A key event in the pathophysiology of headache pain is dilation of intracranial, extracerebral (ie, meningeal) vessels located within the dura mater (upper left of figure at bottom of screen).1,21–23
Meningeal vessels are innervated by primary or first-order sensory neurons (dark blue line with arrowhead—also called meningeal nociceptors) whose cell bodies are located in the trigeminal ganglion.22
During migraine, dilation of meningeal vessels mechanically activates the peripherally projecting nerve endings of these neurons, causing neurogenic inflammation, which is characterized by the release of neuropeptides, including calcitonin-gene related peptide (CGRP), within the meninges. This release causes vasodilation, blood vessel leakage (plasma extravasation), and mast cell degranulation.21–23
Activated primary sensory neurons also relay pain information along the first division of the trigeminal nerve (V1, the ophthalmic branch) through the trigeminal ganglion to the trigeminal nucleus caudalis (TNC, shaded green), where neuropeptides and neurotransmitters are released from their centrally projecting nerve terminals.23
These primary sensory neurons relay information from dilated meningeal blood vessels to second-order neurons within the TNC, where it is relayed (see light yellow line with arrowhead) to the thalamus (shaded black), then ultimately via third-order neurons (see black line with arrowhead) to the primary somatosensory cortex, where sensory aspects of pain (location, quality, type, intensity) are processed.21
As a migraine attack progresses, second-order neurons in the TNC become sensitized (central sensitization), resulting in increased headache pain severity along with increased sensitivity to environmental (light and sound) and other stimuli (eg, touch, resulting in cutaneous allodynia).23
In addition, activation of primary sensory neurons can trigger activation of a parasympathetic reflex (not included in the schematic) that involves neurons originating in the superior salivatory nucleus of the pons and reaching meningeal vessels through the pterygopalatine ganglion. These neurons release vasoactive neuropeptides and nitric oxide (NO) within and around meningeal vessels that help sustain the inflammatory response within the dura (vasodilation, vessel leakage, and mast cell degranulation).24
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23. Borsook D, Burstein R, Moulton E, Becerra L. Functional
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