The monosodium iodoacetate-induced model of osteoarthritis pain: Behaviour, pharmacological, immunohistochemical and electrophysiological studies

Osteoarthritis (OA), a chronic degenerative joint disease, will affect an increasing number of individuals as the population ages. It is only recently that pain, the main cause of complaint from patients, has become a source of interest. This thesis investigates a chemical model of knee osteoarthritis pain induced by intra-articular injection of monosodium iodoacetate, an inhibitor of glycolysis. After validating this model and developing new behavioural tests to assess mechanical and cooling hypersensitivity as well as ambulatory-evoked pain, the effects of existing analgesics such as morphine and gabapentin following chronic administration were studied. Both agents decreased pain behaviour but with different time-courses. Using the same techniques as well as hindpaw weight-bearing distribution, the role of inflammation in the model was investigated using clinically available drugs: a glucocorticosteroid, methylprednisolone, a TNF (tumor necrosis factor) alpha antagonist, etanercept, and a COX (cyclo-oxygenase) inhibitor, metacam. Based on the effects of these different drugs, inflammation must play a major role during the early stages of the OA induction rather than during the later pain state. Furthermore, in vivo electrophysiology studies revealed a trend towards higher excitability of deeper wide dynamic range neurones to mechanical stimuli in OA rats. Superficial dorsal horn neurokinin-1 (NK-1) receptor expressing neurones were not found to play a significant role in OA-induced behavioural changes. This indicates differences in central sensitisation and descending modulation from the brainstem, compared to other models. A detailed study of neuronal markers in dorsal root ganglia using immunohistochemistry showed no major neuropathic pain component. Finally, AS006, a novel peripherally selective mu-opioid receptor agonist, was shown to reduce pain behaviour. These behavioural, immunohistochemical and electrophysiological results not only validate the use of this model for the study of osteoarthritis pain but reveal several important underlying mechanisms of nociceptive transmission in this condition

Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain

Background: Descending facilitation, from the brainstem, promotes spinal neuronal hyperexcitability and behavioural hypersensitivity in many chronic pain states. We have previously demonstrated enhanced descending facilitation onto dorsal horn neurones in a neuropathic pain model, and shown this to enable the analgesic effectiveness of gabapentin. Here we have tested if this hypothesis applies to other pain states by using a combination of approaches in a rat model of osteoarthritis (OA) to ascertain if 1) a role for descending 5HT mediated facilitation exists, and 2) if pregabalin (a newer analogue of gabapentin) is an effective antinociceptive agent in this model. Further, quantitative-PCR experiments were undertaken to analyse the alpha(2)delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG in order to assess whether changes in these molecular substrates have a bearing on the pharmacological effects of ondansetron and pregabalin in OA.Results: Osteoarthritis was induced via intra-articular injection of monosodium iodoacetate (MIA) into the knee joint. Control animals were injected with 0.9% saline. Two weeks later in vivo electrophysiology was performed, comparing the effects of spinal ondansetron (10-100 mu g/50 mu l) or systemic pregabalin (0.3-10 mg/kg) on evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimuli in MIA or control rats. In MIA rats, ondansetron significantly inhibited the evoked responses to both innocuous and noxious natural evoked neuronal responses, whereas only inhibition of noxious evoked responses was seen in controls. Pregabalin significantly inhibited neuronal responses in the MIA rats only; this effect was blocked by a pre-administration of spinal ondansetron. Analysis of alpha(2)delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG revealed a significant increase in alpha(2)delta-1 levels in ipsilateral L3&4 DRG in MIA rats. 5-HT3A subunit mRNA levels were unchanged.Conclusion: These data suggest descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in alpha(2)delta-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain

Characterisation of a Peripheral Neuropathic Component of the Rat Monoiodoacetate Model of Osteoarthritis

