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Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABAA receptor point-mutated mice

Knabl, Juliaa,b,1; Zeilhofer, Ulrike B.a,b,1; Crestani, Florencea; Rudolph, Uwec; Zeilhofer, Hanns Ulricha,b,d,*

doi: 10.1016/j.pain.2008.10.015
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ABSTRACT Ionotropic γ-aminobutyric acid (GABAA) receptors control the relay of nociceptive signals at several levels of the neuraxis. Experiments with systemically applied benzodiazepines, which enhance the action of GABA at these receptors, have suggested both anti- and pronociceptive effects. The interpretation of such experiments has been notoriously difficult because of confounding sedation. Here, we have used genetically engineered mice, which carry specific benzodiazepine-insensitive GABAA receptor subunits, to test whether diazepam, a frequently used classical benzodiazepine, exerts antihyperalgesia after systemic administration in the formalin test, a model of tonic nociception. In wild-type mice, systemic diazepam (3–30 mg/kg, p.o.) dose-dependently reduced the number of formalin-induced flinches during both phases of the test by about 40–70%. This antinociception was reversed by the benzodiazepine site antagonist flumazenil (10 mg/kg, i.p.), but fully retained in GABAA receptor α1 point-mutated mice, which were resistant against the sedative action of diazepam. Experiments carried out in mice with two diazepam-insensitive subunits (α1/α2, α1/α3 and α1/α5 double point-mutated mice) allowed addressing the contribution of α2, α3 and α5 subunits to systemic diazepam-induced antihyperalgesia in the absence of sedation. The relative contributions of these subunits were α2 ≈ α3 > α5, and thus very similar to those found for intrathecal diazepam (0.09 mg/kg). Accordingly, SL-651498 (10 mg/kg, p.o.), an “anxioselective” benzodiazepine site agonist with preferential activity at α2/α3 subunits, significantly reduced formalin-induced flinching in wild-type mice. We conclude that systemic diazepam exerts a genuine antihyperalgesic effect, which depends on spinal GABAA receptors containing α2 and/or α3 subunits.

aInstitute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

bInstitute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany

cLaboratory of Genetic Neuropharmacology, McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, USA

dInstitute of Pharmaceutical Sciences, ETH Zürich, CH-8057 Zürich, Switzerland

*Corresponding author. Address: Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Tel.: +41 44 6355912; fax: +41 44 6355988.

E-mail address:zeilhofer@pharma.uzh.ch

1 Both first-authors contributed equally to this work.

ARTICLE INFO

Article history:

Received July 7, 2008

Received in revised form September 8, 2008

Accepted October 20, 2008.

© 2009 Lippincott Williams & Wilkins, Inc.
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