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HCN2 Ion Channels Drive Pain in Rodent Models of Migraine

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)7513-7529
Number of pages17
JournalJournal of Neuroscience
Issue number40
Accepted/In press16 Aug 2022
Published5 Oct 2022

Bibliographical note

Funding Information: This work was supported by the Brain Research United Kingdom Grant 201718-16 and the Wellcome Trust Grant 205006/Z/16/Z. We thank Joseph Lloyd for assisting with single-unit recording and Bruno Vilar for helpful discussions and assistance with patch clamp. Publisher Copyright: © 2022 Society for Neuroscience. All rights reserved.

King's Authors


Migraine is believed to be initiated by neuronal activity in the CNS, that triggers excitation of nociceptive trigeminal ganglion (TG) nerve fibers innervating the meninges and thus causes a unilateral throbbing headache. Drugs that precipitate or potentiate migraine are known to elevate intracellular levels of the cyclic nucleotides cAMP or cGMP, while anti-migraine treatments couple to signaling pathways that reduce cAMP or cGMP, suggesting an involvement of these cyclic nucleotides in migraine. Members of the HCN ion channel family are activated by direct binding of cAMP or cGMP, suggesting in turn that a member of this family may be a critical trigger of migraine. Here, we show that pharmacological block or targeted genetic deletion of HCN2 abolishes migraine-like pain in three rodent migraine models (in both sexes). Induction of migraine-like pain in these models triggered expression of the protein C-FOS, a marker of neuronal activity, in neurons of the trigeminocervical complex (TCC), where TG neurons terminate, and C-FOS expression was reversed by peripheral HCN2 inhibition. HCN2 block in vivo inhibited both evoked and spontaneous neuronal activity in nociceptive TG neurons. The NO donor glyceryl trinitrate (GTN) caused an increase in cGMP in the TG in vivo. Exposing isolated TG neurons to GTN caused a rightward shift in the voltage dependence of HCN currents and thus increased neuronal excitability. This work identifies HCN2 as a novel target for the development of migraine treatments.

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