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

Trends Pharmacol Sci. 2012 Aug;33(8):456-63. doi: 10.1016/j.tips.2012.04.004. Epub 2012 May 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Action Potentials
  • Acute Pain / etiology
  • Acute Pain / metabolism*
  • Animals
  • Cyclic AMP / metabolism
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Inflammation / metabolism
  • Ion Channels / metabolism*
  • Neuralgia / etiology
  • Neuralgia / metabolism*
  • Nociceptive Pain / etiology
  • Nociceptive Pain / metabolism*
  • Potassium Channels
  • Prostaglandins E / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Sensory Receptor Cells / metabolism


  • HCN2 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Potassium Channels
  • Prostaglandins E
  • Receptors, G-Protein-Coupled
  • Cyclic AMP