mTOR activation by constitutively active serotonin6 receptors as new paradigm in neuropathic pain and its 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.

• Authors: Pierre-Yves Martin, Stéphane Doly, Al Mahdy Hamieh, Eric Chapuy, Vittorio Canale, Marcin Drop, Séverine Chaumont-Dubel, Xavier Bantreil, Frédéric Lamaty, Andrzej J Bojarski, Pawel Zajdel, Alain Eschalier, Philippe Marin, Christine Courteix
• Journal: Progress in neurobiology (Prog Neurobiol) Vol. 193 Pg. 101846 (10 2020) ISSN: 1873-5118 [Electronic] England
• PMID: 32512114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Receptors, Serotonin
• Serotonin Agents
• serotonin 6 receptor
• TOR Serine-Threonine Kinases

Topics

• Animals
• Behavior, Animal (drug effects)
• Cognitive Dysfunction (drug therapy, etiology, metabolism)
• Disease Models, Animal
• HEK293 Cells
• Humans
• Hyperalgesia (drug therapy, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Neuralgia (complications, drug therapy, metabolism)
• Nociception (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Serotonin (drug effects, metabolism)
• Serotonin Agents (administration & dosage, pharmacology)
• TOR Serine-Threonine Kinases (drug effects, metabolism)