title: Antihyperalgesia by α2-GABAA receptors occurs via a genuine spinal action and does not involve supraspinal sites.
abstract: Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABAA receptors (GABAARs) containing α2 subunits (α2-GABAARs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal α2-GABAARs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABAAR-mutated mice, which either lack α2-GABAARs specifically from the spinal cord, or, which express only benzodiazepine-insensitive α2-GABAARs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all α2-GABAARs were benzodiazepine insensitive. The major (α2-dependent) component of GABAAR-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal α2-GABAARs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target α2-GABAARs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions.
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland [2] Zurich Neuroscience Center (ZNZ), Zurich, Switzerland.
authors.forename: Jolly
authors.initials: J
authors.lastname: Paul
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors.forename: Gonzalo E
authors.initials: GE
authors.lastname: Yévenes
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland [2] Zurich Neuroscience Center (ZNZ), Zurich, Switzerland.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Benke
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland [2] Zurich Neuroscience Center (ZNZ), Zurich, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Lio
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland [2] Zurich Neuroscience Center (ZNZ), Zurich, Switzerland [3] Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: William T
authors.initials: WT
authors.lastname: Ralvenius
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland [2] Zurich Neuroscience Center (ZNZ), Zurich, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Witschi
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors.forename: Louis
authors.initials: L
authors.lastname: Scheurer
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, and Department of Psychiatry, Harvard Medical School, MA, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland [2] Zurich Neuroscience Center (ZNZ), Zurich, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.affiliation: 1] Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland [2] Zurich Neuroscience Center (ZNZ), Zurich, Switzerland [3] Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: Hanns Ulrich
authors.initials: HU
authors.lastname: Zeilhofer
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D058785:GABA-A Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology*
chemical_list: C558116:8-ethynyl-6-(2'-pyridine)-4H-2,5,10b-triazabenzo(e)azulene-3-carboxylic acid ethyl ester; D058785:GABA-A Receptor Agonists; C493920:Gabra2 protein, mouse; D007093:Imidazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines
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