Neuropharmacology and Analgesia
Pharmacological modulation of movement-evoked pain in a rat model of osteoarthritis

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Abstract

This study was conducted to characterize movement-induced pain in a rat model of knee joint osteoarthritis and validate this behavioral assessment by evaluating the effects of clinically used analgesic compounds. Unilateral intra-articular administration of a chondrocyte glycolytic inhibitor monoiodoacetate, was used to induce knee joint osteoarthritis in Sprague–Dawley rats. In this osteoarthritis model, histologically erosive disintegration of the articular surfaces of the ipsilateral joint are observed which closely mimic the clinical picture of osteoarthritis. Movement-induced pain behavior was measured using hind limb compressive grip force evaluation. The animals exhibited pain behaviors epitomized by a long-lasting decrement in bilateral compressive hind limb grip force following unilateral knee injury. The effects of clinically used reference analgesics were evaluated 20 days following i.a. injection of monoiodoacetate. Full analgesic activity was observed for tramadol, celecoxib and diclofenac; moderate effects for indomethacin, duloxetine and gabapentin but weak or no effects for acetaminophen, ibuprofen and lamotrigine. As morphine reduced grip force in naïve rats, its analgesic effects could not be accurately evaluated in this model. Finally, the effects of celecoxib were maintained following chronic dosing. The results indicate that this in vivo model utilizing a movement-induced pain behavior spawned by knee joint osteoarthritis may provide a valuable tool in examining the role of potential analgesic targets in osteoarthritic pain. As the model is clinically relevant, it will further enhance the mechanistic understanding of chronic arthritic joint pain and help in developing newer and better therapeutic strategies to manage osteoarthritis pain.

Introduction

Osteoarthritis is by far the most common type of degenerative arthritis and afflicts millions of people worldwide including an estimated 20 million people in the US (Lawrence et al., 1998). Pain worsened by weight bearing activity is one of the cardinal symptoms of osteoarthritis and is the leading cause of disability and quality of life impairment due to functional limitations (O'Reilly et al., 1998, American College of Rheumatology Subcommittee on Osteoarthritis Guidelines, 2000). In the US, the percentage of people with osteoarthritis-induced functional limitation is projected to increase from 2.8 in 1990 to 3.6% of the population in 2020 (Yasmin et al., 2000). Therefore, pain management is a challenging but critical cornerstone for the pharmacotherapy of osteoarthritis, which in effect facilitates maintaining or improving joint mobility and minimizing functional impairment.

Relief from chronic joint pain secondary to osteoarthritis is often refractory to currently available pharmacological interventions including non-steroidal anti-inflammatory drugs and opioid formulations, posing a challenge for the clinicians (Kidd, 2006). Osteoarthritis pain is complex as its etiology is often from multiple sources and can be either inflammatory or non-inflammatory in origin (Pinals, 1996). Clinically, the patients afflicted with osteoarthritis describe their joint pain as being a deep and dull ache that is exacerbated with motion or activity. Movement-induced pain is a characteristic early symptom however, with the progression of the disease, a continuous aching pain or pain at rest is the main clinical presentation (Sinkov and Cymet, 2003). Recent clinical studies have reported a difference in pharmacological profile for relief of pain at rest versus movement-induced pain in osteoarthritic patients (Petrella et al., 2002). Therefore, a thorough understanding of the mechanisms of actions of currently used analgesics and their utility in treating the different qualities of pain is vital.

Evaluation of hind limb compressive grip force in animal models of osteoarthritis may reproduce clinically observed symptoms of movement-induced pain in osteoarthritis patients. There have been reports of several animal models of osteoarthritis evaluating the pathogenesis and potential therapeutic modulation of the disease (Bendele, 2001). Intra-articular administration (i.a.) of sodium monoiodoacetate in rodents causes a disruption of the articular cartilage by inhibiting chondrocyte metabolism (Guingamp et al., 1997, van der Kraan et al., 1992). The progressive joint degeneration and functional impairment following monoiodoacetate injection mimics clinical signs and symptoms of osteoarthritis (van der Kraan et al., 1992, Clarke et al., 1997, Guingamp et al., 1997). However, the emphasis for the study of pain in this rodent osteoarthritis model has been a recent phenomenon with all the reports in the literature assessing hind limb weight bearing as an index for resting pain behavior (Schött et al., 1994, Bove et al., 2003, Kobayashi et al., 2003, Fernihough et al., 2004, Pomonis et al., 2005, Vermeirsch et al., 2007).

The purpose of this study is to pharmacologically characterize a novel compressive grip force movement-induced pain behavior in osteoarthritic rats and validate this model using clinically available analgesics.

Section snippets

Animals

All experiments have been approved by the Institutional Animal Care and Use Committee at Abbott Laboratories and are in strict accordance with the ethical guidelines laid down by the International Association for the Study of Pain (Zimmermann, 1983) for the care and use of laboratory animals. Male Sprague–Dawley rats (Charles River Labs, Portage, MI) group housed (5 per cage) and with free access to food and water, were used for the study (150–175 g at the start of the experiment). The animals

Time course of pain behavior assessment

Intra-articular administration of either monoiodoacetate or saline had no effect on the general health of the animals. The animals in both the saline and monoiodoacetate injected groups gained body weight normally and there was no statistically significant difference in body weight gain between the two groups.

The rats following i.a. administration of monoiodoacetate exhibited long lasting compressive grip force movement-induced pain behavior throughout the 20-day study period (Fig. 1). When

Discussion

Assessment of pain associated with osteoarthritis in animals is a challenging task. Intra-articular (i.a.) injection of monosodium iodoacetate, a cellular glycolytic inhibitor has been used to induce osteoarthritis-like changes in the articular cartilage of rodents to examine the pathophysiology of the disease (Kalbhen, 1987, Guingamp et al., 1997, van der Kraan et al., 1992). A lesioning of the articular cartilage is observed and there is a marked depletion of proteoglycans as indicated by the

Acknowledgements

The authors wish to thank Brenda Weaver and Dr. Robert S. Bitner for their assistance on the histological evaluation.

References (39)

  • Torres-LopezJ.E. et al.

    Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test

    Life Sci.

    (2002)
  • VermeirschH. et al.

    Evaluation of pain behavior and bone destruction in two arthritic models in guinea pig and rat

    Pharmacol. Biochem. Behav.

    (2007)
  • WacnikP.W. et al.

    Tumor implantation in mouse humerus evokes movement-related hyperalgesia exceeding that evoked by intramuscular carrageenan

    Pain

    (2003)
  • ZimmermannM.

    Ethical guidelines for investigations of experimental pain in conscious animals

    Pain

    (1983)
  • American College of Rheumatology Subcommittee on Osteoarthritis Guidelines

    Recommendations for the medical management of osteoarthritis of the hip and knee

    Arthritis Rheum.

    (2000)
  • American Pain Society

    The Use of Opioids for the Treatment of Chronic Pain: A Consensus Statement from American Academy of Pain Medicine and American Pain Society

    (1996)
  • BendeleA.M.

    Animal models of osteoarthritis

    J. Musculoskelet. Neuronal Interact.

    (2001)
  • ChandranP. et al.

    Pharmacological characterization of monoiodoacetate-induced osteoarthritic pain in rats

  • di VadiP.P. et al.

    The use of lamotrigine in neuropathic pain

    Anaesthesia

    (1998)
  • Cited by (0)

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