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

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. CatlowT. M. Jones, F. Porreca, Jodi Smith, K. L. Knopp, J. M. Cook

Research output: Contribution to journalArticle

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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 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 α2/3- over α1-associated GABA A 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 ED 50 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 α2/3-selective GABA A receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABA A receptor PAMs offer an additional inroad into the management of pain.

Original languageEnglish (US)
Pages (from-to)22-31
Number of pages10
JournalPharmacology Biochemistry and Behavior
Volume180
DOIs
StatePublished - May 1 2019

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Spinal Nerves
GABA-A Receptors
Formaldehyde
Ligation
Rats
Modulators
Analgesics
Anti-Anxiety Agents
Diazepam
Brain
Oxazoles
Alprazolam
Plasmas
Spinal Ganglia
Neurology
Neuralgia
Pain Management
Locomotion
Anxiety Disorders
Respiratory Insufficiency

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

Cite this

The α2,3-selective potentiator of GABA A receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats . / Witkin, J. M.; Cerne, R.; Davis, P. G.; Freeman, K. B.; do Carmo, J. M.; Rowlett, J. K.; Methuku, K. R.; Okun, A.; Gleason, S. D.; Li, X.; Krambis, M. J.; Poe, M.; Li, G.; Schkeryantz, J. M.; Jahan, R.; Yang, L.; Guo, W.; Golani, L. K.; Anderson, W. H.; Catlow, J. T.; Jones, T. M.; Porreca, F.; Smith, Jodi; Knopp, K. L.; Cook, J. M.

In: Pharmacology Biochemistry and Behavior, Vol. 180, 01.05.2019, p. 22-31.

Research output: Contribution to journalArticle

Witkin, JM, Cerne, R, Davis, PG, Freeman, KB, do Carmo, JM, Rowlett, JK, Methuku, KR, Okun, A, Gleason, SD, Li, X, Krambis, MJ, Poe, M, Li, G, Schkeryantz, JM, Jahan, R, Yang, L, Guo, W, Golani, LK, Anderson, WH, Catlow, JT, Jones, TM, Porreca, F, Smith, J, Knopp, KL & Cook, JM 2019, ' The α2,3-selective potentiator of GABA A receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats ', Pharmacology Biochemistry and Behavior, vol. 180, pp. 22-31. https://doi.org/10.1016/j.pbb.2019.02.013
Witkin, J. M. ; Cerne, R. ; Davis, P. G. ; Freeman, K. B. ; do Carmo, J. M. ; Rowlett, J. K. ; Methuku, K. R. ; Okun, A. ; Gleason, S. D. ; Li, X. ; Krambis, M. J. ; Poe, M. ; Li, G. ; Schkeryantz, J. M. ; Jahan, R. ; Yang, L. ; Guo, W. ; Golani, L. K. ; Anderson, W. H. ; Catlow, J. T. ; Jones, T. M. ; Porreca, F. ; Smith, Jodi ; Knopp, K. L. ; Cook, J. M. / The α2,3-selective potentiator of GABA A receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats In: Pharmacology Biochemistry and Behavior. 2019 ; Vol. 180. pp. 22-31.
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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 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 α2/3- over α1-associated GABA A 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 ED 50 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 α2/3-selective GABA A receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABA A receptor PAMs offer an additional inroad into the management of pain.",
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T1 - The α2,3-selective potentiator of GABA A receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats

AU - Witkin, J. M.

AU - Cerne, R.

AU - Davis, P. G.

AU - Freeman, K. B.

AU - do Carmo, J. M.

AU - Rowlett, J. K.

AU - Methuku, K. R.

AU - Okun, A.

AU - Gleason, S. D.

AU - Li, X.

AU - Krambis, M. J.

AU - Poe, M.

AU - Li, G.

AU - Schkeryantz, J. M.

AU - Jahan, R.

AU - Yang, L.

AU - Guo, W.

AU - Golani, L. K.

AU - Anderson, W. H.

AU - Catlow, J. T.

AU - Jones, T. M.

AU - Porreca, F.

AU - Smith, Jodi

AU - Knopp, K. L.

AU - Cook, J. M.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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 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 α2/3- over α1-associated GABA A 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 ED 50 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 α2/3-selective GABA A receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABA A receptor PAMs offer an additional inroad into the management of pain.

AB - 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 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 α2/3- over α1-associated GABA A 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 ED 50 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 α2/3-selective GABA A receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABA A receptor PAMs offer an additional inroad into the management of pain.

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