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Etude du mécanisme antalgique du Paracétamol ; région cérébrale et mécanisme mis en jeu.

Abstract : Paracetamol is since its discovery controversial. Whether with respect to the mechanism of action, its side effects or effectiveness, many studies have been performed, at times contradictory. Sometimes criticized for its limited effectiveness, it has nothing to envy in contrast to other analgesics whose effectiveness are often associated with side effects. Paracetamol has proven itself to relieve low to moderate pain without side effects at therapeutic doses. This makes it drug of choice for pregnant women, infants and children. According to a report by the ANSM of the 30 top-selling active substances in France in 2013, with a total of 1.15 billion boxes, paracetamol largely dominates this ranking as its sales are over 500 million boxes. Thus it has become the analgesic and antipyretic most consumed in the world. Today, the pharmacopoeia of analgesics is outdated; evolution of the therapeutic arsenal for 50 years is limited with few major discoveries reported. This observation leads to the need to reassess research strategies to innovate new and more effective molecules. Until now, the aim was to focus on a few molecules with high therapeutic potential in order to optimize their effectiveness without understanding their mechanisms. Now our interest is to understand the mechanisms and targets of these analgesics in order to develop more comparable molecules while limiting their adverse effects. Based on this strategy, paracetamol is a perfect candidate. Indeed, its mechanism of action is not fully known, but its effectiveness is proven. The aim of this work is to elucidate the mystery surrounding its mechanism of action and discover its targets. The latest studies redefine paracetamol as a metabolic precursor to the origin of an active lipid derivative, called AM404. The latter is synthesized in certain regions of the brain expressing the FAAH enzyme capable of catalyzing this reaction. The mechanism thus put into play shows that paracetamol, via AM404, activates TRPV1 receptors and the central CB1 receptors indirectly to reinforce a central mechanism of pain relief via serotonergic descending pathways. However, the cerebral area concerned and the cellular mechanism involved remain unknown. Behavioral data associated with a functional imaging study unveiled several brain regions potentially involved in the action of paracetamol, including the periaqueductal gray matter. The latter sparked our interest for two reasons: one because it expresses the core triad FAAH/TRPV1/CB1; and two it also represents a crossroad of descending serotonergic pathways. Activation in the periaqueductal gray matter of the TRPV1 and CB1 receptors is adapted to produce an antinociceptive effect dependent on these descendant control systems. This work of this thesis has led to re-affirm that the analgesic action induced by paracetamol involves a supra-spinal mechanism dependent on the FAAH enzyme in pathological conditions. Specifically, we investigated the role of the triad FAAH/TRPV1/CB1 in the periaqueductal gray matter. We found that paracetamol interacted with the cell signaling pathway mGluR5-PLC-DAGL responsible for production of the endocannabinoid 2-AG. This mechanism can explain both the close collaboration between the TRPV1 and CB1 receptors in the analgesic effect of paracetamol and the reinforcing of serotonergic descending pathways. Paracetamol is thus a prodrug whose cerebral action involves a set of complex systems to mediate its analgesic effect. This attractive mechanism opens the track to new painkillers ever more effective with fewer side effects, reflected paracetamol mechanism.
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Romain Dalmann. Etude du mécanisme antalgique du Paracétamol ; région cérébrale et mécanisme mis en jeu.. Médecine humaine et pathologie. Université d'Auvergne - Clermont-Ferrand I, 2015. Français. ⟨NNT : 2015CLF1MM08⟩. ⟨tel-01874965⟩

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