The role of neurogenic inflammation and CGRP in migraine headache

The last 40 years have witnessed a thorough change in our understanding of the mechanisms underlying migraine, initiated by the discovery of calcitonin gene‐related peptide (CGRP). A century ago, William Bayliss, Thomas Lewis and other pioneers introduced a visionary neurophysiological mechanism, brought about by peripheral terminals of a specialized subset of primary sensory neurons, which was named ‘neurogenic inflammation’; in both mammal and human skin, action potentials generated by injured nerve terminals of primary sensory neurons can invade collateral fibres via antidromic conduction and release a mediator that ‘produces the flare and enhances sensitivity of other sensory axons responsible for pain’. This mediator, much later identified as CGRP, provides the missing link between these early observations and modern therapeutic targets. Multiple monoclonal antibodies against CGRP or its receptor along with orally available small molecule antagonists of the CGRP receptor have revolutionized the prevention and acute treatment of migraine. The pharmacokinetic features of anti‐CGRP drugs and the paracrine actions of CGRP suggest the proposal that the mechanism underlying migraine headache occurs in a spatially limited microenvironment located outside the blood–brain barrier. According to this hypothesis, the migraine headache milieu comprises CGRP‐containing peripheral sensory nerve endings (C‐fibre nociceptors) and neighbouring cells, including other nerve fibres (Aδ‐fibres), vascular smooth muscle cells and Schwann cells wrapping these nerve fibres.