Enhancing neuronal chloride extrusion rescues _2 and _3 GABA A-mediated analgesia in neuropathic pain
Send a publication request

Publication request

Thank you for your interest in our product range and your request for this publication, which will be sent to you if the research team and the journal allow it. Our commercial team will contact you as soon as possible.

- Categories : Neuropathic pain , Pain , Publications

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

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

Nature Communications

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)

Related products

Share this content