Protease activated receptor 2 (PAR2) activation causes migraine-like pain behaviors in mice.
Hassler Shayne N,Ahmad Fatima B,Burgos-Vega Carolina C,Boitano Scott,Vagner Josef,Price Theodore J,Dussor Gregory
Cephalalgia : an international journal of headache
BACKGROUND:Pain is the most debilitating symptom of migraine. The cause of migraine pain likely requires activation of meningeal nociceptors. Mast cell degranulation, with subsequent meningeal nociceptor activation, has been implicated in migraine pathophysiology. Degranulating mast cells release serine proteases that can cleave and activate protease activated receptors. The purpose of these studies was to investigate whether protease activated receptor 2 is a potential generator of nociceptive input from the meninges by using selective pharmacological agents and knockout mice. METHODS:Ratiometric Ca imaging was performed on primary trigeminal and dural cell cultures after application of 2at-LIGRL-NH, a specific protease activated receptor 2 agonist. Cutaneous hypersensitivity and facial grimace was measured in wild-type and protease activated receptor 2 mice after dural application of 2at-LIGRL-NH or compound 48-80, a mast cell degranulator. Behavioral experiments were also conducted in mice after dural application of 2at-LIGRL-NH (2AT) in the presence of either C391, a selective protease activated receptor 2 antagonist, or sumatriptan. RESULTS:2at-LIGRL-NH evoked Ca signaling in mouse trigeminal neurons, dural fibroblasts and in meningeal afferents. Dural application of 2at-LIGRL-NH or 48-80 caused dose-dependent grimace behavior and mechanical allodynia that were attenuated by either local or systemic application of C391 as well as in protease activated receptor 2 mice. Nociceptive behavior after dural injection of 2at-LIGRL-NH was also attenuated by sumatriptan. CONCLUSIONS:Functional protease activated receptor 2 receptors are expressed on both dural afferents and fibroblasts and activation of dural protease activated receptor 2 produces migraine-like behavioral responses. Protease activated receptor 2 may link resident immune cells to meningeal nociceptor activation, driving migraine-like pain and implicating protease activated receptor 2 as a therapeutic target for migraine in humans.
Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine.
Al-Karagholi Mohammad Al-Mahdi,Hansen Jakob Møller,Guo Song,Olesen Jes,Ashina Messoud
Brain : a journal of neurology
Migraine is one of the most disabling and prevalent of all disorders. To improve understanding of migraine mechanisms and to suggest a new therapeutic target, we investigated whether opening of ATP-sensitive potassium channels (KATP) would cause migraine attacks. In this randomized, double-blind, placebo-controlled, crossover study, 16 patients aged 18-49 years with one to five migraine attacks a month were randomly allocated to receive an infusion of 0.05 mg/min KATP channel opener levcromakalim and placebo on two different days (ClinicalTrials.gov number, NCT03228355). The primary endpoints were the difference in incidence of migraine attacks, headaches and the difference in area under the curve (AUC) for headache intensity scores (0-12 h) and for middle cerebral artery blood flow velocity (0-2 h) between levcromakalim and placebo. Between 24 May 2017 and 23 November 2017, 16 patients randomly received levcromakalim and placebo on two different days. Sixteen patients (100%) developed migraine attacks after levcromakalim compared with one patient (6%) after placebo (P = 0.0001); the difference of incidence is 94% [95% confidence interval (CI) 78-100%]. The incidence of headache over the 12 h observation period was higher but not significant after levcromakalim (n = 16) than after placebo (n = 7) (P = 0.016) (95% CI 16-71%). The AUC for headache intensity was significantly larger after levcromakalim compared to placebo (AUC0-12h, P < 0.0001). There was no change in mean middle cerebral artery blood flow velocity after levcromakalim compared to placebo (AUC0-2hP = 0.46). Opening of KATP channels caused migraine attacks in all patients. This suggests a crucial role of these channels in migraine pathophysiology and that KATP channel blockers could be potential targets for novel drugs for migraine.