ATP-Sensitive Potassium Channels Trigger Migraine Attacks

Post by Shireen Parimoo

What's the science?

Migraines are persistent, throbbing headaches that can last for days and lead to nausea, light sensitivity, and dizziness, among other symptoms. Migraines often occur in response to triggers like stress and physical activity, but despite being quite common in the population, it is not clear what causes them. There is evidence to suggest that inappropriate activation of certain cell membrane receptors in blood vessels might lead to a migraine attack, as drugs that target these receptors are effective in treating migraines in the short-term. Interestingly, one of the downstream effects of activating these receptors is the opening of ATP-sensitive potassium (KATP) channels, which are also activated by molecules that trigger migraines. However, the role of KATP channels in migraines has not yet been established. This week in Brain, Al-Karagholi and colleagues used pharmacological intervention to investigate the effect of opening KATP channels on migraines and arterial blood flow.

How did they do it?

Sixteen adults suffering from migraines participated in the study over two days. They were given 20ml of levcromakalim (LKM, a drug that opens KATP channels) on one day and a saline placebo on the other day. The study was a randomized, double-blind, crossover study, which means that the treatments were administered in a randomized manner, the participants and researchers did not know which treatment was being administered on a given day, and the participants took both LKM and the placebo over the course of the two days. The authors acquired baseline measures of migraine symptoms and physiological measures like blood pressure, heart rate, and electrocardiogram before treatment. After LKM and placebo injection, they monitored the physiological measures regularly for two hours in addition to blood flow velocity in the middle cerebral artery (in the brain), the diameter of the left superficial temporal artery (in the forehead) and radial artery (in the forearm), and the partial pressure of CO2 in the left radial artery. Participants also recorded the incidence and intensity of migraines and headaches for 12 hours after receiving treatment. To determine the effect of opening KATP channels on migraines, the authors compared these measures across the placebo and LKM conditions. 

What did they find?

All participants experienced migraines within hours of being treated with LKM, whereas only one person experienced a migraine after the placebo treatment. The migraines were focused on frontal and temporal areas on the head and were accompanied by nausea, sensitivity to light and sound, palpitations, flushing, and a warm sensation. Unlike migraines, the frequency of headaches did not differ significantly across the two treatment conditions, although the headaches were more intense after LKM injection than after placebo treatment. This suggests that the opening of KATP channels selectively induces migraine attacks. After LKM treatment, there was also an increase in heart rate, reduction in blood pressure, and an increase in the diameter of the superficial temporal artery. However, the change in blood flow velocity or radial artery diameter was not different across the two treatments. The superficial temporal artery supplies blood to the temples, which is one of the main areas where participants report experiencing pain during a migraine attack. Thus, the effect of LKM on the temporal artery further strengthens the role of KATP channels in inducing migraines.

What's the impact?

This study is the first to establish a role of KATP channels in migraine attacks by using a pharmacological intervention to induce migraines. As KATP channels are found in various types of cells and tissues and serve many different functions, it is still unclear how and when these channels cause migraines. This opens the door for future research in identifying which KATP channels result in migraines, further characterizing the mechanistic pathway underlying migraine onset, and developing novel drugs to treat migraines. 

Al-Karagholi et al. Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine. Brain (2019). Access the original scientific publication here.