Review
HCN2 ion channels: an emerging role as the pacemakers of pain

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Acute nociceptive pain is caused by the direct action of a noxious stimulus on pain-sensitive nerve endings, whereas inflammatory pain (both acute and chronic) arises from the actions of a wide range of inflammatory mediators released following tissue injury. Neuropathic pain, which is triggered by nerve damage, is often considered to be very different in its origins, and is particularly difficult to treat effectively. Here we review recent evidence showing that members of the hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channel family – better known for their role in the pacemaker potential of the heart – play important roles in both inflammatory and neuropathic pain. Deletion of the HCN2 isoform from nociceptive neurons abolishes heat-evoked inflammatory pain and all aspects of neuropathic pain, but acute pain sensation is unaffected. This work shows that inflammatory and neuropathic pain have much in common, and suggests that selective blockers of HCN2 may have value as analgesics in the treatment of pain.

Section snippets

Types of pain

The ability to sense noxious stimuli is an essential protective mechanism that initiates effective behavioral responses in order to avoid damaging stimuli. The vital role this primeval sense plays in survival is illustrated by the cases of people suffering from congenital insensitivity to pain, a rare disorder in which individuals often die prematurely from accidental injuries [1]. Not all pain is advantageous, however, because pain can also manifest itself as a chronic, pathological state, in

Role for HCN ion channels in modulating action potential frequency

HCN ion channels carry an inward current (termed If in cardiac tissue and Ih in neurons) which is unusual because it is activated by membrane hyperpolarization between approximately –60 and –90 mV. In cardiac pacemaker tissue, the hyperpolarization following an action potential activates If, generating an inward membrane current and depolarizing the membrane to threshold for the next action potential 9, 10. A crucial property of If is that its range of activation is shifted towards more positive

In vivo experiments: HCN2 and inflammatory pain

Experiments in vivo are the ultimate test for any hypothesis relating ion channels to pain. Pharmacological blockade of HCN channels by the pan-HCN inhibitor, ZD-7288, gives significant analgesia in a variety of inflammatory tests in both rats and mice, including the PGE2, formalin, carrageenan and mild thermal injury models 20, 26, 27, 28. Although these observations support a role for one or more of the HCN ion channel isoforms in pain, they do not identify the isoforms involved. Off-target

In vivo experiments: HCN2 and neuropathic pain

There is little agreement about what causes neuropathic pain, apart from that the initiating factor is damage to peripheral nerves. Nerve damage causes an ongoing firing of action potentials in both large- and small-diameter afferent nerve fibers 34, 35, 36, 37, but it remains unresolved whether it is this ectopic firing or some other change that triggers neuropathic pain, nor whether ectopic firing in large- or small-diameter fibers is important. Altered gene expression in peripheral sensory

Bridging the gap between inflammatory and neuropathic pain

Inflammatory and neuropathic pain have traditionally been regarded as discrete entities, differing in their origins, which in the case of neuropathic pain are still enigmatic. This view is also reflected in how these conditions are treated. Inflammatory pain is in general well-treated with NSAIDs and opioid analgesics, albeit with many side effects. By contrast, current treatments for neuropathic pain are frequently ineffective and carry with them a substantial burden of side effects.

Concluding remarks

The work discussed in this review supports a central role for HCN2 ion channels in both inflammatory and neuropathic pain. One striking difference between the two is that inflammatory pain usually disappears as the injury heals, whereas neuropathic pain often continues long after inflammation associated with the nerve injury has, at least apparently, completely disappeared. Whether HCN channels remain important in long-term neuropathic pain is still unclear and will form an interesting topic

Acknowledgments

Work in the authors’ lab was supported by a grant from the UK Biotechnology and Biological Sciences Research Council (BBSRC) to P.A.M., a European Commission Marie Curie fellowship, and a BBSRC CASE PhD studentship (part-funded by Organon Inc.) to E.C.E.

