title: Acute inhibition of signalling phenotype of spinal GABAergic neurons by tumour necrosis factor-alpha.
abstract: Spinal application of TNFα induces both allodynia and hyperalgesia, and at least part of the pronociceptive effects of TNFα have been suggested as due to the impaired function of spinal inhibitory neurons (disinhibition). The present study explores the effects of TNFα on the signalling phenotype of spinal GABAergic neurons identified in transgenic mice expressing green fluorescent protein at the glutamic acid decarboxylase 67 (GAD67) promoter. Acute application of TNFα directly inhibits the excitability of a subset of GAD67(+) spinal neurons. TNFα-induced inhibition was dependent on the activation of p38 mitogen-activated protein kinase (MAPK) within these GAD67(+) neurons. TNFα receptor 1 (TNFR1) but not receptor 2 (TNFR2) was identified on spinal GAD67(+) neurons, suggesting that TNFα signals through TNFR1. Voltage-clamp recordings of GAD67(+) neurons indicated that the inhibitory effect of TNFα was through suppression of the hyperpolarization-activated cation current (I(h)). This study defines a novel mechanism of spinal disinhibition mediated by a TNFα-TNFR1-p38 pathway within GABAergic inhibitory interneurons.
authors.affiliation: Department of Pain Medicine, The University of Texas MD Anderson Cancer Centre, Houston, TX 77030, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhang
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dougherty
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D005260:Female; D059330:GABAergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1