Article

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.

Download full-text

Full-text

Available from: James D Pomonis, Sep 17, 2014
1 Follower
 · 
86 Views
  • Source
    • "Thus the MIA model has, so far, proved useful for the understanding of osteoarthritic pain mechanisms (Zhang et al., 2013). In the present study joint pathology was not assessed, however , MIA injection produced hypersensitivity to mechanical stimulation of the ipsilateral hind paw and a decrease in hind limb weight bearing of the injected side, confirming pain development and in addition, we have previously observed loss of articular cartilage using this dose of MIA in rats at day 14 post injection (Thakur et al., 2012) as have others (Fernihough et al., 2004; Pomonis et al., 2005; Im et al., 2010), therefore it is highly likely that the animals used in the present study developed OA of the knee and supports the relevance of this model of MIAinduced arthritis for studying OA pain mechanisms (Vincent et al., 2012; Malfait et al., 2013). Pain symptoms in knee OA patients are largely located within the area surrounding the affected joint, however many OA patients also exhibit areas of referred pain and tenderness, which correlates with the hypersensitivity of the ipsilateral hind paw in MIA rats, and implicates mechanisms of central sensitisation contributing to the pain experience (Farrell et al., 2000; Bajaj et al., 2001; Gwilym et al., 2009; Graven-Nielsen and Arendt-Nielsen, 2010; Aranda-Villalobos et al., 2013) Indeed, experimental human studies in OA patients suggest that central sensitization is an important contributor to their pain and a direct link between sensitization levels in referred areas and clinical pain intensity experienced by OA patients was shown (Arendt-Nielsen et al., 2010). "
  • Source
    • "Thus the MIA model has, so far, proved useful for the understanding of osteoarthritic pain mechanisms (Zhang et al., 2013). In the present study joint pathology was not assessed, however, MIA injection produced hypersensitivity to mechanical stimulation of the ipsilateral hind paw and a decrease in hind limb weight bearing of the injected side, confirming pain development and in addition, we have previously observed loss of articular cartilage using this dose of MIA in rats at day 14 post injection (Thakur et al., 2012) as have others (Fernihough et al., 2004, Pomonis et al., 2005, Im et al., 2010), therefore it is highly likely that the animals used in the present study developed osteoarthritis of the knee and supports the relevance of this model of MIA induced arthritis for studying OA pain mechanisms (Vincent et al., 2012, Malfait et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteoarthritis (OA) remains one of the greatest healthcare burdens in western society, with chronic debilitating pain dominating clinical presentation yet therapeutic strategies are inadequate in many patients. Development of better analgesics is contingent on improved understanding of the molecular mechanisms mediating OA pain. Voltage gated calcium channels 2.2 (Cav2.2) play a critical role in spinal nociceptive transmission, therefore blocking Cav2.2 activity represents an attractive opportunity for OA pain treatment, but the only available licensed Cav2.2 antagonist ziconitide (PrilatTM) is of limited use. TROX-1 is an orally available, use dependent and state selective Cav2 antagonist, exerting its analgesic effect primarily via Cav2.2 blockade, with an improved therapeutic window compared with ziconitide. Using a rat model of monosodium iodoacetate (MIA), 2mg, induced osteoarthritis we used in vivo electrophysiology to assess the effects of spinal or systemic administration of TROX-1 on the evoked activity of wide dynamic range spinal dorsal horn neurons in response to electrical, natural mechanical (dynamic brush and von Frey 2, 8, 26 and 6g) and thermal (40, 45 and 45 °C) stimuli applied to the peripheral receptive field. MIA injection into the knee joint resulted in mechanical hypersensitivity of the ipsilateral hind paw and weight bearing asymmetry. Spinal administration of TROX-1 (0.1 and 1 μg/50 μl) produced a significant dose related inhibition of dynamic brush, mechanical (vF 8g, 26 and 60g) and noxious thermal (45 and 48°C) evoked neuronal responses in MIA rats only. Systemic administration of TROX-1 produced a significant inhibition of the mechanical (vF 8g, 26 and 60g) evoked neuronal responses in MIA rats. TROX-1 did not produce any significant effect on any neuronal measure in Sham controls. Our in vivo electrophysiological results demonstrate a pathological state dependent effect of TROX-1, which suggests an increased functional role of Cav2, likely Cav2.2, channels in mediating OA pain.
    Neuroscience 08/2015; DOI:10.1016/j.neuroscience.2015.07.073 · 3.33 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
Show more