26.04 Neurogenic Inflammation Theory

The trigeminocerebrovascular system comprises the ophthalmic trigeminal ganglia, the cells of which innervate major vessels regulating cerebral blood flow, smaller meningeal (especially dura mater) vessels, the meninges, and centrally projecting sensory fibres synapsing on to the trigeminal nucleus caudalis in the caudal brainstem and cervical spinal cord. The pain sensitive structures include the blood vessels and meninges, thus trigeminal fibres afford a conduit for nociceptive information originating in the blood vessels and meninges to the central nervous system.

Stimulation of the trigeminal fibres, which are nociceptive C fibres, causes pain directly, as well as release of neuropeptides such as calcitonin gene-related peptide (CGRP), substance P and neurokinin, and also nitric oxide, leading to vasodilation. Following sufficient activation resulting perhaps from cortical excitation, blood vessel constriction or lowered sensitisation threshold to certain stimuli, inflammatory events occur including plasma extravasation (leakage from vessels), platelet activation, 5-HT secretion, mast cell degranulation and secretion of bradykinin, histamine and prostaglandins. This provides a localised “inflammatory soup” that continues to sensitise and activate the C fibres, contributing to neurogenic inflammation of the dura mater and blood vessels.

CGRP release is thought to regulate normal blood flow, since vasoconstriction triggers antidromic (feed forward) release of CGRP from trigeminal nerves, leading to vasodilation. Interestingly, CGRP is released in correspondence with the pain of migraine and its concentration has been shown to correlate with headache intensity. CGRP is also a marker of trigeminal activity. Thus, migraine may involve a lowered threshold of trigeminal activation, and hypersensitivity to local neuropeptide release, including CGRP, which not only causes vasodilation in pain-sensitive structures, but causes chemical irritation and may lower the pain threshold to previously innocuous stimuli.

Figure 26.1 schematically depicts the trigeminocerebrovascular pathways and highlights the important neuropeptides and neurotransmitters involved in these pathways.

Figure 26.1: Schematic depiction of the trigeminocerebrovascular pathway highlighting the role of neurogenic inflammation in the pathogenesis of migraine and the neurpetides involved. Location of 5-HT receptors is also shown, highlighting their crucial role in migraine and its treatment. (Copyright The University of Sydney, Tina Hinton)