Enhancing neuronal chloride extrusion rescues _2 and _3 GABA A-mediated analgesia in neuropathic pain
Envoyer une demande de publication
close

Demande de publication

Merci pour votre intérêt pour nos produits et votre demande concernant cette publication, qui vous sera envoyée si le chercheur et le journal l'autorisent. Notre équipe commerciale vous contactera rapidement.



- Catégories : Douleur , Douleurs neuropathiques , Publications - ID: 1226

Authors
LE Lorenzo, AG Godin, F Ferrini, K Bachand et al


Lab
CERVO Brain Research Centre, Quebec Mental Health Institute, Québec, QC, Canada

Journal
Nature Communications

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 alpha1-to-alpha2GABAAR subunit switch, providing a mechanistic rationale for the analgesic action of the alpha2,3GABAAR 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.

BIOSEB Instruments Used:
Von Frey Filaments (Bio-VF-M)

Produits associés

Partager ce contenu