Effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats: comparison with ketorolac and diazepam.

Abstract

This study examined effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 in an assay of pain-related behavioral depression. Adult, male Sprague-Dawley rats responded for electrical brain stimulation in a frequency-rate intracranial self-stimulation (ICSS) procedure. Intraperitoneal injection of 1.8% lactic acid served as an acute noxious stimulus to depress ICSS. Effects of KRM-II-81 were evaluated in the absence and presence of the acid noxious stimulus. The NSAID ketorolac and the benzodiazepine diazepam were tested as comparators. Neither ketorolac nor KRM-II-81 altered ICSS in the absence of the acid noxious stimulus; however, diazepam produced facilitation consistent with its abuse liability. Ketorolac blocked acid-induced depression of ICSS, and effects of 1.0 mg/kg ketorolac lasted for at least 5 h. KRM-II-81 (1.0 mg/kg) produced significant antinociception after 30 min that dissipated by 60 min. Diazepam also attenuated acid-depressed ICSS, but only at doses that facilitated ICSS when administered alone. The lack of ketorolac or KRM-II-81 effects on ICSS in the absence of the acid noxious stimulus suggests low abuse liability for both compounds. The effectiveness of ketorolac to block acid-induced ICSS depression agrees with clinical analgesic efficacy of ketorolac. KRM-II-81 produced significant but less consistent and shorter-acting antinociception than ketorolac.