GABAA α5 subunit-containing receptors do not contribute to reversal of inflammatory-induced spinal sensitization as indicated by the unique selectivity profile of the GABAA receptor allosteric modulator NS16085

Biochem Pharmacol. 2015 Feb 1;93(3):370-9. doi: 10.1016/j.bcp.2014.12.010. Epub 2014 Dec 25.


GABAA receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain. Restoration of diminished spinal GABAA-α2 and -α3 subunit-containing receptor function is a principal contributor to this analgesia, albeit involvement of GABAA-α5-receptors has not been excluded. Thus, we compared NS11394 and TPA023 (PAMs with selectivity/efficacy at GABAA-α2/α3/α5 receptors) with TP003 (a reportedly GABAA-α3 selective PAM) against spinal sensitization. However, in-house electrophysiology studies designed to confirm the selectivity of TPA023 and TP003 for human GABAA receptors did not corroborate published data, with TP003 displaying considerable GABAA-α5 receptor efficacy. Therefore, we identified a novel PAM, NS16085, which possesses negligible efficacy at GABAA-α5 receptors, but with GABAA-α2/α3 efficacy equivalent to NS11394. At the GABAA-α1 receptor the compound gives low level of negative modulation further separating it from the other compounds. Rat pups with carrageenan-induced hindpaw inflammatory hyperalgesia were used to make ex vivo spinal dorsal root-evoked ventral root recordings. Some spontaneous activity and large numbers of spikes to repetitive stimulation of dorsal roots at C-fibre intensity, indicative of wind-up and sensitization were observed. Equimolar concentrations of NS11394, TP003 and NS16085 all attenuated wind-up to a similar degree; TPA023 was clearly less effective. In adult rats, NS16085 (3-30 mg/kg, p.o.) dose-dependently reduced formalin-induced hindpaw flinching with efficacy comparable to NS11394. Thus, potentiation of GABAA-α2 and-α3 receptors is sufficient to depress spinal sensitization and mediate analgesia after inflammatory injury. Positive modulation at GABAA-α5-receptors is apparently dispensable for this process, an important consideration given the role of this receptor subtype in cognitive function.

Keywords: Analgesia; Central sensitization; Hyperalgesia; Pain; Spinal inhibition; Wind-up.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • Animals, Newborn
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Dose-Response Relationship, Drug
  • Female
  • GABA Modulators / chemistry*
  • GABA Modulators / pharmacology*
  • GABA Modulators / therapeutic use
  • Humans
  • Hyperalgesia / drug therapy
  • Hyperalgesia / pathology
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Male
  • Organ Culture Techniques
  • Pain / drug therapy
  • Pain / pathology
  • Pain Measurement / drug effects*
  • Pain Measurement / methods
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, GABA-A / physiology*
  • Spinal Nerve Roots / drug effects*
  • Spinal Nerve Roots / pathology
  • Spinal Nerve Roots / physiology
  • Xenopus laevis


  • 4-chloro-3-(6-(5-(2-hydroxypropan-2-yl)-1H-1,3-benzodiazol-1-yl)pyridin-2-yl)benzonitrile
  • Benzimidazoles
  • GABA Modulators
  • GABRA5 protein, human
  • Pyridines
  • Receptors, GABA-A