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

Nat Commun. 2020 Feb 13;11(1):869. doi: 10.1038/s41467-019-14154-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia / methods
  • Analgesics / metabolism
  • Analgesics / pharmacology*
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Chlorides / metabolism*
  • Disease Models, Animal
  • Fluorobenzenes / metabolism
  • Fluorobenzenes / pharmacology
  • GABA-A Receptor Agonists / pharmacology
  • Ion Transport / drug effects
  • Ligands
  • Male
  • Neuralgia / drug therapy*
  • Neuralgia / physiopathology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Peripheral Nerve Injuries / drug therapy
  • Peripheral Nerve Injuries / pathology
  • Peripheral Nerve Injuries / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, trkB / metabolism
  • Receptors, GABA-A / physiology*
  • Symporters / metabolism
  • Synapses / drug effects
  • Synapses / metabolism
  • Triazoles / metabolism
  • Triazoles / pharmacology

Substances

  • Analgesics
  • Bdnf protein, rat
  • Brain-Derived Neurotrophic Factor
  • Chlorides
  • Fluorobenzenes
  • GABA-A Receptor Agonists
  • Ligands
  • Receptors, GABA-A
  • Symporters
  • Triazoles
  • potassium-chloride symporters
  • L 838,417
  • Ntrk2 protein, rat
  • Receptor, trkB