“HCN2 ion channels drive neuropathic pain, migraine, and tinnitus”

Peter McNaughton, Ph.D. (King’s College London)

Monday, 3/7/22 @ 12pm EST

Please email el147 at hunter dot cuny dot edu for link

We would all like to avoid pain – but acute pain (the pain felt shortly after injury) is essential for life, because it is a critical warning system that protects us from damage. Chronic pain, by contrast, is a long lasting pain that often serves no useful purpose.

HCN (Hyperpolarization-activated, Cyclic Nucleotide gated) ion channels are activated both by membrane hyperpolarization and by inflammatory mediators that activate G-protein coupled receptors and thus elevate the intracellular level of cAMP. When activated, HCN channels generate an inward current that can depolarize a nerve cell to threshold and initiate action potential generation. In painsensing neurons (nociceptors, receptors for noxious stimuli) these action potentials transmit a sensation of pain to the spinal cord and then on up to conscious levels. We found that genetically deleting the HCN2 isoform in nociceptors abolished the neuropathic pain caused by nerve injury. Similar results were obtained with a drug that blocks HCN ion channels. Importantly, there was no effect on acute pain thresholds. These results show that HCN2 is a key driver of chronic pain.

In more recent work we have extended the idea that HCN2 may drive abnormal excitability of sensory neurons to other pathologies – painful diabetic neuropathy, arthritis, migraine and tinnitus, with promising results in all these apparently distinct conditions.

We conclude that HCN2 is a critical target for the development of novel analgesics. A challenge has been to develop selective blockers that will inhibit HCN2 ion channels without interfering with the closely - related HCN4 ion channels that are important in driving the heartbeat.