STOWE, VT—A new class of drugs that regulate calcitonin gene-related peptide (CGRP) responses could become an additional option for migraine therapy, according to Lars Edvinsson, MD, PhD, who spoke at the Headache Cooperative of New England’s 22nd Annual Headache Symposium.
The CGRP receptor, a G-protein-coupled receptor of the B subtype, comprises calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and receptor component protein (RCP). Blocking CGRP receptors could be an effective mechanism for future drugs to treat migraine.
Prof. Edvinsson, Professor of Internal Medicine at Lund University in Sweden, described his decades of research on CGRP. His studies began in 1984, when he and his colleagues first observed that CGRP, which incorporates 37 amino acids, could potentially mediate trigeminal action by causing vasodilation and neuroinflammation.
A Challenge to the Prevailing View of Migraine
Prof. Edvinsson has often collaborated with Peter Goadsby, MD, PhD, Professor of Neurology and Director of the Headache Center at the University of California, San Francisco, in the study of CGRP. In 1988, the two researchers found that stimulating the trigeminal ganglion in cats and in humans increases the level of CGRP in cranial circulation.
During the 1990s, “everyone was interested in substance P,” because it was believed to play a major role in migraine, said Prof. Edvinsson. But in a 1990 study, Prof. Edvinsson and Dr. Goadsby concluded that patients’ levels of substance P did not change between control and migraine states. CGRP, however, was present at greater levels during migraine than during a control state. Treatment with sumatriptan returned CGRP to control levels. The study contradicted the prevailing view of migraine, and the researchers “had to defend it quite a lot,” said Prof. Edvinsson.
CGRP in the Trigeminal Ganglion
CGRP and its receptors are located in several parts of the nervous system. The large cells of the trigeminal ganglion (ie, approximately 33% of all cells in the ganglion) contain CLR and RAMP1 receptor molecules. These molecules are also expressed in satellite glial cells, which are located around each of the trigeminal neurons. More than 90% of the cells in the trigeminal ganglion are satellite glial cells. In addition, the mast cells in the dura mater contain CLR and RAMP1. CGRP itself is expressed in the cytoplasm of small and medium-sized trigeminal ganglion cells (ie, about 50% of all cells in the ganglion). The trigeminal ganglion also contains CGRP nerve fibers, which enable neurons to communicate with each other.
CGRP in the Spine and Brain Stem
Prof. Edvinsson recently investigated whether CGRP and its receptors occurred in the brain stem, which is activated during migraine attacks. He found that the molecules are present in laminae I and II of the spinal trigeminal nucleus. Tracing studies also showed that CGRP and its receptors are distributed in laminae I of the spine. In the spine, CGRP is expressed in unmyelinated fibers and C-fibers, stored, and released from nerve terminals. It may act postsynaptically in this area because the myelinated Aδ-fibers originate in the large neurons of the trigeminal ganglion and express the CGRP receptor elements.
CGRP in the Cerebellum
PET scans have demonstrated that the cerebellum is activated during migraine attacks. The literature suggests that mutations of CACNA1, the Purkinje cell calcium channel gene that is highly expressed in the cerebellum, is associated with familial hemiplegic migraine. These factors prompted Prof. Edvinsson to investigate whether CGRP also was distributed in the cerebellum.
He and his colleagues detected CGRP in the main body of the Purkinje cells of the cerebellum in a clearly vesicular mode. The Purkinje cells are connected to the brain stem in the pons. “We were quite astonished when we saw this picture with a very rich CGRP immunoreactivity,” said Prof. Edvinsson.
The researchers also found a rich distribution of CLR and RAMP1 in the molecular layer, on the surface of Purkinje cells, and in the granular layer of the cerebellum. The receptor molecules were distributed together in the same places. The receptors did not occur in the Bergman glia, but on the surface of the Purkinje cells, while the CGRP immunoreactivity was in the cytoplasm of these cells. The role of CGRP and its receptor in the cerebellum is still unclear, but might offer a way to modify pain signaling in the brainstem.
CGRP in the Sphenopalatine Ganglion and Other Sites in the Brain
In a recent study, Prof. Edvinsson found CGRP expressed in nerve fibers in the sphenopalatine ganglion of humans. CGRP could be directed from the trigeminal ganglion into the sphenopalatine, he noted. The same study revealed CLR and RAMP1 on the satellite glial cells of the sphenopalatine ganglion. The trigeminal ganglion might influence the sphenopalatine ganglion’s function by releasing CGRP to receptors in the satellite glial cells. The role of satellite glial cells is still a subject of discussion. “It’s kind of insulation around the cells like the myelin for nerves,” said Prof. Edvinsson. Another function might be related to inflammation.
Prof. Edvinsson also found other sites of CGRP binding in the brain, such as the periaqueductal gray matter, the ventral medial nucleus of the thalamus, the superior colliculus, the solitary tract nucleus, the hippocampus, and the amygdala. He and his colleagues are currently studying CGRP and CGRP receptors in the brain stem in detail.
Targets for Migraine Therapy
Investigators soon began to examine whether drugs that regulate CGRP could be effective palliatives. Various studies, including one in 1993 by Prof. Edvinsson and Dr. Goadsby, showed that blocking the release of CGRP presynaptically with drugs such as triptans can relieve the pain of migraine. More recently, CGRP receptor antagonists have emerged as a new class of migraine medication.
CGRP and its receptors are particularly highly expressed in the cerebellum, which would be an excellent target for CGRP receptor antagonists, said Prof. Edvinsson. The trigeminal ganglion, brain stem, and spinal cord also are potential targets for new CGRP receptor antagonists.
Drugs that regulate CGRP have been a boon to patients with migraine. “If we use this kind of drug, it works,” said Prof. Edvinsson, speaking of triptans. Further research into CGRP receptors could lead to the development of new therapies that alleviate the pain experienced by patients with migraine. Combining pre- and postsynaptic targets might provide additional remedies.
—Erik Greb
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