Antidromic vasodilatation and the migraine mechanism

Abstract

Despite the fact that an unprecedented series of new discoveries in neurochemistry, neuroimaging, genetics and clinical pharmacology accumulated over the last 20 years has significantly increased our current knowledge, the underlying mechanism of the migraine headache remains elusive. The present review article addresses, from early evidence that emerged at the end of the nineteenth century, the role of 'antidromic vasodilatation' as part of the more general phenomenon, currently defined as neurogenic inflammation, in the unique type of pain reported by patients suffering from migraine headaches. The present paper describes distinctive orthodromic and antidromic properties of a subset of somatosensory neurons, the vascular- and neurobiology of peptides contained in these neurons, and the clinical-pharmacological data obtained in recent investigations using provocation tests in experimental animals and human beings. Altogether, previous and recent data underscore that antidromic vasodilatation, originating from the activation of peptidergic somatosensory neurons, cannot yet be discarded as a major contributing mechanism of the throbbing head pain and hyperalgesia of migraine.

Fig. 1

Neurogenic vasodilation in migraine. Activation of peptidergic trigeminal sensory neurons results in the release of calcitonin gene-related peptide (CGRP), which acting at the CGRP-like receptor (CLR) coupled to receptor activity-modifying protein-1 (RAMP1), relaxes smooth muscle cells of intra- and extracranial arteries. Exogenous or endogenous agonists of transient receptor potential vanilloid 1 (TRPV1) or ankyrin 1 (TRPA1) promote the release of CGRP. Prostaglandins (PGs), bradykinin (BK) or other proalgesic agents, either directly via activation of their specific G protein coupled receptors (GPCR) or indirectly (through channel activation) also contribute to neuropeptide release. Nitric oxide (NO) generated from glyceryl trinitrate (GTN) acts downstream to CGRP to evoke vasodilatation and probably headache. Neurogenic vasodilatation in addition to cause the headache may also contribute to neuronal sensitization. Sumatriptan and other triptans inhibit CGRP release acting at prejunctional serotonin 5-HT1D receptors or evoke arterial vasoconstriction via stimulation of 5-HT1B receptors on vascular smooth muscle. Botulinum neurotoxin type A (BoNTA) has also been shown to inhibit CGRP release