The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats

Abstract

Clinical evidence indicates that positive allosteric modulators (PAMs) of GABA(A) receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABA(A) receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABA(A) receptors associated with alpha 2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo [f] imidazo[1,5-a] [1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRMII-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for alpha 2/3- over al-associated GABA(A) receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of ICRM-H-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED50 of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that alpha 2/3-selective GABA(A) receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, alpha 2/3-selective GABA(A) receptor PAMs offer an additional inroad into the management of pain.