The current understanding of migraine pathophysiology suggests a generalised neuronal hyperexcitability involving multiple neuronal systems.1 This abnormal functioning of the central nervous system (CNS) can explain the particular sensitivities patients with migraine have towards changes in sleep and diet patterns, as well as light and stress stimuli.1 In Prof. Dickenson’s opinion, a migraine attack occurs when abnormal messages from the peripheral nervous system – coupled with other disturbances – reach the hyperexcitable brain. CGRP represents one of these peripheral messages and understanding its role in migraine pathophysiology has led to the development of anti-CGRP biologics.
CGRP as a target for migraine treatment
CGRP is primarily located in C and A∂ sensory fibres originating from the dorsal root and trigeminal ganglia, as well as the CNS.2 Activation of the trigeminal system results in the release of CGRP, which in turn leads to vasodilation and release of nitric oxide, and ultimately causes pain.2 CGRP is widely distributed in the central and peripheral nervous systems, where increased levels are found in patients with migraine.3 In addition to the therapeutic potential of CGRP, it could also serve as a diagnostic biomarker of migraine.
Stopping pain where it starts
Prof. Dickenson explained that a migraine attack originates in the CNS and activation of the trigeminal ganglion acts to amplify pain. Presence of CGRP and the activation of the trigeminovascular pain pathway trigger ascending CNS pain pathways, which ultimately result in headache pain.4 Anti-CGRP biologics – CGRP receptor antagonists, anti-CGRP monoclonal antibodies and anti-CGRP receptor antibodies – sequester CGRP from the peripheral nervous system, thus interrupting the message leading to migraine before it reaches the CNS.
At the end of his presentation, Prof. Dickenson shared his optimism that there is great promise in CGRP and CGRP therapies. He predicted we could see further advances, not only in the understanding and management of migraine (e.g. role as a diagnostic and treatment response biomarker), but also in the management of other headache disorders and even different therapy areas (e.g. neurogenic pain and inflammation, arthritis, diabetes and obesity).
“With anti-CGRP biologics, we can interfere with the initiation of the messages that lead to migraine”
– Anthony Dickenson (University College London, UK)
Akerman S, et al. Current and novel insights into the neurophysiology of migraine and its implication for therapeutics. Pharmacol Ther. 2017;172:151–70.
Iyengar S, et al. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain. 2017;158:543–59.
Russell FA, et al. Calcitonin gene-related peptide: Physiology and pathophysiology. Physiol Rev. 2014;94:1099–142.
Edvinsson L, et al. CGRP as the target of new migraine therapies – successful translation from bench to clinic. Nat Rev Neurol. 2018;14:338–50.