title: Presynaptic alpha2-GABAA receptors in primary afferent depolarization and spinal pain control.
abstract: Spinal dorsal horn GABA(A) receptors are found both postsynaptically on central neurons and presynaptically on axons and/or terminals of primary sensory neurons, where they mediate primary afferent depolarization (PAD) and presynaptic inhibition. Both phenomena have been studied extensively on a cellular level, but their role in sensory processing in vivo has remained elusive, due to inherent difficulties to selectively interfere with presynaptic receptors. Here, we address the contribution of a major subpopulation of GABA(A) receptors (those containing the α2 subunit) to spinal pain control in mice lacking α2-GABA(A) receptors specifically in primary nociceptors (sns-α2(-/-) mice). sns-α2(-/-) mice exhibited GABA(A) receptor currents and dorsal root potentials of normal amplitude in vitro, and normal response thresholds to thermal and mechanical stimulation in vivo, and developed normal inflammatory and neuropathic pain sensitization. However, the positive allosteric GABA(A) receptor modulator diazepam (DZP) had almost completely lost its potentiating effect on PAD and presynaptic inhibition in vitro and a major part of its spinal antihyperalgesic action against inflammatory hyperalgesia in vivo. Our results thus show that part of the antihyperalgesic action of spinally applied DZP occurs through facilitated activation of GABA(A) receptors residing on primary nociceptors.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Witschi
authors.forename: Pradeep
authors.initials: P
authors.lastname: Punnakkal
authors.forename: Jolly
authors.initials: J
authors.lastname: Paul
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Walczak
authors.forename: Fernando
authors.initials: F
authors.lastname: Cervero
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
authors.forename: Ruth
authors.initials: R
authors.lastname: Keist
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.forename: Hanns Ulrich
authors.initials: HU
authors.lastname: Zeilhofer
mesh_terms: D000818:Animals; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology*; D007278:Injections, Spinal; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology*; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000502:physiology*
chemical_list: D011963:Receptors, GABA-A; D017661:Receptors, Presynaptic; D003975:Diazepam