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Métrologie De La Douleur Animale Sur Modèles Expérimentaux : Développement Et Validation De Biomarqueurs Neuroprotéomiques

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Métrologie De La Douleur Animale Sur Modèles Expérimentaux : Développement Et Validation De Biomarqueurs Neuroprotéomiques Université de Montréal Métrologie de la douleur animale sur modèles expérimentaux : développement et validation de biomarqueurs neuroprotéomiques. par Colombe Otis Département de biomédecine vétérinaire Faculté de médecine vétérinaire Thèse présentée à la Faculté de médecine vétérinaire en vue de l’obtention du grade de philosophiæ doctor (Ph. D.) en sciences vétérinaires option pharmacologie Août, 2017 © Colombe Otis, 2017 Résumé La douleur est un phénomène complexe et dynamique comprenant un processus primaire et sensoriel, la nociception, auquel se rajoutent des réactions de défense et d'alarme psychophysiologiques. Ceci conduit au développement d'une véritable mémoire de la douleur, individuelle et modulée (plasticité neuronale) par des expériences précédentes de douleur, incluant entre autres, des phénomènes de sensibilisation nociceptive. Pour bien comprendre les mécanismes de sensibilisation centrale, les modèles animaux mimant les pathologies humaines sont d’une importance primordi ale. Or, pour ce faire, nous avons proposé une série d'approches expérimentales translationnelles par le développement de modèles expérimentaux de douleur bovine, canine et murine afin de caractériser les atteintes du protéome spinal en fonction du niveau de douleur perçu par l'animal et d’identifier le (les) marqueur (s) potentiellement modulé (s) par la sensibilisation nociceptive. À l’aide de la neuroprotéomique, nous avons identifié sur un modèle bovin de douleur viscérale, la protéine transthyrétine (TTR) comme étant sous-exprimée dans le protéome spinal en présence de douleur et ce, vérifié également dans le modèle canin de douleur chronique liée à l’arthrose chirurgicale. Ces résultats suggèrent la possibilité d’entrevoir la TTR comme un biomarqueur potentiel de la douleur chronique. Notre découverte de la relation entre les niveaux spinaux de TTR par neuroprotéomique et l’ hypersensibilité à la douleur dans les modèles bovin et canin soutiennent l’implication de composantes inflammatoires nociceptives et immunitaires. Par la suite, des procédures de validation métrologique des protocoles d’acclimatation et de conditions environnementales de manipulations ont permis d’identifier les méthodes d’évaluation de la douleur les plus fiables et sensibles . Le modèle d’induction de douleur arthrosique induite chimiquement (injection intra- articulaire de monosodium iodoacétate) chez le rat a ensuite démontré qu’une augmentation de l’expression temporelle des neuropeptides spinaux excitateurs tels que la substance P, le peptide relié au gène de la calcitonine, la bradykinine et celle du peptide inhibiteur somatostatine, supportaient le phénomène de sensibilisation centrale dans ce modèle, tout comme les évaluations fonctionnelles. Les différences observées entre les analgésiques sur les résultats i fonctionnels ont été étayées par différentes influences sur les concentrations des neuropeptides spinaux, permettant ainsi d’augmenter la va lidité ainsi que la sensibilité des méthodes d’évaluation algésimétrique et biomécaniques de la douleur. Afin de développer un modèle expérimental de douleur chronique imitant plus étroitement la progression post-traumatique de l’arthrose , un modèle chirurgical a montré la possibilité d’induire des chan gements compatibles avec de la douleur pathologique chronique. Le modèle chirurgical d’induction de douleur arthrosique a induit des changements neurophysiologiques quantifiables associés à la sensibilisation centrale. Ces modifications des altérations fonctionnelles ont été concomitantes avec la libération de neuropeptides spinaux. La comparaison avec le modèle chimique a montré des modifications plus persistantes et moins agressives qui serait potentiellement utiles pour l'évaluation des modalités thérapeutiques dans l’arthrose . L’utilisati on de la protéomique jumelée avec des méthodes d’évaluation comportementale afin de quantifier la douleur pourrait permettre une gestion complètement nouvelle de la douleur et du bien-être animal. Mots-clés : Biomarqueur, Neuroprotéomique, Sensibilisation centrale, Douleur, Modèle animal, Neuropeptide, Métrologie de la douleur, Validation. ii Abstract Pain is a complex and dynamic phenomenon including a primary and sensory process, nociception, to which are added psychophysiological defense and alarm reactions. This leads to the development of a true memory of pain, individual and modulated (neuronal plasticity) by previous experiences of pain, including nociceptive sensitivity. Animal models mimicking human pathologies are crucial to understand the mechanisms of central sensitization. We proposed a series of