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Calcium channel modulation as a target in chronic pain control.

Calcium channel modulation as a target in chronic pain control.
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Patel R, Montagut-Bordas C, Dickenson AH,


Patel R, Montagut-Bordas C, Dickenson AH, (click to view)

Patel R, Montagut-Bordas C, Dickenson AH,

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British journal of pharmacology 2017 03 20() doi 10.1111/bph.13789
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 (Prialt(TM) ) 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.

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