GABAA α5 subunit-containing receptors do not contribute to reversal of inflammatory-induced spinal sensitization as indicated by the unique selectivity profile of the GABAA receptor allosteric modulator NS16085

de Lucas, A. Garcia; Ahring, P.K.; Larsen, J.S.; Rivera-Arconada, I.; Lopez-Garcia, J.A.; Mirza, N.R.; Munro, G.

doi:10.1016/j.bcp.2014.12.010

Cited by 32Pain Mechanisms and TreatmentsNeuroscience and Neuropharmacology ResearchIon channel regulation and function

GABAA α5 subunit-containing receptors do not contribute to reversal of inflammatory-induced spinal sensitization as indicated by the unique selectivity profile of the GABAA receptor allosteric modulator NS16085

de Lucas, A. Garcia, Ahring, P.K., Larsen, J.S., Rivera-Arconada, I., Lopez-Garcia, J.A., Mirza, N.R., Munro, G.·2015·Biochemical Pharmacology

DOI 10.1016/j.bcp.2014.12.010

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Abstract

GABAA receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain. Restoration of diminished spinal GABAA-α2 and -α3 subunit-containing receptor function is a principal contributor to this analgesia, albeit involvement of GABAA-α5-receptors has not been excluded. Thus, we compared NS11394 and TPA023 (PAMs with selectivity/efficacy at GABAA-α2/α3/α5 receptors) with TP003 (a reportedly GABAA-α3 selective PAM) against spinal sensitization. However, in-house electrophysiology studies designed to confirm the selectivity of TPA023 and TP003 for human GABAA receptors did not corroborate published data, with TP003 displaying considerable GABAA-α5 receptor efficacy. Therefore, we identified a novel PAM, NS16085, which possesses negligible efficacy at GABAA-α5 receptors, but with GABAA-α2/α3 efficacy equivalent to NS11394. At the GABAA-α1 receptor the compound gives low level of negative modulation further separating it from the other compounds. Rat pups with carrageenan-induced hindpaw inflammatory hyperalgesia were used to make ex vivo spinal dorsal root-evoked ventral root recordings. Some spontaneous activity and large numbers of spikes to repetitive stimulation of dorsal roots at C-fibre intensity, indicative of wind-up and sensitization were observed. Equimolar concentrations of NS11394, TP003 and NS16085 all attenuated wind-up to a similar degree; TPA023 was clearly less effective. In adult rats, NS16085 (3-30 mg/kg, p.o.) dose-dependently reduced formalin-induced hindpaw flinching with efficacy comparable to NS11394. Thus, potentiation of GABAA-α2 and-α3 receptors is sufficient to depress spinal sensitization and mediate analgesia after inflammatory injury. Positive modulation at GABAA-α5-receptors is apparently dispensable for this process, an important consideration given the role of this receptor subtype in cognitive function.

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α3GABAARs have been implicated in anxiety, fear and/or response to chronic stress, with contradictory findings.
“In addition, γ2GABAARs [11], α1GABAARs [10, 12], α3GABAARs [13] (but see [14-16] for contradictory findings), and more recently, α5GABAARs [16-18, 4] have been implicated in anxiety, fear and/or response to chronic stress.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [15]

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Authors: de Lucas, A. G., Ahring, P. K., Larsen, J. S., Rivera-Arconada, I., Lopez-Garcia, J. A., Mirza, N. R., & Munro, G.
Affiliations: The University of Sydney (AU)
Saniona (Denmark) (DK)
Universidad de Alcalá (ES)
NeuroSearch (Denmark) (DK)
Corresponding author: Munro, G.
ORCID: Ahring, P.K.
Lopez-Garcia, J.A.
Munro, G.
Venue: Biochemical Pharmacology
Publisher: Elsevier BV
Published: 2015-02
Volume: 93
Issue: 3
Pages: 370-379
ISSN: 0006-2952 (ISSN-L)
DOI: 10.1016/j.bcp.2014.12.010
OpenAlex: W2076336044
Cited by: 32
References: 45
Citations by year: 2024: 1 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 8 · 2017: 4 · 2016: 3 · 2015: 1
FWCI: 1.77
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biochemical Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords: GABAA receptor, positive allosteric modulators, receptor subtype selectivity, spinal sensitization, inflammatory hyperalgesia, wind-up, analgesia, pathological pain, carrageenan, formalin test
MeSH terms: Allosteric Regulation, Animals, Animals, Newborn, Benzimidazoles, Dose-Response Relationship, Drug, Female, Humans, Hyperalgesia, Inflammation, Male, Organ Culture Techniques, Pain, Pain Measurement, Pyridines, Receptors, GABA-A, Spinal Nerve Roots, Xenopus laevis, Rats, Sprague-Dawley, Rats, Wistar, GABA Modulators, Rats

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GABAA α5 subunit-containing receptors do not contribute to reversal of inflammatory-induced spinal sensitization as indicated by the unique selectivity profile of the GABAA receptor allosteric modulator NS16085

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