References (72)

  • C.A. von Hehn

    Deconstructing the neuropathic pain phenotype to reveal neural mechanisms

    Neuron

    (2012)
  • D.H. Lee

    Hyperpolarization-activated, cation-nonselective, cyclic nucleotide-modulated channel blockade alleviates mechanical allodynia and suppresses ectopic discharge in spinal nerve ligated rats

    J. Pain

    (2005)
  • C. Dalle et al.

    Peripheral block of the hyperpolarization-activated cation current (Ih) reduces mechanical allodynia in animal models of postoperative and neuropathic pain

    Reg. Anesth. Pain Med.

    (2005)
  • Q. Sun

    Inhibition of hyperpolarization-activated current by ZD7288 suppresses ectopic discharges of injured dorsal root ganglion neurons in a rat model of neuropathic pain

    Brain Res.

    (2005)
  • Y.Q. Jiang

    Axonal accumulation of hyperpolarization-activated cyclic nucleotide-gated cation channels contributes to mechanical allodynia after peripheral nerve injury in rat

    Pain

    (2008)
  • J.L. Sanchez-Alonso

    ZD 7288 inhibits T-type calcium current in rat hippocampal pyramidal cells

    Neurosci. Lett.

    (2008)
  • J. Lai

    Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8

    Pain

    (2002)
  • H. Tu

    Diabetes alters protein expression of hyperpolarization-activated cyclic nucleotide-gated channel subunits in rat nodose ganglion cells

    Neuroscience

    (2010)
  • S.C. Ahlgren et al.

    Mechanical hyperalgesia in streptozotocin-diabetic rats

    Neuroscience

    (1993)
  • X. Chen et al.

    Hyper-responsivity in a subset of C-fiber nociceptors in a model of painful diabetic neuropathy in the rat

    Neuroscience

    (2001)
  • W. Ma

    Injured nerve-derived COX2/PGE2 contributes to the maintenance of neuropathic pain in aged rats

    Neurobiol. Aging

    (2010)
  • W. Ma et al.

    Does COX2-dependent PGE2 play a role in neuropathic pain?

    Neurosci. Lett.

    (2008)
  • M. Gore

    Clinical characteristics and pain management among patients with painful peripheral neuropathic disorders in general practice settings

    Eur. J. Pain

    (2007)
  • J.P. Syriatowicz

    Hyperalgesia due to nerve injury: role of prostaglandins

    Neuroscience

    (1999)
  • T. Vo

    Non-steroidal anti-inflammatory drugs for neuropathic pain: how do we explain continued widespread use?

    Pain

    (2009)
  • C. Stein et al.

    Peripheral mechanisms of opioid analgesia

    Curr. Opin. Pharmacol.

    (2009)
  • X. Weng

    Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current (Ih) in C- but not Aδ-nociceptors

    Pain

    (2012)
  • A. Latremoliere et al.

    Central sensitization: a generator of pain hypersensitivity by central neural plasticity

    J. Pain

    (2009)
  • C.J. Woolf

    Central sensitization: implications for the diagnosis and treatment of pain

    Pain

    (2011)
  • J.J. Cox

    An SCN9A channelopathy causes congenital inability to experience pain

    Nature

    (2006)
  • J.E. Linley

    Understanding inflammatory pain: ion channels contributing to acute and chronic nociception

    Pflugers Arch.

    (2010)
  • E.R. Perl

    Pain and Nociception

  • C.S. Sherrington

    The Integrative Action of the Nervous System

    (1906)
  • E.D. Adrian et al.

    The impulses produced by sensory nerve-endings. Part 2. The response of a single end-organ

    J. Physiol. Lond.

    (1926)
  • C. Krarup et al.

    Nerve conduction and excitability studies in peripheral nerve disorders

    Curr. Opin. Neurol.

    (2009)
  • H.F. Brown

    How does adrenaline accelerate the heart?

    Nature

    (1979)
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