Could a Paradigm Shift Lead to Better Migraine Therapies?
BOSTON—New research is challenging neurologists’ ideas about the mechanisms of migraine, according to a presentation given at the 2013 International Headache Congress. The research, along with various scientific advances, could provide new therapeutic targets for future migraine drugs.
Researchers in Copenhagen observed no dilation of extracranial arteries in subjects who were evaluated with magnetic resonance angiography during a spontaneous migraine attack, said Andrew Charles, MD. Furthermore, effective treatment with sumatriptan did not cause intracranial vasoconstriction in these patients. The trial is the latest in a series of investigations that have yielded similar results.
“The initial paradigm of migraine as a vascular pain disorder is giving way to an understanding that migraine is a genetic brain disorder,” said Dr. Charles, Director of the Headache Research and Treatment Program at the David Geffen School of Medicine in Los Angeles. “This is not to say that the old paradigm is entirely incorrect, but we need to move on to different ideas that will offer different opportunities for therapy.”
Future Drugs Could Target Cervical Nerve Roots
Migraine traditionally has been viewed as a trigeminal vascular process that leads to the activation of the brainstem, but growing evidence suggests that cervical nerve roots play a significant role. In recent experiments, Mollie Johnston, MD, attempted to treat patients with chronic occipital pain by stimulating and anesthetizing upper cervical nerve roots. Stimulating the C1 nerve root caused pain in the periorbital region, and stimulating the C2 and C3 nerve roots caused pain in other distributions. The results suggest that “the upper cervical nerve roots, and particularly C1, may represent a pathway that could be exploited, in terms of therapeutic mechanisms,” said Dr. Charles.
Research Suggests New Anatomic Targets
Other studies indicate that the hypothalamus is involved during a migraine attack and may also play a role in the premonitory phase of migraine. Hypothalamic involvement could explain migraine symptoms such as mood change and appetite change. The hypothalamus also represents a different kind of pharmacologic target because it controls the release of various peptides and other substances, according to Dr. Charles.
The thalamus, too, may contribute to migraine. Growing evidence from functional imaging studies, clinical studies, and physiologic studies indicates that thalamocortical oscillations are changed during the time before a migraine attack. “This represents an interesting new anatomic target that we haven’t thought about extensively in the past,” said Dr. Charles.
Migraine and Other Pain Syndromes
Researchers have found areas of reduced brain volume in the pain matrix (ie, interconnected regions of the brain involved in the sensation and processing of pain) of patients with migraine. These changes also occur in patients with other pain syndromes. For migraineurs, the changes may represent the brain’s response to chronic pain, but they also could cause chronification of pain in some patients.
Studies of pain disorders indicate that treating the underlying pain condition can reverse these brain changes. “This kind of brain plasticity represents another kind of therapeutic target,” said Dr. Charles. Neural growth factors and trophic factors may prove to be as beneficial for migraineurs and patients with chronic pain as they are for patients with neurodegenerative disease or stroke, he added.
Optogenetics Could Reveal Cell Types Involved in Migraine
Migraine is regarded as a neuronal disorder, and the nervous system comprises many cell types, including several kinds of neurons, astrocytes, and blood vessel cells. The relatively new tool of optogenetics may shed light on how these cell types interact during migraine. Optogenetics entails the expression of light-sensitive ion channels in various cell types in the nervous system. The technique enables neurologists to beam light through the intact skull to activate the cells and observe the functional consequences of that activation, said Dr. Charles.
In a recent application of optogenetics, Serapio Baca, PhD, observed that light-stimulated activation of a channel called channelrhodopsin 2, which is selectively expressed in astrocytes, in mice evoked cortical spreading depression. The study provides direct evidence that astrocytes could play a primary role in the initiation of migraine, said Dr. Charles.
Migraine Triggers Are Potential Targets of Therapy
Migraine triggers such as nitroglycerin, histamine, and prostaglandin could be important therapeutic targets, and a model of human migraine triggers “is instrumental to our understanding of the process,” said Dr. Charles. Investigators have translated human research on migraine triggers into mouse models for further study, and this technique could prove beneficial. In one trial by Amynah Pradhan, PhD, mice given nitroglycerin chronically or acutely became hypersensitive to various sensory stimuli. This study “may model sensory sensitivity in the migraine patient,” said Dr. Charles. “We can use these models as predictive and translational models to identify potential migraine mechanisms that are targets for therapy.”
