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

Publication date: Available online 27 February 2019Source: Pharmacology Biochemistry and BehaviorAuthor(s): J.M. Witkin, R. Cerne, P.G. Davis, K.B. Freeman, J.M. do Carmo, J.K. Rowlett, K.R. Methuku, A. Okun, S.D. Gleason, X. Li, M.J. Krambis, M. Poe, G. Li, J.M. Schkeryantz, R. Jahan, L. Yang, W. Guo, L.K. Golani, W.H. Anderson, J.T. CatlowAbstractClinical 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 α2/3 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 (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...
Source: Pharmacology Biochemistry and Behavior - Category: Biochemistry Source Type: research