Caractérisation d'un modèle animal de douleur articulaire associée à l'arthrose du genou chez le rat Sprague-Dawley

Pain is the most predominant clinical symptom associated with osteoarthritis (OA), mostly among older people. Joint movement and weight bearing often increase the pain intensity. Unfortunately, the proposed pharmacological treatments are frequently associated with side effects and ineffective for pain alleviation for long time periods. Many murine models are used in laboratories for preclinical studies evaluating analgesic compounds. A comparative evaluation of the behavioral pain responses of animals with a joint instability model induced by the transection of the anterior cruciate ligament followed by a partial menisectomy (the ACLT+pMMx model) and of an articular degenerative model induced by an intra-articular injection of monoiodoacetate (the MIA model) was conducted to select an appropriate model for the continuation of the project. Both models demonstrated articular lésions, however the MIA model demonstrated a clearer behavioral pain response over the ACLT+pMMx model. The gait pattern of the MIA model revealed a clear limping gait similar to that observed with unilateral OA in humans. The MIA model was chosen for the subsequent studies. An unresolved issue in pain OA research is the lack of understanding of the pain mechanisms responsible for the induction and maintenance of the pain. Therefore, there is an urgent clinical need to improve the characterization of animal models to effectively discover novel pain relief pharmacological treatment stratégies for OA patients. A characterization of the spinal pain molecular events during the progression of the joint degenerative process in the MIA model was performed on days 3, 7, 14, 21 and 28 post injection. Heterogeneous nociceptive central molecular events were observed in respect to the time course of the pathology’s progression. Changes in selected spinal neuropeptide content (substance P, CGRP, dynorphin A, Big dynorphin) began 7 days following the MIA injection. Most severe joint structural damage on histology occured between days 14 and 21 post injection. These results suggest that preclinical drug evaluation employing this model should be conducted between 7 and 21 days post injection when the lesions resemble most those of human OA. iii As current pharmacological therapy for the alleviation of joint pain does not achieve the unanimity in respect to efficacy, side effects and cost, plant derivate compounds are now interesting alternatives to improve the situation. Eugenol, the main constituent of clove oil, was evaluated for its efficacy for alleviation of joint pain in rats who previously received an intra-articular injection of mono-iodoacetate to induce the MIA model. Eugenol, administered orally for 28 consecutive days at a dose of 40 mg/kg, improved gait pattern and reduced secondary mechanical allodynia. Furthermore, spinal concentrations of pronociceptive neuropeptides were also decreased in the treated animals. No toxic effects of the compoud were identified on histopathological assessment of the various tissues. These results suggest that eugenol could be a potential therapeutic option for alleviating OA joint pain.

Keyphrases: Rat, Neuropeptides, Joint pain, Osteoarthritis, Animal models, Rat, Gait analysis, Secondary mechanical allodynia, Neuropeptides, Eugenol, Pharmacological treatment