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Electrophysiological characterization of activation state-dependent Cav2 channel antagonist TROX-1 in spinal nerve injured rats.

Patel, R; Rutten, K; Valdor, M; Schiene, K; Wigge, S; Schunk, S; Damann, N; ... Dickenson, AH; + view all (2015) Electrophysiological characterization of activation state-dependent Cav2 channel antagonist TROX-1 in spinal nerve injured rats. Neuroscience , 297 47 - 57. 10.1016/j.neuroscience.2015.03.057. Green open access

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Abstract

Prialt, a synthetic version of Cav2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Cav2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Cav2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury.

Type: Article
Title: Electrophysiological characterization of activation state-dependent Cav2 channel antagonist TROX-1 in spinal nerve injured rats.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neuroscience.2015.03.057
Publisher version: http://dx.doi.org/10.1016/j.neuroscience.2015.03.0...
Additional information: © 2015 The Authors. Published by Elsevier Ltd. on behalf of IBRO. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Ca(v)2.2, N-type calcium channel, dorsal horn, dorsal root ganglia, electrophysiology, spinal nerve ligation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1466016
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