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.

Effects of Repeated Treatment with Monoamine-Transporter-Inhibitor Antidepressants on Pain-Related Depression of Intracranial Self-Stimulation in Rats

“…Ketorolac also blocked IP acidinduced weight loss. These findings are consistent with the analgesic effectiveness of ketorolac in human and veterinary medicine (Litvak and McEvoy 1990;Matava 2018;Mathews et al 1996) and also agree with our previous report that acute ketorolac treatment blocked acute IP acid-induced ICSS depression (Moerke et al 2019). Ketorolac and other NSAIDs can produce gastric ulceration upon repeated exposure, and this in turn has the potential to reduce body weight; however, the dosing regimen used here in the absence or presence of repeated IP acid was not sufficient to alter body weight.…”

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

“…The data on KRM-II-81 presented here complement the findings of KRM-II-81 and analogs as a modulator of acid-induced pain (Lewter et al, 2017;Moerke et al, 2019) and inflammatory pain with a structural analog (Fischer et et., 2017). However, it is important to note some discrepancies that require further investigation.…”

“…In conclusion, KRM-II-81 was efficacious in mitigating the increased nociceptive sensitivity induced by formalin and by chronic spinal nerve ligation. These findings add to evidence for analgesic efficacy of KRM-II-81 demonstrated previously against acid-induced (Lewter et al, 2017;Moerke et al, 2019) and against inflammatory pain produced by of analogs of KRM-II-81 (Fischer et al, 2017;Kannampalli et al, 2017). These are the first data showing efficacy of KRM-II-81 and the a2/3-linked GABA A receptor mechanism in chronic mechanical hypersensitivity induced by spinal nerve ligation.…”

“…The pioneering work on single amino acid substitutions to create mouse lines with precise -subtype composition has been a major factor driving interest in this mechanism (Knabl et al, 2009;Ralvenius et al, 2015Ralvenius et al, , 2016. Subsequently, the 2/3-selective GABA A receptor PAM, KRM-II-81 (Poe et al, 2016), was shown to be active in several assays utilizing acid as a pain provocation (Lewter et al, 2017;Moerke et al, 2019) and structural analogs were active against inflammatory pain (Fischer et al, 2017;Kannampalli et al, 2017). Work on inflammatory bladder pain has, in addition, shown that there are significant reductions in the levels of GABA A (2) in the lumbosacral spinal cord in the pain-induced rats (zymosan-treatment) (Kannampalli et al, 2017).…”

“…KRM-II-81 produced anxiolytic (Poe et al, 2016;Witkin et al, 2017), antidepressant , and anticonvulsant (Witkin et al, 2018) effects in mice and rats. KRM-II-81 was also recently reported to have efficacy against acid-induced pain provocation (Lewter et al, 2017;Moerke et al, 2019) and structural analogs protected against inflammatory pain (Fischer et al, 2017;Kannampalli et al, 2017). To date, there are no data on the effects of this mechanism against chronic neuropathic pain.…”