| Author/Editor | Witkin, Jeffrey M.; Černe, Rok; Davis, P. G.; Freeman, K. B.; Carmo, J. M.; Rowlett, J. K.; Methuku, Kashi Reddy; Okun, A.; Gleason, Scott D.; Li, Xin | |
| Title | The [alpha]2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats | |
| Type | članek | |
| Vol. and No. | , št. Vol. 180 | |
| Publication year | 2019 | |
| Volume | str. 22-31 | |
| ISSN | 0091-3057 - Pharmacology, biochemistry, and behavior | |
| Language | eng | |
| Abstract | Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA 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 KRM-II-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 (10mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for [alpha]2/3- over [alpha]1-associated GABAA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-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 32nM. 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 GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, [alpha]2/3-selective GABAA receptor PAMs offer an additional inroad into the management of pain. | |
| Keywords | central nervous system GABA-A receptors anxiety centralni živčni sistem GABA-A receptorji anksioznost |