morphine was able to attenuate hyperalgesia 3, 14 and 28 days after OA induction, and reversed allodynia at days 14 and 28, providing evidence that this behaviour was pain related. Diclofenac and paracetamol were effective 3 days after arthritic induction only, coinciding with a measurable swelling of the knee. Gabapentin varied in its ability to reverse both hyperalgesia and allodynia. The iodoacetate model provides a basis for studies on the mechanisms of pain in OA, and for development of novel therapeutic analgesics.

Abbreviations: OA: osteoarthritis; DRGs: dorsal root ganglia; NSAIDs: non-steroidal anti-inflammatory drugs; PWT: paw withdrawal thresholds; p.o.: orally; s.c.: sub cutaneously.

aNovartis Institute for Medical Sciences, 5 Gower Place, London WCE 6BS, UK

bNovartis Institutes for BioMedical Research Arthritis and Bone Metabolism, East Hanover, NJ, USA

cBone & Joint Research Unit, Bart's & London School of Medicine, London, UK

*Corresponding author. Tel.: +020–7387–4445; fax: +020–7387–4116.

E-mail: janet.winter@pharma.novartis.com

1The first two authors should be considered equal joint first authors in their contribution to this manuscript.

Submitted February 10, 2004; revised July 27, 2004; accepted August 2, 2004.

© 2004 Lippincott Williams & Wilkins, Inc.
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