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Structural pathology in a rodent model of osteoarthritis is associated with neuropathic pain: Increased expression of ATF-3 and pharmacological characterisation

Ivanavicius, Stefan P.a; Ball, Adrian D.a; Heapy, Chris G.a; Westwood, Russell F.b; Murray, Frasera; Read, Simon J.a,*

doi: 10.1016/j.pain.2006.12.022
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Intra-articular injection of mono-iodoacetate (MIA) in the rat knee joint induces a histopathology with similarities to osteoarthritis (OA). Typically, a synovitis (days 1–3) is observed followed by thinning of articular cartilage and subsequent lesion of subchondral bone at days 8–14 onwards. Behaviourally, weight-bearing asymmetry is observed, which is sensitive to anti-inflammatory pharmacology at early but not later (days 14+) time points. As subchondral bone is densely innervated, an intriguing possibility is that focal bone pathology may cause neuropathy in this model. In male Wistar rats, activating transcription factor (ATF)-3-immunofluorescence was used as a marker of nerve injury in lumber (L)4 and L5 dorsal root ganglia of the ipsilateral knee. Significantly increased ATF-3-immunoreactivity following MIA treatment was measured in L5 on days 8 and 14 (P < 0.05, Kruskal–Wallis and Mann–Whitney U-test), compared to saline controls. Furthermore, in an additional study animals were orally dosed vehicle (5 ml/kg), naproxen (0.3–10 mg/kg), celecoxib (1–10 mg/kg), amitriptyline (3–30 mg/kg) and gabapentin (10–100 mg/kg) and evaluated for weight-bearing asymmetry on days 14, 21 and 28 post-MIA. Significant resolution of weight-bearing was observed at high and intermediate doses of amitriptyline and gabapentin at all time points (P < 0.05, ANOVA, post-hoc Bonferroni's, vs pre-dose measurements). Transient and weak effects were observed with naproxen (10 mg/kg) on days 14 and 28, whereas celecoxib showed no significant effects. Collectively, these data suggest that this putative model of OA is associated with an early phase neuropathy in the L5 innervation territory of the knee.

Abbreviations: ANOVA: analysis of variance; ATF-3: activating transcription factor-3; COX: cyclo-oxygenase; DRG: dorsal root ganglia; gadd: growth arrest and DNA damage gene; IR: immunoreactivity; L (prefix): lumbar; MIA: mono-iodoacetate; MRI: magnetic resonance imaging; NSAID: non-steroidal anti-inflammatory drug; OA: osteoarthritis.

aIn Vivo Pharmacology, AstraZeneca, Alderley Park, Mereside, Cheshire SK10 4TG, UK

bSafety Assessment, AstraZeneca, Alderley Park, Mereside, Cheshire SK10 4TG, UK

*Corresponding author. Tel.: +44 1625 232571; fax: +44 1625 510823.

E-mail: Simon.Read@AstraZeneca.com

Submitted June 14, 2006; revised November 16, 2006; accepted December 20, 2006.

© 2007 Lippincott Williams & Wilkins, Inc.
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