TY - JOUR
T1 - HCN2 Ion Channels Drive Pain in Rodent Models of Migraine
AU - Tsantoulas, Christoforos
AU - Ng, Aidan
AU - Pinto, Larissa
AU - Andreou, Anna P.
AU - McNaughton, Peter A.
N1 - 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.
PY - 2022/10/5
Y1 - 2022/10/5
N2 - 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.
AB - 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.
KW - HCN
KW - ion channel
KW - migraine
KW - nociception
KW - pain
KW - trigeminal
UR - http://www.scopus.com/inward/record.url?scp=85140392837&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0721-22.2022
DO - 10.1523/JNEUROSCI.0721-22.2022
M3 - Article
AN - SCOPUS:85140392837
SN - 0270-6474
VL - 42
SP - 7513
EP - 7529
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 40
ER -