title: Amitriptyline and carbamazepine utilize voltage-gated ion channel suppression to impair excitability of sensory dorsal horn neurons in thin tissue slice: An in vitro study.
abstract: Amitriptyline, carbamazepine and gabapentin are often used for the treatment of neuropathic pain. However, their analgesic action on central sensory neurons is still not fully understood. Moreover, the expression pattern of their target ion channels is poorly elucidated in the dorsal horn of the spinal cord. Thus, we performed patch-clamp investigations in visualized neurons of lamina I-III of the spinal cord. The expression of the different voltage-gated ion channels, as the targets of these drugs, was detected by RT-PCR and immunohistochemistry. Neurons of the lamina I-III express the TTX-sensitive voltage-gated Na(+) as well as voltage-gated K(+) subunits assembling the fast inactivating (A-type) currents and the delayed rectifier K(+) currents. Our pharmacological studies show that tonically-firing, adapting-firing and single spike neurons responded dose-dependently to amitriptyline and carbamazepine. The ion channel inhibition consecutively reduced the firing rate of tonically-firing and adapting-firing neurons. This study provides evidence for the distribution of voltage-gated Na(+) and K(+) subunits in lamina I-III of the spinal cord and for the action of drugs used for the treatment of neuropathic pain. Our work confirms that modulation of voltage-gated ion channels in the central nervous system contributes to the antinociceptive effects of these drugs.
authors.affiliation: Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University, Giessen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wolff
authors.affiliation: Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Czorlich
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Chandran
authors.initials: C
authors.lastname: Nagaraj
authors.affiliation: Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University, Giessen, Germany.
authors.forename: Rose
authors.initials: R
authors.lastname: Schnöbel-Ehehalt
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Austria.
authors.forename: Yingji
authors.initials: Y
authors.lastname: Li
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Department of Anaesthesia and Intensive Care Medicine, Medical University of Graz, Austria.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Austria.
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.affiliation: Department of Anaesthesia and Intensive Care Medicine, Medical University of Graz, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Heschl
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Department of Anaesthesia and Intensive Care Medicine, Medical University of Graz, Austria. Electronic address: andrea.olschewski@medunigraz.at.
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
mesh_terms: D000588:Amines / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D005260:Female; D000077206:Gabapentin; D066298:In Vitro Techniques; D008297:Male; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000502:physiology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms; D061566:Voltage-Gated Sodium Channels; D000639:Amitriptyline; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin
keywords: Action potential; Antidepressants; Firing pattern; Lamina I–III; Sensory neurons; Spinal cord