title: Impaired excitatory drive to spinal GABAergic neurons of neuropathic mice.
abstract: Adequate pain sensitivity requires a delicate balance between excitation and inhibition in the dorsal horn of the spinal cord. This balance is severely impaired in neuropathy leading to enhanced pain sensations (hyperalgesia). The underlying mechanisms remain elusive. Here we explored the hypothesis that the excitatory drive to spinal GABAergic neurons might be impaired in neuropathic animals. Transgenic adult mice expressing EGFP under the promoter for GAD67 underwent either chronic constriction injury of the sciatic nerve or sham surgery. In transverse slices from lumbar spinal cord we performed whole-cell patch-clamp recordings from identified GABAergic neurons in lamina II. In neuropathic animals rates of mEPSC were reduced indicating diminished global excitatory input. This downregulation of excitatory drive required a rise in postsynaptic Ca(2+). Neither the density and morphology of dendritic spines on GABAergic neurons nor the number of excitatory synapses contacting GABAergic neurons were affected by neuropathy. In contrast, paired-pulse ratio of Aδ- or C-fiber-evoked monosynaptic EPSCs following dorsal root stimulation was increased in neuropathic animals suggesting reduced neurotransmitter release from primary afferents. Our data indicate that peripheral neuropathy triggers Ca(2+)-dependent signaling pathways in spinal GABAergic neurons. This leads to a global downregulation of the excitatory drive to GABAergic neurons. The downregulation involves a presynaptic mechanism and also applies to the excitation of GABAergic neurons by presumably nociceptive Aδ- and C-fibers. This then leads to an inadequately low recruitment of inhibitory interneurons during nociception. We suggest that this previously unrecognized mechanism of impaired spinal inhibition contributes to hyperalgesia in neuropathy.
authors.affiliation: Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Jörg
authors.initials: J
authors.lastname: Leitner
authors.forename: Sören
authors.initials: S
authors.lastname: Westerholz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Heinke
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Forsthuber
authors.forename: Gabriele
authors.initials: G
authors.lastname: Wunderbaldinger
authors.forename: Tino
authors.initials: T
authors.lastname: Jäger
authors.forename: Doris
authors.initials: D
authors.lastname: Gruber-Schoffnegger
authors.forename: Katharina
authors.initials: K
authors.lastname: Braun
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sandkühler
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D020013:Calcium Signaling; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D049229:Dendritic Spines; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D051379:Mice; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism; D009437:Neuralgia / Q000503:physiopathology; D017288:Pain Threshold; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D016760:Proto-Oncogene Proteins c-fos; D043884:Receptor, Cannabinoid, CB1; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1