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 neuron...