title: Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype.
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.
authors: 1] Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland [2] Center for Neuroscience Zurich (ZNZ), Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors: William T
authors: WT
authors: Ralvenius
authors: 1] Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland [2] Center for Neuroscience Zurich (ZNZ), Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors: Dietmar
authors: D
authors: Benke
authors: 1] Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland [2] Center for Neuroscience Zurich (ZNZ), Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors: Mario A
authors: MA
authors: Acuña
authors: 1] Laboratory of Genetic Neuropharmacology, McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02478, USA [2] Department of Psychiatry, Harvard Medical School, 401 Park Drive, Boston, Massachusetts 02215, USA.
authors: Uwe
authors: U
authors: Rudolph
authors: 1] Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland [2] Center for Neuroscience Zurich (ZNZ), Winterthurerstrasse 190, CH-8057 Zurich, Switzerland [3] Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
authors: Hanns Ulrich
authors: HU
authors: Zeilhofer
mesh_terms: D000698:Analgesia / Q000379:methods; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D015870:Gene Expression; D006639:Histidine / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008874:Midazolam / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D059408:Pain Management / Q000379:methods; D017354:Point Mutation; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D006639:Histidine; D001120:Arginine; D003975:Diazepam; D008874:Midazolam