Neurogenic inflammation in the context of migraine

Abstract

Despite considerable research into the pathogenesis of idiopathic headaches, such as migraine, the pathophysiological mechanisms underlying them remain poorly understood. Although it is well established that the trigeminal nerve becomes activated during migraine, the consequences of this activation remain controversial. One theory, based on preclinical observations, is that activation of trigeminal sensory fibers leads to a painful neurogenic inflammation within the meningeal (dural) vasculature mediated by neuropeptide release from trigeminal sensory fibres and characterized by plasma protein extravasation, vasodilation, and mast cell degranulation. Effective antimigraine agents such as ergots, triptans, opioids, and valproate inhibit preclinical neurogenic dural extravasation, suggesting that this activity may be a predictor of potential clinical efficacy of novel agents. However, several clinical trials with other agents that inhibit this process preclinically have failed to show efficacy in the acute treatment of migraine in man. Alternatively, it has been proposed that painful neurogenic vasodilation of meningeal blood vessels could be a key component of the inflammatory process during migraine headache. This view is supported by the observation that jugular plasma levels of the potent vasodilator, calcitonin gene-related peptide (CGRP) are elevated during the headache and normalized by successful sumatriptan treatment. Preclinically, activation of trigeminal sensory fibers evokes a CGRP-mediated neurogenic dural vasodilation, which is blocked by dihydroergotamine, triptans, and opioids but unaffected by NK1 receptor antagonists that failed in clinical trials. These observations suggest that CGRP release with associated neurogenic dural vasodilation may be important in the generation of migraine pain, a theory that would ultimately be tested by the clinical testing of a CGRP receptor antagonist.

CGRP and migraine: neurogenic inflammation revisited

“…Thus, BIBN4096BS could produce, at a postjunctional level (by CGRP receptor blockade), effects similar to those that triptans cause by reducing CGRP release, and that result in inhibition of CGRP receptor signalling. Indeed, triptans inhibit trigeminal CGRP release in animal experimental models [55,63], and clinical data show that sumatriptan normalised the elevated CGRP levels with alleviation of migraine [55] and cluster headache attack [65]. These findings have suggested that BIBN4096BS could be developed as an effective antimigraine drug.…”

“…Trigeminal nuclei as well as non-myelinated trigeminal sensory nerve fibres express an abundant CGRPlike immunoreactivity and cerebral blood vessels are innervated by sensory nerves that store several neuropeptides amongst which CGRP is the most abundant [63]. A Ca 2+ -dependent and capsaicin-sensitive release of CGRP, but not SP, has been documented from human tissues containing non-trigeminal [13] or trigeminal [11] sensory nerve endings.…”

Migraine and motion sickness: What is the link?

“…The trigeminal nerve contains sensory and motor components but the sensory component, in particular, appears to be associated with migraine pathophysiology (Williamson and Hargreaves, 2001;Borsook, Burstein, Moulton and Becerra, 2006).…”

“…Migraine has long been considered a vascular headache (Wolff, 1948;Lance, 1993;Williamson and Hargreaves, 2001). Dilatation of extracranial vessels during attacks (Drummond and Lance, 1983;Iversen, Nielsen, Olesen and Tfelt-Hansen, 1990) may be mediated, at least in part, by release of CGRP from trigeminal nerve terminals as levels were found to be elevated in the external jugular vein (Goadsby, Edvinsson and Ekman, 1990).…”

Efficacy measurement of ketorolac in reducing the severity of headache

“…This agent is an efficient non-narcotic pain killer with intermediate anti-inflammatory effect. Therefore consider as a preferable option for pain management of different type of primary headache cases admitted to the ED (16)(17)(18)(19). Current study was conducted with the aim of ketorolac efficacy measurement as a non-narcotic antiinflammatory pain killer agent for controlling the primary headache in of patients presented to the ED with all types of primary headaches.…”