Pre-treatment with capsaicin in a rat osteoarthritis model reduces the symptoms of pain and bone damage induced by monosodium iodoacetate

Abstract

A rat model of osteoarthritis was used to investigate the effect of pre-treatment with capsaicin on the symptoms of osteoarthritis induced by the injection of monosodium iodoacetate. This model mimics both histopathology and symptoms associated of human osteoarthritis. Injection of monosodium iodoacetate, an inhibitor of glycolysis, into the femorotibial joints of rodents promotes loss of articular trabecular bone and invokes pain symptoms similar to those noted in human osteoarthritis. Twenty rats were divided in two groups either receiving placebo or monosodium iodoacetate. Each group was subdivided in two groups either receiving pre-treatment with capsaicin two weeks before monosodium iodoacetate injection or not, resulting in four groups of five rats each. The impact of a single intra-articular administration of capsaicin (0.5%) on the generation of evoked mechanical pain (hind limb weight bearing, automated von Frey monofilament and RotaRod tests) and bone lesions (micro-CT scan radiographic analyses of bone structure) following monosodium iodoacetate-induced osteoarthritis in rats was determined. Evoked mechanical pain as monitored over a period of 4 weeks after monosodium iodoacetate injection was abolished in capsaicin pre-treated animals and pain values are comparable to those of capsaicin controls. Chronic joint pathological changes such as bone erosion and trabecular damage were significantly reduced by pre-treatment with a single administration of capsaicin. Decrease of bone volume was considerably ameliorated and trabecular connectivity was substantially better in capsaicin pre-treated animals. Capsaicin, an agonist activator of the vanilloid nociceptors (TRPV1), appears to be effective in protecting bone from arthritic damage. The present results support the hypothesis that capsaicin-sensitive sensory neurons contribute to bone lesions in the monosodium iodoacetate-induced osteoarthritis rat model.

Introduction

Osteoarthritis is a complex degenerative disease of the joints characterised by the progressive destruction and erosion of trabecular bone as a characteristic pathological feature, and accompanied with pain as the most prominent and debilitating symptom (Felson et al., 2000). Moreover, osteoarthritis is regarded as an age associated disease, and its prevalence is significantly increasing, but the underlying mechanisms of osteoarthritis are not yet clearly elucidated. Thus, there is a tremendous unmet medical need for therapeutics to treat osteoarthritis (March and Bachmeier, 1997) and related pain. Although destruction of trabecular bone is a hallmark of osteoarthritis and rheumatoid arthritis, and one of the most critical clinical problems, the relation between pain and joint deformation is not completely understood.

Because osteoarthritis is a complex disease and neither its etiology nor its pathology is fully understood, it is difficult to evaluate how well any animal model of osteoarthritis mimics the disease in humans (Brandt, 2002). However, many experimental animal models of osteoarthritis have been developed in various species but none of them appears to fully reproduce all aspects of human osteoarthritis (Pritzker, 1994, Bendele et al., 1999). While no consensus currently exists regarding the most relevant animal model of osteoarthritis, the diversity of the available models provides us with a wealth of valuable information on joint biology and OA pathology. These animal models are also useful for the exploration of the efficacy and mechanism of action of analgesic treatments used in osteoarthritis.

In the present study the rat model of monosodium iodoacetate-induced osteoarthritis was applied.

The immune response has long been thought to be involved in the pathogenesis of osteoarthritis (Decaris et al., 1999, Levine et al., 1985a). Clinical and experimental observations also suggest that the nervous system, via particular neuropeptides, is involved in the pathogenesis of osteoarthritis (Kidd et al., 1990). In an osteoarthritis rat model, higher levels of neuropeptides such as substance P were found in the synovial membrane and in the spinal cord (Calzà et al., 1998). Thus, the modulation of the nervous system may also play a critical role in the development of this disease (Levine et al., 1985b). However, the location of peripheral nerve endings where pain originates in osteoarthritis is disputed (Felson, 2005) and the contribution of these nociceptors to neurogenic inflammation-mediated chronic osteoarthritic pain and osteopathological changes has not been well studied.

The small-diameter dorsal root ganglion neurons and associated Aδ- and C-fiber afferents are critical for detecting noxious stimuli and initiating pain sensation (Harper and Lawson, 1985, Slugg et al., 2000). Capsaicin, the pungent agent originally isolated from the Chili pepper, is a potent agonist of the transient receptor potential vanilloid type 1 (TRPV1) which plays an essential role in detecting thermal and mechanical nociception (Walker et al., 2003). In this regard, mice deficient of TRPV1 (Caterina et al., 2000) and rats with TRPV1-expressing sensory neurons ablation by systemic injection of capsaicin show impaired pain response to heat (Pan et al., 2003, Xu et al., 1997). The TRPV1 receptor equipped neuron acts as a molecular integrator of multiple chemical and physical stimuli, including noxious heat, low pH, capsaicin, and lipid metabolites (Tominaga et al., 1998) and it has been documented that capsaicin can eliminate the primary sensory C-fiber neurons through calcium influx and overloading (Olah et al., 2001).

In the present study, to investigate the role of small C-fiber afferents in the development of osteoarthritis, the effects of intra-articular injection of capsaicin 14 days prior to the induction of an experimental osteoarthritis by monosodium iodoacetate in the rat were assessed. Behavioural tests as well as and micro-computed tomography (µCT) were applied to investigate the effect of capsaicin pre-treatment on pain behaviour, joint structure and bone resorption, respectively.