MTOR activation by constitutively active serotonin6 receptors as new paradigm in neuropathic pain and its treatment. (October 2020)

• Record Type: Journal Article
• Authors: Martin, Pierre-Yves; Doly, Stéphane; Hamieh, Al Mahdy; Chapuy, Eric; Canale, Vittorio; Drop, Marcin; Chaumont-Dubel, Séverine; Bantreil, Xavier; Lamaty, Frédéric; Bojarski, Andrzej J.; Zajdel, Pawel; Eschalier, Alain; Marin, Philippe; Courteix, Christine
• Is Part Of: Progress in neurobiology. Volume 193(2020)
• Publication Date: 2020-10
• Subjects: AUC area under the curve -- CIPN chemotherapy-induced peripheral neuropathy -- CPPQ (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3, 2-c]quinoline dihydrochloride -- IIQ 4-{[5-methoxy-3-(1, 2, 3, 6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}isoquinoline dihydrochloride -- MPE maximal possible effect -- NNT number needed to treat -- NOR novel object recognition -- OXA oxaliplatin -- PZ-1388 2-(3-fluorophenyl)-1-[(3-chlorophenyl)sulfonyl]-N-(piperidin-4-yl)-1H-pyrrole-3-carboxamide hydrochloride -- RM repeated measure -- SNL spinal nerve ligation -- SNRI serotonin-noradrenaline reuptake inhibitor -- SSRI selective serotonin reuptake inhibitor -- TCA tricyclic antidepressant; Neuropathic pain -- Cognitive deficit -- 5-HT6 receptor -- Constitutive activity -- mTOR -- Inverse agonist; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2020.101846
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: Constitutively active spinal 5-HT6 receptors activate mTOR in neuropathic pain. 5-HT6 receptor inverse agonists prevent allodynia and co-morbid cognitive deficits. Disrupting 5-HT6 receptor/mTOR complex prevents allodynia and cognitive deficits. Blocking the 5-HT6 /mTOR pathway is a new avenue for neuropathic pain treatment. Abstract: Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT6 receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT6 receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT6 receptors mediates allodynia in oxaliplatin-induced peripheral neuropathy in rats but not mechanical nociception in healthy rats. Furthermore, both painful and co-morbid cognitive symptoms in neuropathic rats are strongly reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT6 receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities.