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

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

Nature communications (2020-02-15)
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, Yves De Koninck
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
CNQX, ≥98% (HPLC), solid
Sigma-Aldrich
Anti-Calcitonin Gene Related Peptide antibody produced in rabbit, whole antiserum
Sigma-Aldrich
Anti-GABA A Receptor β 2,3 Chain Antibody, clone BD17, clone BD17, Chemicon®, from mouse
Sigma-Aldrich
Anti-Calcitonin Gene-Related Peptide antibody, Mouse monoclonal, clone 4901, purified from hybridoma cell culture
Sigma-Aldrich
N-Methyl-D-aspartic acid, ≥98% (TLC), solid
Sigma-Aldrich
D(−)-2-Amino-5-phosphonopentanoic acid, NMDA receptor antagonist
Sigma-Aldrich
GAD, control peptide for AB1511
Sigma-Aldrich
Anti-K+/Cl- Cotransporter (KCC2) Antibody, Upstate®, from rabbit