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Calcium channel modulation as a target in chronic pain control

Patel, RA; Montagut Bordas, C; Dickenson, AH; (2017) Calcium channel modulation as a target in chronic pain control. British Journal of Pharmacology 10.1111/bph.13789. (In press). Green open access

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Abstract

Neuropathic pain remains poorly treated for large numbers of patients and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (PrialtTM ) was developed and approved as a first in class synthetic version of ω-conotoxin MVIIA, a Cav 2.2 peptide blocker. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide has restricted its use to exceptional circumstances. Ziconotide exhibits no state or use dependent block of Cav 2.2 channels; activation state dependent blockers were hypothesised to circumvent the side effects of state independent blockers by selectively targeting high frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state dependent calcium channel blockers, have displayed efficacy in pre-clinical models but have subsequently disappointed in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients, and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus evoked endpoints in pre-clinical studies and a failure to utilise translatable endpoints has likely contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant based assays provide insight into sensory and affective aspects of pain in animal models, and how these may relate to chronic pain patients in order to improve bench-to-bedside translation of calcium channel modulators.

Type: Article
Title: Calcium channel modulation as a target in chronic pain control
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bph.13789
Publisher version: http://dx.doi.org/10.1111/bph.13789
Language: English
Additional information: © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Calcium channel blockers, chronic pain
UCL classification: UCL > Provost and Vice Provost Offices
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: http://discovery.ucl.ac.uk/id/eprint/1546122
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