AbstractSpinal 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 GABA_ARs and by an α1-to-α2GABA_AR subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABA_AR 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 GABA_AR-subtypes and restoring Cl^- homeostasis.