Review
Voltage-Gated Ion Channels in the PNS: Novel Therapies for Neuropathic Pain?

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Neuropathic pain results from injury to the central and/or peripheral nervous system. Such injury can result in neuronal excitability, the basis of which includes altered expression, trafficking, and functioning of ion channels expressed by primary sensory neurons, including CaV, HCN, and NaV channels.

Extensive pharmacological data indicate that it is possible to synthesize novel chemical entities (NCEs) that selectively inhibit channel function within each channel family. In preclinical tests, NCEs that selectively target CaV, HCN, and NaV channels have all demonstrated efficacy in various models of neuropathic pain; replicating those results in humans has been difficult, but NaV blockers (at least) show promise.

Improvements in animal and human testing methodologies are needed to identify and develop safe and effective NCEs as antihyperalgesics.

Neuropathic pain arises from injury to the nervous system. Conditions associated with neuropathic pain are diverse, and lesions and/or pathological changes in the central nervous system (CNS) or peripheral nervous system (PNS) can frequently, but not always, be identified. It is difficult to treat, with patients often on multiple, different classes of medications, all with appreciable adverse side effect profiles. Consequently, there is a pressing need for the development of new medications. The development of such therapeutics is predicated on a clear understanding of the relevant molecular and cellular processes that contribute to the development, and maintenance, of the neuropathic pain state. One proposed mechanism thought to contribute to the ontogeny of neuropathic pain is altered expression, trafficking, and functioning of ion channels expressed by primary sensory neurons. Here, we will focus on three voltage-gated ion channel families, CaV, HCN, and NaV, first reviewing the preclinical data and then the human data where it exists.

Section snippets

Neuropathic Pain

As defined by the International Association for the Study of Paini [1], pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage; chronic pain is pain that persists beyond the normal tissue healing time (usually 3 months); neuropathic pain is pain caused by a lesion of, or damage to, the somatosensory nervous system (Figure 1A). Chronic pain greatly impairs an individual's quality of life, is widely prevalent, and has significant cost. In the USA

CaV Channels

Voltage-gated Ca2+ channels (CaV) are broadly classified into three closely related groups based on genes coding the obligatory pore-forming α subunit: CaV1, CaV2, and CaV3 18, 19 (Figure 2). Three genes comprise the CaV3 subfamily (Figure 2A), and these channels give rise to the low-voltage activated (LVA) ‘T’-type current. T-type Ca2+ currents are present in dorsal root ganglia (DRG) neurons 20, 21, 22, 23, the basis of which is CaV3.2 and CaV3.3, at least in small- and medium-sized sensory

Concluding Remarks

It is evident that the data from preclinical animal models offers, in many instances, compelling arguments for a particular molecular pathway as being of fundamental importance to the development, maintenance, and therapeutic target value in neuropathic pain. Based on those results, human clinical trials are designed, subjects enrolled, data collated and subjected to multivariate analysis, and report, all too frequently, no significant effect [199]; the results with the CaV3.2 blocker ABT-639

References (241)

  • J. Mao

    Current challenges in translational pain research

    Trends Pharmacol. Sci.

    (2012)
  • M.F. Jarvis

    A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats

    Biochem. Pharmacol.

    (2014)
  • A.V. Apkarian

    Pain and the brain: specificity and plasticity of the brain in clinical chronic pain

    Pain

    (2011)
  • K. Wartolowska et al.

    Neuroimaging as a tool for pain diagnosis and analgesic development

    Neurotherapeutics

    (2009)
  • S.P. Yusaf

    Expression of voltage-gated calcium channel subunits in rat dorsal root ganglion neurons

    Neurosci. Lett.

    (2001)
  • Z.P. Feng

    Residue Gly1326 of the N-type calcium channel a1B subunit controls reversibility of ω-conotoxin GVIA and MVIIA block

    J. Biol. Chem.

    (2001)
  • E.A. Matthews et al.

    Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy

    Pain

    (2001)
  • T. Ogiyama

    Discovery of a 1-isopropyltetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain

    Bioorg. Med. Chem.

    (2015)
  • T. Ogiyama

    Discovery of an 8-methoxytetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain without CYP inhibition liability

    Bioorg. Med. Chem.

