Hyperpolarization-activated cation (HCN) channels have recently been implicated in neuropathic and inflammatory pain processes through their hyperfunction and/or overexpression, and HCN channels may play a significant role in migraine pathophysiology, as both an inflammatory and a neuropathic component has been hypothesized to contribute to migraine, and HCN channel activity is facilitated by cyclic nucleotides, e.g. cAMP and cGMP (molecules thought to be central in migraine pathophysiology) and increases in extracellular K+ concentration causing Ih current amplification. Indeed, increases in cAMP or directly opening adenosine 5'-triphosphate-sensitive K+ channels (KATP channel) by levcromakalim leads to migraine attacks in a high proportion of patients, suggesting a crucial role for these channels in migraine pathophysiology. KATP channel activation leads to hyperpolarization, which in turn could increase the open probability of HCN channels. To uncover the role of HCN channels in migraine, the researchers will investigate the anti-migraine effect of ivabradine, the only HCN channel blocker available for clinical use, on levcromakalim-induced migraine.~The investigators anticipate that this project will contribute greatly to the current understanding of migraine pathophysiology and the hypothesized role of HCN channels in migraine pain mechanisms. This is of great interest in future research, as such knowledge is an important prerequisite for further investigation and understanding of intracellular signalling mechanisms in migraine, which in turn will lead to the development of more effective and mechanism-based drugs.
Hyperpolarization-activated cation (HCN) channels have recently been implicated in neuropathic and inflammatory pain processes, and HCN channel activity is modulated by signalling molecules, such as cyclic nucleotides (cAMP, cGMP) and extracellular potassium, known to induce migraine. To uncover the role of HCN channels in migraine, the researchers will investigate the anti-migraine effect of ivabradine, the only HCN channel blocker available for clinical use, on levcromakalim-induced migraine.