Activation of 5-HT2A Receptors Restores KCC2 Function and Reduces Neuropathic Pain after Spinal Cord Injury.

Abstract

Downregulation of the potassium chloride cotransporter type 2 (KCC2) after a spinal cord injury (SCI) disinhibits motoneurons and dorsal horn interneurons causing spasticity and neuropathic pain, respectively. We showed recently (Bos et al., 2013) that specific activation of 5-HT2A receptors by TCB-2 [(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide] upregulates KCC2 function, restores motoneuronal inhibition and reduces SCI-induced spasticity. Here, we tested the potential analgesic effect of TCB-2 on central (thoracic hemisection) and peripheral [spared nerve injury (SNI)] neuropathic pain. We found mechanical and thermal hyperalgesia reduced by an acute administration of TCB-2 in rats with SCI. This analgesic effect was associated with an increase in dorsal horn membrane KCC2 expression and was prevented by pharmacological blockade of KCC2 with an intrathecal injection of DIOA [(dihydroindenyl)oxy]alkanoic acid]. In contrast, the SNI-induced neuropathic pain was not attenuated by TCB-2 although there was a slight increase of membrane KCC2 expression in the dorsal horn ipsilateral to the lesion. Up-regulation of KCC2 function by targeting 5-HT2A receptors, therefore, has therapeutic potential in the treatment of neuropathic pain induced by SCI but not by SNI.

• Authors: Irene Sánchez-Brualla, Pascale Boulenguez, Cécile Brocard, Sylvie Liabeuf, Annelise Viallat-Lieutaud, Xavier Navarro, Esther Udina, Frédéric Brocard
• Journal: Neuroscience (Neuroscience) Vol. 387 Pg. 48-57 (09 01 2018) ISSN: 1873-7544 [Electronic] United States
• PMID: 28844001 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine
• Acetates
• Bridged Bicyclo Compounds
• Indenes
• Methylamines
• Receptor, Serotonin, 5-HT2A
• Serotonin 5-HT2 Receptor Agonists
• Symporters
• potassium-chloride symporters
• ((2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy)acetic acid

Topics

• Acetates (pharmacology)
• Animals
• Bridged Bicyclo Compounds (pharmacology)
• Female
• Hyperalgesia (prevention & control)
• Indenes (pharmacology)
• Methylamines (pharmacology)
• Neuralgia (complications, metabolism, prevention & control)
• Peripheral Nerve Injuries (complications, metabolism)
• Rats
• Receptor, Serotonin, 5-HT2A (metabolism)
• Serotonin 5-HT2 Receptor Agonists (pharmacology)
• Spinal Cord Dorsal Horn (metabolism)
• Spinal Cord Injuries (complications, metabolism)
• Symporters (antagonists & inhibitors, metabolism)
• Up-Regulation (drug effects)