Joint degeneration observed in the rat monoiodoacetate (MIA) model of osteoarthritis shares many histological features with the clinical condition. The accompanying pain phenotype has seen the model widely used to investigate the pathophysiology of osteoarthritis pain, and for preclinical screening of analgesic compounds. We have investigated the pathophysiological sequellae of MIA used at low (1 mg) or high (2 mg) dose. Intra-articular 2 mg MIA induced expression of ATF-3, a sensitive marker for peripheral neuron stress/injury, in small and large diameter DRG cell profiles principally at levels L4 and 5 (levels predominated by neurones innervating the hindpaw) rather than L3. At the 7 day timepoint, ATF-3 signal was significantly smaller in 1 mg MIA treated animals than in the 2 mg treated group. 2 mg, but not 1 mg, intra-articular MIA was also associated with a significant reduction in intra-epidermal nerve fibre density in plantar hindpaw skin, and produced spinal cord dorsal and ventral horn microgliosis. The 2 mg treatment evoked mechanical pain-related hypersensitivity of the hindpaw that was significantly greater than the 1 mg treatment. MIA treatment produced weight bearing asymmetry and cold hypersensitivity which was similar at both doses. Additionally, while pregabalin significantly reduced deep dorsal horn evoked neuronal responses in animals treated with 2 mg MIA, this effect was much reduced or absent in the 1 mg or sham treated groups. These data demonstrate that intra-articular 2 mg MIA not only produces joint degeneration, but also evokes significant axonal injury to DRG cells including those innervating targets outside of the knee joint such as hindpaw skin. This significant neuropathic component needs to be taken into account when interpreting studies using this model, particularly at doses greater than 1 mg MIA

Transsexualisme et psychiatrie (quelle place pour le psychiatrie dans la démarche de changement de sexes des sujets transsexuels?)

En février 2010, un décret d'application de loi paraît au Journal Officiel, retirant les troubles précoces de l'identité de genre de la liste des affections psychiatriques de longue durée (ALD 23). Cette évolution législative française pose la question de la place des psychiatrie, désormais, dans la prise en charge des sujets transsexuels. Après un aperçu historique, sociologique et anthropologique de la conception de la différence des sexes et du transsexualisme dans différentes sociétés, l'auteur expose les conceptualisations psychiatriques élaborées au sujet du transsexualisme. A cette disparité des savoirs théoriques sur le transsexualisme s'oppose l'univocité du discours transsexuel, dont l'auteur étudie les aspects principaux. Les réactions du psychiatrie qui rencontre un patient transsexuel sont également repérées, avant d'aborder le difficile contexte d'exercice de ce praticien.BREST-BU Médecine-Odontologie (290192102) / SudocSudocFranceF

The monosodium iodoacetate-induced model of osteoarthritis pain : behavioural, pharmacological, immunohistochemical and electrophysiological studies

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La LTP (Long-Term Potentiation) dans la moelle épinière (étude électrophysiologique in vivo du rôle de différentes voies de transmission de la douleur et investigation des modifications d'expression protéique induites)

La LTP (Long-term potentiation) correspond à une excitabilité ou une transmission synaptique accrues. Modèle d'étude de la mémoire, elle a aussi été montrée dans des zones impliquées dans la nociception de la moelle épinière. L'ablation chimique des neurones superficiels exprimant les récepteurs NK1 (neurokinine 1) modifie le codage mécanique et thermique des neurones profonds WDR (Wide Dynamic Range), comme un antagoniste des récepteurs sérotonergiques 5HT-3, l'ondansetron, suggérant une voie activatrice sérotonergique depuis le tronc cérébral. Notre étude électrophysiologique in vivo montre que les neurones superficiels NK1 paraissent essentiels à l'induction de la LTP dans les neurones WDR alors que les récepteurs spinaux 5HT-3 sont nécessaires mais pas indispensables, suggérant un phénomène intraspinal mais modulable via une boucle spino-cérébrospinale. Nous avons ensuite montre que les protéines c-fos, Zif268/EGR1, Homer1a et RGS2 se sont trouvées augmentées dans la LTP spinale.TOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE-EN Vétérinaire (315552301) / SudocSudocFranceF