Discovery of CGRP in relation to migraine

Soon after CGRP (calcitonin gene-related peptide) was discovered in 1983, it was linked to the trigeminovascular system with implications for migraine. Early studies of the calcitonin gene revealed that alternative splicing occurred in neural tissue, resulting in the expression of a second peptide named calcitonin-gene related peptide (1). We had already set up all necessary methodology for studies of the role of perivascular neuropeptides. The first perivascular neuropeptide to be detected in the intracranial vasculature was vasoactive intestinal peptide (VIP), which occurs in the parasympathetic system and is a potent vasodilator. The work continued with the discovery of nearly one new perivascular neuronal candidate every year (2). When we had learned of CGRP there were no tools available, so we had to do it all ourselves. CGRP was then synthesized for in vitro and in vivo studies as well as for production of antibodies to use in quantitative radioimmunoassay and immunohistochemical studies.

The initial data on CGRP in the trigeminovascular system were presented in Paris in 1984 at a CNRS meeting on Regulatory Peptides and later in a series of publications (3–6). In the trigeminal ganglion, over half of the neurons contain CGRP, and CGRP-positive fibres in intracranial arteries could be eliminated by lesioning of the ganglion (6). Subsequent tracing studies from intra and extracranial arteries confirmed that the sensory CGRP positive fibres originate in the trigeminal neurons (6–8). Functional studies showed that CGRP is a very potent vasodilator of cerebral arteries and arterioles by activating adenylyl cyclase in the smooth muscle cells (4). We had a long-standing, well-established collaboration with Professor James McCulloch in Glasgow and much of the in vivo work was done there: CGRP potently relaxed cortical arterioles but not venules (9). Lesioning of the perivascular sensory CGRP nerves, however, did not modify resting cerebral blood flow or any of its fundamental regulation mechanisms. Instead, CGRP was demonstrated to play a key role in the protective trigeminovascular reflex (9), whereby CGRP is released by trigeminal nerves in response to local cerebral vasoconstriction to cause dilation and maintain cerebral blood flow. Together, these findings suggested CGRP was involved in migraine pathophysiology (3). The decisive results for demonstration of its involvement in primary headaches appeared a few years later, when we had started an excellent collaboration with Professor Peter J Goadsby, at that time in Sydney. CGRP was found to be selectively released from the trigeminal ganglion during migraine headache, and this release could be prevented by anti-migraine drugs such as sumatriptan (10–12).

This was the starting point for building up the clinical background for CGRP in migraine. For a decade we tried to convince our headache interested colleagues that CGRP was important, largely in vain, until the key proof-of-concept study of intravenous olcegepant was reported in 2004 (13). This was followed by development of several small molecule CGRP receptor antagonists, gepants, which in clinical trials were all found to be effective with minor side effects. This program was halted due to hepatic toxicity in a preventive study (14), although it was positive; we had earlier predicted a preventive effect for the CGRP mechanism. Fortunately, the gepants were not dead – two have completed phase III studies that were all positive (see paper by PJG). Blocking the CGRP pathway has taken another direction with the development of antibodies toward CGRP and CGRP receptor, both to be presented shortly (paper by DD). The antibody approach has the advantage of being extremely target specific and not broken down in the liver, which limits side effects. The antibodies have by now been approved by the FDA and the EMA and are at various stages of implementation in therapy worldwide (5). The CGRP pathway represents a quantum therapeutics approach to migraine, having a duality of mechanism: Acute and preventive treatment, which is resolved when appropriately measured. We present in this volume of Cephalalgia a few overviews on this subject, but in addition a collection of top notch, topical and important original papers that provides the recent state of the art.