Trigeminovascular system

The trigeminovascular system is a functional neurovascular network. It consists of sensitive afferents of the trigeminal nerve and the meningeal and intracranial blood vessels innervated by them, neuropeptidergic signaling substances and central processing structures in the brain stem and thalamus.

The trigeminal nerve innervates supratentorially the dura mater, the middle meningeal artery, the large intracranial vessels and the sinus durae matris. The skin of the central parts of the face is also innervated (see illustration).

The nerves of the CNS are exclusively nociceptive afferents (pain fibers). Infratentorial areas are innervated by fibers of the cervical spinal nerves C1 and C2. The nociceptive fibers are pseudounipolar neurons. The soma and perikaryon are located in the trigeminal ganglion. From there, their neurites first run peripherally to the meninges and blood vessels and then centrally in the trigeminal nuclei.

The trigeminal neuronal networks consist of: C-fibres (unmyelinated) and Aδ-fibres (thinly myelinated). They contain neuropeptides such as CGRP (Calcitonin Gene-Related Peptide), substance P, neurokinin A and PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide). They are released from the axon terminals of Aδ and C fibers whose cell bodies are located in the trigeminal ganglion. PACAP is a neuropeptide that stimulates adenylate cyclase and increases cyclic adenosine monophosphate/cAMP levels, leading to transcriptional activation of target genes. PACAP is an important mediator of neuroendocrine stress responses; it is similar to the " vasoactive intestinal peptide /VIP".

Activation of nociceptive trigeminal afferents is generally accepted as the cause of migraine headaches (May A et al. 1999; Ashina M et al. 2019). The release of neuropeptides and vasoactive substances leads to increased vasodilation, plasma extravasation, mast cell activation and sterile neurogenic inflammatory responses.

In the early migration phase, activation of the hypothalamus leads to sensitization of the trigeminovascular system. CGRP (Calcitonin Gene-Related Peptide) plays a central role here. CGRP is the strongest known vasodilator. The neuropeptide has a direct pain-modulating effect. CGRP is significantly elevated during migraine attacks (Edvinsson L 2017). Normalization correlates with freedom from pain.

The unilateral sensitization of peripheral neurons also explains the hemiplegic, usually pulsating headache. Convergences with extracranial afferents can lead to transmitted pain sensation in the neck or occipital region. It is noteworthy that in migraine, the sensory nerve endings of the trigeminal nerve release calcitonin gene-related peptide (CGRP), which leads to nociception and vasodilation in areas of skin innervated by the trigeminal nerve (central parts of the face - see figure). (Ibrahimi K et al. 2015).

1. Ashina M et al. (2019) Migraine and the trigeminovascular system-40 years and counting. Lancet Neurol 18:795-804.
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3. Ibrahimi K et al. (2015) Reduced trigeminovascular cyclicity in patients with menstrually related migraine. Neurology 84:125-131.
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6. Rubio-Beltrán E et al. (2022) Trigeminovascular effects of propranolol in men and women, role for sex steroids. Ann Clin Transl Neurol 9:1405-1416.