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

William T. Ralvenius, Dietmar Benke, Mario A. Acuña, Uwe Rudolph and Hanns Ulrich Zeilhofer ()
Additional contact information
William T. Ralvenius: Institute of Pharmacology and Toxicology, University of Zurich
Dietmar Benke: Institute of Pharmacology and Toxicology, University of Zurich
Mario A. Acuña: Institute of Pharmacology and Toxicology, University of Zurich
Uwe Rudolph: Laboratory of Genetic Neuropharmacology, McLean Hospital
Hanns Ulrich Zeilhofer: Institute of Pharmacology and Toxicology, University of Zurich

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract 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.

Date: 2015
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms7803 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7803

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms7803

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().