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™) was developed and approved as a first‐in‐class synthetic version of ω‐conotoxin MVIIA, a peptide blocker of Cav2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use‐dependent block of Cav2.2 channels; activation state‐dependent blockers were hypothesized 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 preclinical models but have subsequently been disappointing 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 preclinical studies and a failure to utilize translatable endpoints, all are likely to have 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 the bench‐to‐bedside translation of calcium channel modulators.Linked ArticlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc
Highlights
Neuropathic syndromes are often characterized by a complex combination of positive and negative sensory phenomena including allodynia (perceiving non-noxious stimuli as pain), hyperalgesia (increased pain to normally painful stimuli) and paroxysmal or persistent paraesthesias (abnormal sensations, e.g. numbness and tingling) and dysaesthesias (abnormal and unpleasant sensations, e.g. shocking and paradoxical burning)
Neuropathic syndromes are often characterized by a complex combination of positive and negative sensory phenomena including allodynia, hyperalgesia and paroxysmal or persistent paraesthesias and dysaesthesias
We provide an updated overview of the effects of calcium channel blockers in chronic pain models, with a particular focus on how electrophysiological and conditioned place preference (CPP) studies may provide insight into sensory and affective dimensions of pain
Summary
Neuropathic syndromes are often characterized by a complex combination of positive and negative sensory phenomena including allodynia (perceiving non-noxious stimuli as pain), hyperalgesia (increased pain to normally painful stimuli) and paroxysmal or persistent paraesthesias (abnormal sensations, e.g. numbness and tingling) and dysaesthesias (abnormal and unpleasant sensations, e.g. shocking and paradoxical burning). In models where central sensitization is evident, even in the absence of pathology or where neuropathy is not the only component, gabapentin and pregabalin reduce spinal neuronal firing to both mechanical- and heat-evoked responses across low and high intensities of stimulation (Donovan-Rodriguez et al, 2005; Omori et al, 2009; Bannister et al, 2011; Thakur et al, 2012).
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