HZ166, a novel GABAA receptor subtype-selective benzodiazepine site ligand, is antihyperalgesic in mouse models of inflammatory and neuropathic pain

Neuropharmacology. 2011 Mar;60(4):626-32. doi: 10.1016/j.neuropharm.2010.11.026. Epub 2010 Dec 8.


Diminished GABAergic and glycinergic inhibition in the spinal dorsal horn contributes significantly to chronic pain of different origins. Accordingly, pharmacological facilitation of GABAergic inhibition by spinal benzodiazepines (BDZs) has been shown to reverse pathological pain in animals as well as in human patients. Previous studies in GABA(A) receptor point-mutated mice have demonstrated that the spinal anti-hyperalgesic effect of classical BDZs is mainly mediated by GABA(A) receptors containing the α2 subunit (α2-GABA(A) receptors), while α1-GABA(A) receptors, which mediate the sedative effects, do not contribute. Here, we investigated the potential analgesic profile of HZ166, a new partial BDZ-site agonist with preferential activity at α2- and α3-GABA(A) receptors. HZ166 showed a dose-dependent anti-hyperalgesic effect in mouse models of neuropathic and inflammatory pain, triggered by chronic constriction injury (CCI) of the sciatic nerve and by subcutaneous injection of the yeast extract zymosan A, respectively. This antihyperalgesic activity was antagonized by flumazenil and hence mediated via the BDZ-binding site of GABA(A) receptors. A central site of action of HZ166 was consistent with its pharmacokinetics in the CNS. When non-sedative doses of HZ166 and gabapentin, a drug widely used in the clinical management of neuropathic pain, were compared, the efficacies of both drugs against CCI-induced pain were similar. At doses producing already maximal antihyperalgesia, HZ166 was devoid of sedation and motor impairment, and showed no loss of analgesic activity during a 9-day chronic treatment period (i.e. no tolerance development). These findings provide further evidence that compounds selective for α2- and α3-GABA(A) receptors might constitute a novel class of analgesics suitable for the treatment of chronic pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzodiazepines / pharmacology
  • Benzodiazepines / therapeutic use*
  • Dose-Response Relationship, Drug
  • Flumazenil / pharmacology
  • GABA Modulators / pharmacology
  • GABA-A Receptor Agonists / pharmacology
  • GABA-A Receptor Agonists / therapeutic use*
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / etiology
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use*
  • Inflammation / drug therapy*
  • Inflammation / etiology
  • Mice
  • Motor Activity / drug effects
  • Neuralgia / drug therapy*
  • Neuralgia / etiology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pain Measurement / drug effects
  • Receptors, GABA-A / metabolism*
  • Sciatic Neuropathy / complications


  • 8-ethynyl-6-(2'-pyridine)-4H-2,5,10b-triazabenzo(e)azulene-3-carboxylic acid ethyl ester
  • GABA Modulators
  • GABA-A Receptor Agonists
  • Imidazoles
  • Receptors, GABA-A
  • Benzodiazepines
  • Flumazenil