    (2015)
  • B. Santoro

    Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain

    Cell

    (1998)
  • T.M. Ishii

    Molecular characterization of the hyperpolarization-activated cation channel in rabbit heart sinoatrial node

    J. Biol. Chem.

    (1999)
  • G.M. Whitaker

    HCN2 and HCN4 isoforms self-assemble and co-assemble with equal preference to form functional pacemaker channels

    J. Biol. Chem.

    (2007)
  • B. Much

    Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels

    J. Biol. Chem.

    (2003)
  • Q. Zhang

    Associated changes in HCN2 and HCN4 transcripts and If pacemaker current in myocytes

    Biochim. Biophys. Acta

    (2009)
  • C. He

    Neurophysiology of HCN channels: from cellular functions to multiple regulations

    Prog. Neurobiol.

    (2014)
  • E.V. Kouranova

    Hyperpolarization-activated cyclic nucleotide-gated channel mRNA and protein expression in large versus small diameter dorsal root ganglion neurons: correlation with hyperpolarization-activated current gating

    Neuroscience

    (2008)
  • F. Stillitano

    Molecular basis of funny current (If) in normal and failing human heart

    J. Mol. Cell. Cardiol.

    (2008)
  • International Association for the Study of Pain, Subcommittee on Taxonomy

    Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms

    Pain Suppl.

    (1986)
  • B. Meier et al.

    The soaring cost of the opioid economy

    The New York Times

    (2013)
  • L.J. Paulozzi

    Vital signs: overdoses of prescription opioid pain relievers – United States, 1999–2008

    Morb. Mortal. Wly Rep.

    (2011)
  • Centers for Disease Control and Prevention

    National Vital Statistics System Mortality Data

    (2015)
  • T. Lyapustina et al.

    The prescription opioid addiction and abuse epidemic: how it happened and what we can do about it

    Pharm. J.

    (2015)
  • L. Degenhardt

    The global epidemiology and burden of opioid dependence: results from the global burden of disease 2010 study

    Addiction

    (2014)
  • G. Campbell

    Pharmaceutical opioid use and dependence among people living with chronic pain: associations observed within the Pain and Opioids in Treatment (POINT) cohort

    Pain Med.

    (2015)
  • A.S. Bohnert

    Association between opioid prescribing patterns and opioid overdose-related deaths

    JAMA

    (2011)
  • I. Giraudon

    Prescription opioid abuse in the UK

    Br. J. Clin. Pharmacol.

    (2013)
  • H. Gaskell

    Oxycodone for neuropathic pain and fibromyalgia in adults

    Cochrane Database Syst. Rev.

    (2014)
  • P.J. Wiffen

    Buprenorphine for neuropathic pain in adults

    Cochrane Database Syst. Rev.

    (2015)
  • R. Freynhagen et al.

    Diagnosis and management of neuropathic pain

    BMJ

    (2009)
  • M. Costigan

    Neuropathic pain: a maladaptive response of the nervous system to damage

    Annu. Rev. Neurosci.

    (2009)
  • J. Scholz et al.

    The neuropathic pain triad: neurons, immune cells and glia

    Nat. Neurosci.

    (2007)
  • W.A. Catterall

    International Union of Pharmacology. XLVIII. Nomenclature and structure–function relationships of voltage-gated calcium channels

    Pharmacol. Rev.

    (2005)
  • T. Furukawa

    Types of voltage-gated calcium channels: molecular and electrophysiological views

    Curr. Hypertens. Rev.

    (2013)
  • E. Carbone et al.

    A low voltage-activated, fully inactivating Ca channel in vertebrate sensory neurones

    Nature

    (1984)
  • M.C. Nowycky

    Three types of neuronal calcium channel with different calcium agonist sensitivity

    Nature

    (1985)
  • J.L. Bossu

    Depolarization elicits two distinct calcium currents in vertebrate sensory neurones

    Pflügers Arch.

    (1985)
  • S.A. Fedulova

    Two types of calcium channels in the somatic membrane of new-born rat dorsal root ganglion neurones

    J. Physiol.

    (1985)
  • E.M. Talley

    Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels

    J. Neurosci.

    (1999)
  • J.B. Shin

    A T-type calcium channel required for normal function of a mammalian mechanoreceptor

    Nat. Neurosci.

    (2003)
  • M.M. Jagodic

    Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons

    J. Neurosci.

    (2007)
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