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Le récepteur 5-HT6, une nouvelle cible pour le traitement des douleurs neuropathiques

Abstract : Neuropathic pains affects 6.9% of the French adult population. They have a significant impact on the quality of life of the patient, and often coexist with depression, anxiety, sleep disturbances and cognitive dysfunction. Chronic neuropathic pain and these co-morbidities are poorly controlled and represent a public health problem. First-line treatments (antidepressants (tricyclic and serotonin-norepinephrine reuptake inhibitors) and anti-epileptic drugs (gabapentin / pregabalin)) are unsatisfactory due to a lack of efficiency. Despite the major role of serotonin in pain modulation, selective serotonin reuptake inhibitors (SSRIs) are poorly effective while they exhibit fewer adverse effects than tricyclic antidepressants. The 5-HT 6 receptor, known for its effects on cognitive functions, has recently emerged as a new target for serotoninergic modulation of pain. In addition to its coupling to the Gs protein, the 5-HT 6 receptor is physically associated with intracellular protein partners including mTOR (mammalian Target Of Rapamycin), also involved in neuropathic pain and in regulation of cognitive functions. In the present work, we characterize the sub-cellular localization of the 5-HT 6 receptor in primary cilium of neurons in dorsal horn spinal cord, suggesting the involvement of primary cilia in pain modulation. The administration of 5-HT 6 receptor inverse agonists exerts an anti- allodynic effect and abolishes co-morbid cognitive deficits in SNL rats, whereas neutral antagonists are devoid of effects, suggesting a constitutive activity of the receptor involved in pain hypersensitivity. Similarly, administration of rapamycin, an mTOR inhibitor, reduces tactile allodynia and co-morbid cognitive deficits in SNL rats. We also demonstrate the interaction between the 5-HT 6 receptor and mTOR in vitro and in vivo in painful rats. Thus, thanks to an interfering peptide inhibiting the physical interaction between 5-HT 6 receptor and mTOR (intrathecally injected), we improve mechanical and thermal allodynia confirming the deleterious role of the spinal 5-HT 6 receptor-mTOR interaction under neuropathic pain condition. Taken together, these results contribute to a better understanding of the role of the 5-HT 6 receptor and its mTOR partner in chronic pain and opens new ways in its management with, in particular, the development of new 5-HT 6 receptor inverse agonists.
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Pierre-Yves Martin. Le récepteur 5-HT6, une nouvelle cible pour le traitement des douleurs neuropathiques. Médecine humaine et pathologie. Université Clermont Auvergne, 2018. Français. ⟨NNT : 2018CLFAS023⟩. ⟨tel-03189535⟩

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