Trigeminovascular system

The trigeminovascular system, often described as the 'ground zero' of migraine pathophysiology, consists of the trigeminal nerve (cranial nerve V) and the cranial blood vessels it innervates [2, 7]. This network is responsible for sensing nociceptive stimuli in the meninges and transmitting these signals to the brainstem, a process mediated by the release of potent neuropeptides like calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) [3, 6]. Activation of these nerves triggers neurogenic inflammation and vasodilation, resulting in the intense, throbbing pain characteristic of migraine attacks [2, 6]. Modern pharmacological treatments target this system by modulating specific G protein-coupled receptors, such as 5-HT1B/1D/1F (triptans and ditans) and the CGRP receptor (gepants and monoclonal antibodies) [7, 10, 11]. Furthermore, the system is a primary target for neuromodulation devices that provide external stimulation to the trigeminal, vagus, or occipital nerves to disrupt pathological pain cycles and reduce attack frequency [1, 4, 15].

Other names

Nerves involved in migraineTrigeminal nerve systemCranial nerve V pathwayTrigeminal ganglion neuronsMigraine pain pathwayTrigeminal-vascular complex

Migraine pharmacotherapy works by modulating neurotransmission within the trigeminovascular system. Triptans and ditans act as agonists at serotonin receptors (5-HT1B, 5-HT1D, and 5-HT1F) on trigeminal nerve endings to inhibit the release of proinflammatory neuropeptides and, in the case of triptans, induce cranial vasoconstriction [2, 10, 15]. Gepants and monoclonal antibodies (mAbs) target the CGRP pathway, with gepants and erenumab blocking the CGRP receptor, while other mAbs bind the CGRP ligand itself, thereby preventing neurogenic inflammation and peripheral sensitization [7, 11, 16]. Additionally, neuromodulation devices (e.g., eTNS, nVNS) deliver non-invasive electrical or magnetic stimulation to the trigeminal, vagus, or occipital nerves to alter neural excitability and interrupt pathological pain signaling [4, 9, 15].