A potential HCN channel-sensitive mechanism for verapamil’s action in cluster headache

Background Cluster headache, a primary headache disorder characterized by recurrent bouts of severe unilateral head pain and characteristic autonomic features, including lacrimation, is often described as the worst pain imaginable to humankind. Current treatments are nonspecific, and preventive treatments particularly are associated with adverse effects, low and delayed efficacy. The first line preventive treatment verapamil is effective in over 50% of patients, albeit at very high doses and with significant cardiovascular effects that limit its utility. Therefore, we sought to dissect the potential mechanisms of action of verapamil. Methods In this study, we used two related preclinical models of trigeminal autonomic cephalalgias (TACs) and a preclinical model of migraine in rats, combined with pharmacological interventions to determine the potential mechanisms of action of verapamil. Results We demonstrate that verapamil reduces superior salivatory nucleus stimulation-evoked cranial autonomic activation and nociceptive responses. However, verapamil has no effect on durovascular-evoked nociceptive responses, in agreement with verapamil’s clinical effectiveness in cluster headache, a TAC subtype but not migraine. Interestingly, verapamil’s effect was prevented or reversed by blockade of hyperpolarization-activated cyclic nucleotide-gated channels (HCN), but not calcium channels, in the current setup. HCN blockade further prevented the effect of oxygen, a first line acute therapy for cluster headache, but not the effect of lamotrigine nor indomethacin, treatments for other TACs. Finally, we identified the expression of different HCN isoforms in areas relevant for the pathophysiology of TACs, including the trigeminal and sphenopalatine ganglia. Conclusions Our results are consistent with the selective effectiveness of verapamil in cluster headache, highlighting a potential HCN-sensitive mechanism of action that offers promise for future mechanistic testing and therapeutic development.