Spinal administration of
GABA(A) receptor modulators, such as the
benzodiazepine drug diazepam, partially alleviates neuropathic
hypersensitivity that manifests as spontaneous
pain,
allodynia, and
hyperalgesia. However,
benzodiazepines are hindered by
sedative impairments and other side effect issues occurring mainly as a consequence of binding to
GABA(A) receptors containing the alpha(1) subunit. Here, we report on the novel subtype-selective
GABA(A) receptor-positive modulator
NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-
biphenyl-2-carbonitrile], which possesses a functional efficacy selectivity profile of alpha(5) > alpha(3) > alpha(2) > alpha(1) at
GABA(A) alpha subunit-containing receptors.
Oral administration of
NS11394 (1-30 mg/kg) to rats attenuated spontaneous nociceptive behaviors in response to hindpaw injection of
formalin and
capsaicin, effects that were blocked by the
benzodiazepine site antagonist
flumazenil. Ongoing inflammatory nociception, observed as hindpaw weight-bearing deficits after
Freund's adjuvant injection, was also completely reversed by
NS11394. Likewise, hindpaw
mechanical allodynia was fully reversed by
NS11394 in two rat models of peripheral
neuropathic pain. Importantly, NS11394-mediated antinociception occurred at doses 20 to 40-fold lower than those inducing minor
sedative or ataxic impairments. In contrast, putative antinociception associated with administration of either
diazepam,
zolpidem, or
gaboxadol only occurred at doses producing intolerable side effects, whereas
bretazenil was completely inactive despite minor influences on motoric function. In electrophysiological studies,
NS11394 selectively attenuated spinal nociceptive reflexes and C-fiber-mediated wind-up in vitro pointing to involvement of a spinal site of action. The robust therapeutic window seen with
NS11394 in animals suggests that compounds with this in vitro selectivity profile could have potential benefit in clinical treatment of
pain in humans.