translational experimental approaches by developing experimental models of bovine, canine and murine pain in order to characterize spinal proteome modifications according to the level of pain perceived by the animal and consequently, to identify the biomarkers (s) potentially modulated by nociceptive sensitization. By using a neuroproteomic method, in a bovine model of visceral pain, the transthyretin (TTR) protein was identified and down-regulated in the spinal proteome in the presence of pain, and this was verified in a canine model of chronic pain related to surgical osteoarthritis (OA) induction. These findings suggest the possibility of considering TTR as a potential biomarker of chronic pain. Our discovery of the relationship between spinal levels of TTR by neuroproteomic and pain hypersensitivity in bovine and canine models supports the involvement of inflammatory, nociceptive and immune components. Subsequently, procedures for metrological validation of acclimatization protocols and environmental conditions of manipulation have identified the most reliable and sensitive methods of pain assessment. The chemical model (intraarticular injection of monosodium iodoacetate) of chronic pain induction related to OA in rats also allowed us to demonstrate that an increase in the temporal expression of excitatory spinal neuropeptides such as substance P, calcitonin gene-related peptide, bradykinin and the anti-nociceptive somatostatin, is associated with central sensitization phenomenon in this model, as also supported by functional evaluations. The differences observed on functional results between the analgesic drugs were supported by different influences on spinal neuropeptide concentrations, thus increasing the validity and psychometric sensitivity of quantitative sensory testing and biomechanical pain assessment methods. iii In the aim to elaborate an experimental model of chronic pain related to OA reproducing more closely post-traumatic progression, the development of a surgical model in rodent has shown the possibility of inducing changes compatible with chronic pathological pain. The surgical model of OA pain induction generated quantifiable neurophysiological changes associated with central sensitization. These changes in functional alterations were concomitant with the release of spinal neuropeptides. The comparison with the chemical model showed more persistent and less aggressive modifications which would be potentially useful for the evaluation of therapeutic modalities in OA. The use of objective proteomic methods combined with subjective evaluation to quantify pain could lead to a completely new management of pain and animal welfare. Keywords : Biomarker, Neuroproteomic, Central sensitization, Pain, Animal model, Neuropeptide, Pain metrology, Validation. iv Table des matières Résumé ......................................................................................................................................... i Abstract ...................................................................................................................................... iii Table des matières....................................................................................................................... v Liste des tableaux ..................................................................................................................... xix Liste des figures ....................................................................................................................... xxi Liste des sigles et abréviations ............................................................................................... xxiv Remerciements ..................................................................................................................... xxxiii Introduction ................................................................................................................................. 1 1. Recension de la littérature ....................................................................................................... 3 1.1 La douleur ......................................................................................................................... 3 1.1.1 Les bases neurophysiologiques de la douleur ............................................................ 4 1.1.1.1 De la périphérie à la moelle épinière .................................................................. 6 1.1.1.1.1 Au niveau périphérique ................................................................................ 7 1.1.1.1.2 Au niveau spinal .......................................................................................... 9 1.1.1.1.3 De la moelle épinière au cerveau ............................................................... 11 1.1.2 Les mécanismes de modulation de la douleur ......................................................... 12 1.1.2.1 Modulations
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