A New Link to Migraine’s Pain
More than 2,400 years after Hippocrates described migraines, the exact mechanisms that produce these throbbing, long-lasting headaches, often preceded by an “aura” of bizarre visual and other sensations, have remained elusive to neuroscientists.
The long-held view that migraines are primarily caused by the constriction and rebound dilation of blood vessels in the head has largely been abandoned for lack of any convincing evidence. Instead, researchers have been piecing together a complex picture of electrophysiological and inflammatory events that start in the brain cortex and end with activation of pain-producing trigeminal sensory nerve fibers that innervate the large blood vessels in the meninges surrounding the brain. Not all the steps in the activation process have yet been filled in.
Now, researchers led by Turgay Dalkara and colleagues at Hacettepe University in Ankara, Turkey, have identified what they call a “missing link” in the signaling chain from stressed cortical neurons to meningeal pain. Their paper, appearing in the March 1 issue of Science, is the first to implicate the recently characterized pannexin 1 (Panx1) “megachannels” that form large transmembrane pores in neurons. The results support their hypothesis that the opening of the Panx1 megachannels, in response to cortical stress, is the spark that ignites the inflammatory cascade that causes and sustains the prolonged misery of migraneurs.
In the scenario proposed by Dalkara and colleagues, Panx1 megachannels are opened by cortical spreading depression (CSD), a self-propagating wave of electrophysiological hyperactivity in the cortex, followed by a wave of inhibition. The CSD wave travels at about 2 to 5 mm per minute, and is believed to be responsible for the migraine aura described by sufferers as scintillating defects in the visual field, often accompanied by sensitivity to light and sound, and sometimes deficits in reading and speaking.
“This is a very exciting and important study because it may provide the answer to two key open questions in the pathophysiology of migraine,” commented Daniela Pietrobon, University of Padua, Italy, who was not involved in the current work. “How does CSD activate the trigeminal nociceptors, and, in particular, how does CSD produce the delayed, sustained activation of meningeal nociceptors?”
In migraine-susceptible patients, CSD is a response to migraine triggers such as emotional stress, lack of sleep, hormonal fluctuations and changing weather. In these experiments, the researchers administered a pinprick to the brains of anesthetized mice to initiate CSD, and used a fluorescent dye and electrical recordings to trace the ensuing events.
They demonstrated that the CSD-driven opening of Panx1 channels led to caspase 1 activation, a proinflammatory signal that, in turn, spurred the release of high-mobility group box 1 (HMGB1) proteins and the activation of the transcription factor nuclear factor κB in astrocytes. These stimuli caused sustained production and release of inflammatory mediators from the glia limitans—the thin protective membrane covering the brain that regulates the movement of small molecules and cells into the parenchymal tissue of the brain.
Administration of a specific Panx1 channel inhibitor abolished the inflammatory cascade, trigeminal activation, and headache (as assessed using the mouse grimace scale of Langford et al., 2010), but did not suppress CSD, validating the critical role of the megachannels in the migraine process.
The authors note in the paper that HMGB1 is a member of the “alarmin” family —proinflammatory molecules secreted by cells under stress, such as the metabolic stress created by CSD on cortical neurons. “By promoting sustained headache,” the researchers suggest, “HMGB1 may thus serve to alarm the organism that the brain parenchyma has been stressed by CSD or CSD-like events.”
The scenario they describe is compelling, noted Michael Moskowitz, a migraine investigator at the Neuroscience Center at Massachusetts General Hospital, Boston, US. He commented that the proposed mechanism provides “a plausible explanation for the delay in pain onset after migraine aura (20 to 40 minutes) because of time-dependent transcriptional and translational events.” The scenario also can explain how trigeminal activation can be maintained for the hours to days that a migraine can persist, said Moskowitz.
Dalkara cautioned that these experiments only documented the inflammatory stimulus for one hour’s duration. Nevertheless, he noted, “even one hour of stimulation can be enough to trigger a headache lasting hours to days because of the sensitization mechanisms shown by Rami Burstein’s group [at Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, US] and the sterile neurogenic meningeal inflammation secondary to trigeminal activation as proposed by Moskowitz’s pioneering studies.”
The authors suggest that Panx1 channels may be a new target for migraine prophylaxis. “The downstream inflammatory mediators may also be selectively targeted, or should be considered in mechanisms of action of anti-inflammatory drugs already used in treatment of migraine headache,” said Dalkara.
Currently, he said, his lab is conducting studies to investigate the relationship between the new pathway and classical migraine triggers, as well as working toward the development of new anti-migraine compounds.
VIDEO: The researchers describe a molecular pathway that connects a wave of neuron activation in the brain with the release of inflammatory proteins that may produce the pain of migraine. Credit: Kivilcim Kilic, Hacettepe University.
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