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Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Ralvenius William T, Benke Dietmar, Acuña Mario A, Rudolph Uwe, Zeilhofer Hanns Ulrich,
Project Dorsal Horn Neuronal Circuits Processing Itch
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Original article (peer-reviewed)

Journal Nature communications
Volume (Issue) 6
Page(s) 6803
Title of proceedings Nature communications
DOI 10.1038/ncomms7803

Open Access

Type of Open Access Website


Agonists at the benzodiazepine-binding site of GABAA receptors (BDZs) enhance synaptic inhibition through four subtypes (α1, α2, α3 and α5) of GABAA receptors (GABAAR). When applied to the spinal cord, they alleviate pathological pain; however, insufficient efficacy after systemic administration and undesired effects preclude their use in routine pain therapy. Previous work suggested that subtype-selective drugs might allow separating desired antihyperalgesia from unwanted effects, but the lack of selective agents has hitherto prevented systematic analyses. Here we use four lines of triple GABAAR point-mutated mice, which express only one benzodiazepine-sensitive GABAAR subtype at a time, to show that targeting only α2GABAARs achieves strong antihyperalgesia and reduced side effects (that is, no sedation, motor impairment and tolerance development). Additional pharmacokinetic and pharmacodynamic analyses in these mice explain why clinically relevant antihyperalgesia cannot be achieved with nonselective BDZs. These findings should foster the development of innovative subtype-selective BDZs for novel indications such as chronic pain.