Calcium channel modulation as a target in chronic pain control

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 Ca_v 2.2 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 Ca_v 2.2 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 articles: This 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.

Figure 1

Approaches to calcium channel modulation in chronic pain. To date, targeting trafficking of VGCCs has been the favoured approach to modulating channel activity. The gabapentinoids (GBP) bind to an arginine motif of the α₂ subunit of α₂δ‐1 and α₂δ‐2 and inhibit axonal trafficking of α₂δ‐1 and Rab11‐dependent recycling of endosomal channels to the synapse (Bauer et al., 2009; Tran‐Van‐Minh and Dolphin, 2010). Novel approaches to reduce trafficking include utilizing CBD3 peptides to disrupt the interaction between VGCCs and CRMP2. Channel activity can be regulated via inhibitory GPCRs such as α₂ adrenoreceptors, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=26 and μ‐opioid receptors. Peptide blockers act by either altering gating by targeting voltage sensitive domains (such as ω‐agatoxin) or by directly blocking the pore (ω‐conotoxins) (Bourinet and Zamponi, 2016).

Figure 2

Expression of VGCCs in the dorsal horn. Ca_V2.1 (P/Q‐type) and Ca_V2.2 (N‐type) channels are largely expressed in distinct populations of primary afferents with the latter associated with peptidergic transmitters (Westenbroek et al., 1998). Ca_V3.2 (T‐type) channels are expressed in CGRP+ and IB4+ DRG neurones and also in cutaneous nerve endings (Rose et al., 2013). Both populations synapse with markers of excitatory (EI) and inhibitory (II) interneurons which subsequently converge onto second‐order sensory neurones (SN). The effects of state‐independent blockers on reducing excitatory transmission from primary afferents may be countered by opposing effects in reducing inhibitory transmitter release; for example, Ca_V2.2 channels have been shown to mediate noradrenaline release from sympathetic neurones, though it is unclear precisely how monoamines are released in the dorsal horn. L‐type (Ca_V1) and T‐type (Ca_V3) channels influence post‐synaptic excitability; neuroplasticity in L‐type expression after injury may influence neuronal sensitization (Radwani et al., 2016), whereas spinally expressed T‐type channels, unlike peripherally expressed channels, are not thought to have a pathophysiological role in neuropathy. R‐type (Ca_V2.3) channels, however, have been implicated in neuronal hyperexcitability in SNL rats (Matthews et al., 2007).

Figure 3

Effects of calcium channel modulators in the pain neuraxis. There are conflicting reports as to whether Ca_V2.2 channels contribute to ectopic firing in injured primary afferent fibres (Chaplan et al., 1994; Xiao and Bennett, 1995). However, numerous studies demonstrate that state‐dependent and ‐independent blockers can reduce spinal neuronal hyperexcitability when given systemically or spinally. In addition, systemic pregabalin reduces neuronal firing in the amygdala and VPL. Neuropathy can be associated with diminished descending noradrenergic inhibitory control of pain and enhanced serotonergic facilitatory drive. Both Ca_V2.1 and Ca_V2.2 channels have complex roles in descending modulation and exert pro‐ and anti‐nociceptive actions when micro‐injected into different regions (Knight et al., 2002; Finn et al., 2003; Urban et al., 2005). However, state‐dependent blockers targeting high‐frequency neuronal firing may avoid the confounding actions of state‐independent blockers (Ce, central nucleus of amygdala; LC, locus coeruleus; PAG, periaqueductal gray; RVM, rostral ventromedial medulla; VP, ventral posterior thalamus).