Enhancing neuronal chloride extrusion rescues α2/α3 GABAA-mediated analgesia in neuropathic pain

Louis-Etienne Lorenzo, Antoine G. Godin, Francesco Ferrini, Karine Bachand, Isabel Plasencia-Fernandez, Simon Labrecque, Alexandre A. Girard, Dominic Boudreau, Irenej Kianicka, Martin Gagnon, Nicolas Doyon, Alfredo Ribeiro-da-Silva and Yves De Koninck ()
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Louis-Etienne Lorenzo: Quebec Mental Health Institute
Antoine G. Godin: Quebec Mental Health Institute
Francesco Ferrini: Quebec Mental Health Institute
Karine Bachand: Quebec Mental Health Institute
Isabel Plasencia-Fernandez: Quebec Mental Health Institute
Simon Labrecque: Quebec Mental Health Institute
Alexandre A. Girard: Quebec Mental Health Institute
Dominic Boudreau: Quebec Mental Health Institute
Irenej Kianicka: Chlorion Pharma, Laval
Martin Gagnon: Quebec Mental Health Institute
Nicolas Doyon: Quebec Mental Health Institute
Alfredo Ribeiro-da-Silva: McGill University
Yves De Koninck: Quebec Mental Health Institute

Nature Communications, 2020, vol. 11, issue 1, 1-23

Abstract: Abstract Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABAARs and by an α1-to-α2GABAAR subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABAAR benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl- extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl- gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAAR-subtypes and restoring Cl- homeostasis.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14154-6

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DOI: 10.1038/s41467-019-14154-6

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