title: Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction.
abstract: The gate control theory proposes the importance of both pre- and post-synaptic inhibition in processing pain signal in the spinal cord. However, although postsynaptic disinhibition caused by brain-derived neurotrophic factor (BDNF) has been proved as a crucial mechanism underlying neuropathic pain, the function of presynaptic inhibition in acute and neuropathic pain remains elusive. Here we show that a transient shift in the reversal potential (EGABA) together with a decline in the conductance of presynaptic GABAA receptor result in a reduction of presynaptic inhibition after nerve injury. BDNF mimics, whereas blockade of BDNF signalling reverses, the alteration in GABAA receptor function and the neuropathic pain syndrome. Finally, genetic disruption of presynaptic inhibition leads to spontaneous development of behavioural hypersensitivity, which cannot be further sensitized by nerve lesions or BDNF. Our results reveal a novel effect of BDNF on presynaptic GABAergic inhibition after nerve injury and may represent new strategy for treating neuropathic pain.
authors.affiliation: Centre for Integrative Neuroscience, Otfried-Mueller-Strasse 25, 72076 Tübingen, Germany.
authors.forename: Jeremy Tsung-chieh
authors.initials: JT
authors.lastname: Chen
authors.affiliation: Centre for Integrative Neuroscience, Otfried-Mueller-Strasse 25, 72076 Tübingen, Germany.
authors.forename: Da
authors.initials: D
authors.lastname: Guo
authors.affiliation: 1] Centre for Integrative Neuroscience, Otfried-Mueller-Strasse 25, 72076 Tübingen, Germany [2] Hearing Research Centre, Elfriede Aulhornstrasse 5, 72076 Tübingen, Germany.
authors.forename: Dario
authors.initials: D
authors.lastname: Campanelli
authors.affiliation: Centre for Integrative Neuroscience, Otfried-Mueller-Strasse 25, 72076 Tübingen, Germany.
authors.forename: Flavia
authors.initials: F
authors.lastname: Frattini
authors.affiliation: Centre for Integrative Neuroscience, Otfried-Mueller-Strasse 25, 72076 Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Mayer
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany.
authors.forename: Luming
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Pharmacology Institute, University of Heidelberg, Im Neuenheimer Feld 584, 69120 Heidelberg, Germany.
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
authors.affiliation: Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Via Ramarini 32, 00016 Monterotondo, Italy.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Heppenstall
authors.affiliation: Hearing Research Centre, Elfriede Aulhornstrasse 5, 72076 Tübingen, Germany.
authors.forename: Marlies
authors.initials: M
authors.lastname: Knipper
authors.affiliation: Centre for Integrative Neuroscience, Otfried-Mueller-Strasse 25, 72076 Tübingen, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000209:etiology*; D059225:Nociception; D009619:Nociceptors / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011963:Receptors, GABA-A