Development and pharmacological characterization of a rat model of osteoarthritis pain

Purdue Pharma L.P., Stamford, Connecticut, United States
Pain (Impact Factor: 5.84). 05/2005; 114(3):339-46. DOI: 10.1016/j.pain.2004.11.008
Source: PubMed

ABSTRACT Osteoarthritis (OA) is an age-related joint disease characterized by degeneration of articular cartilage and is associated with chronic pain. Although several experimental models of OA have been employed to investigate the underlying etiologies of the disease, there has been relatively little investigation into development of animal models of OA to study the pain associated with the condition. In the present study, we investigated OA induced by injection of either iodoacetate or papain into the knee joint of rats, and assessed the joint degeneration with radiographic analyses and measured pain behavior using hind limb weight bearing. We found that injection of iodoacetate, but not papain, resulted in a chronic joint degeneration as measured by decreased bone mineral content and bone mineral density, necrosis of articular cartilage and osteophyte formation. These pathological changes were associated with pain that manifested as time- and concentration-dependent alterations in hind limb weight bearing. These alterations in hind limb weight bearing were reversed with morphine, but were not significantly affected by acute administration of either indomethacin or celecoxib. However, administration of 30 mg/kg celecoxib twice daily for 10 days resulted in a significant restoration of hind limb weight bearing. We conclude that the iodoacetate model of OA is a relevant animal model to study pain associated with OA, and can be used to test potential therapeutic agents.

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Available from: James D Pomonis, Sep 17, 2014
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    • "In addition this dose of 466 MIA has been shown to produce OA associated with 467 markers of neuropathy (Ivanavicius et al., 2007; Im 468 et al., 2010; Thakur et al., 2012, 2014) and therefore 469 may be indicative of those patients with advanced disease 470 that display an additional neuropathic pain phenotype 471 (Hochman et al., 2011; Duarte et al., 2014). Knee joint 472 pathology was not assessed here, however we have pre- 473 viously demonstrated cartilage loss following injection of 474 2 mg of MIA, which is characteristic of human OA, 475 (Thakur et al., 2012) as have others (Fernihough et al., 476 2004; Pomonis et al., 2005; Im et al., 2010), also MIA 477 injection produced hypersensitivity to mechanical and 478 cooling stimulation of the ipsilateral hind paw and a 479 decrease in hind limb weight bearing of the injected side 480 confirming OA pain development (Vincent et al., 2012; 481 Malfait et al., 2013). "
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    ABSTRACT: Voltage gated sodium channel blockers are not traditionally recommended for osteoarthritis (OA) pain therapy, but given the large peripheral drive that follows OA development there is a rationale for their use. Using a rat model of monosodium iodoacetate (MIA) induced osteoarthritis we used in vivo electrophysiology to assess the effects of the Nav1.7 and Nav 1.8 selective antagonists, ProTxII and A-803467 respectively, on the evoked activity of spinal dorsal horn neurons in response to electrical, mechanical and thermal stimuli applied to the peripheral receptive field. These studies allow examination of the roles of these channels in suprathreshold stimuli, not amenable to behavioural threshold measures. Spinal administration of ProTxII significantly reduced neuronal responses evoked by mechanical punctate (von Frey (vF) 8- 60g) and noxious thermal (45 and 48 (0)C) stimuli in MIA rats only. A-803467 significantly inhibited neuronal responses evoked by vF 8 - 60g and 48(0)C heat after spinal administration; significantly inhibited responses evoked by brush, vFs 26-60g and 40- 48(0)C stimuli after systemic administration; significantly inhibited the electrically evoked Aδ-, C-fiber, post-discharge, Input and wind-up responses and the brush, vFs 8- 60g and 45 - 48(0)C evoked neuronal responses after intra plantar injection in the MIA group. In comparison A-803467 effects in the sham group were minimal and included a reduction of the neuronal response evoked by vF60g and 45(0)C heat stimulation after spinal administration, no effect after systemic administration and an inhibition of the evoked response to 45(0)C heat after intra plantar injection only. The observed selective inhibitory effect of ProTxII and A-803467 for the MIA treated group suggest an increased role of Nav 1.7 and 1.8 within nociceptive pathways in the arthritic condition, located at peripheral and central sites. These findings demonstrate the importance of, and add to, the mechanistic understanding of these channels in osteoarthritic pain. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 03/2015; 15. DOI:10.1016/j.neuroscience.2015.03.042 · 3.33 Impact Factor
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    • "In light of biomechanics, pain is also an important aspect that is likely to have influenced our outcome . Rats that suffer pain from OA induction are known to change their weight-bearing behavior [52]. Unfortunately, we were not able to record their discomfort using an incapacitance test or pain measurement. "
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    ABSTRACT: Osteoarthritis (OA) is a non-rheumatoid joint disease characterized by progressive degeneration of extra-cellular cartilage matrix (ECM), enhanced subchondral bone remodeling, osteophyte formation and synovial thickening. Alendronate (ALN) is a potent inhibitor of osteoclastic bone resorption and results in reduced bone remodeling. This study investigated the effects of pre-emptive use of ALN on OA related osteoclastic subchondral bone resorption in an in vivo rat model for severe OA. Using multi-modality imaging we measured effects of ALN treatment within cartilage and synovium. Severe osteoarthritis was induced in left rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with subcutaneous ALN injections and compared to twenty untreated controls. Animals were longitudinally monitored for 12 weeks with in vivo μCT to measure subchondral bone changes and SPECT/CT to determine synovial macrophage activation using a folate-based radiotracer. Articular cartilage was analyzed at 6 and 12 weeks with ex vivo contrast enhanced μCT and histology to measure sulfated-glycosaminoglycan (sGAG) content and cartilage thickness.
    Bone 06/2014; 66. DOI:10.1016/j.bone.2014.06.009 · 4.46 Impact Factor
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    • "Incapacitance test (weight bearing). Weight-bearing changes were measured using an incapacitance apparatus (Linton Instrumentation, UK) detecting changes in postural equilibrium after a hind paw injury (Pomonis et al., 2005). Rats were trained to stand on their hind paws in a box with an inclined plane (65 from horizontal). "
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    ABSTRACT: Dimiracetam, a bicyclic 2-pyrrolidinone derivative originally developed as cognition enhancer, is a member of the nootropic family for which anedoctal efficacy in models of neuropathic pain has been reported. Its antineuropathic activity was evaluated in established models of neuropathic pain induced by nerve injury, chemotherapy or MIA-induced osteoarthritis. Acutely, dimiracetam was very effective in models of antiretroviral drug induced painful neuropathy, oxaliplatin-induced hyperalgesia and in the MIA-osteoarthritis. Chronic dimiracetam dosing in the MIA and ART- induced models completely reverted hyperalgesia back to the level of healthy controls. Once reached, the maximal effect was maintained despite dose diminution and increased inter-dose interval. The effect of the last dose outlasted dimiracetam half-life longer than 12 times. In synaptosomal preparations, dimiracetam counteracted the NMDA-induced release of glutamate with highest potency in the spinal cord, possibly via NMDA receptor isoforms containing pH-sensitive GluN1 and GluN2A subunits. Dimiracetam appears to be a promising and safe treatment for neuropathic pain conditions for which there are very limited therapeutic options.
    Neuropharmacology 01/2014; DOI:10.1016/j.neuropharm.2014.01.029 · 4.82 Impact Factor
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