Disorder-specific substitutions at the trigger node: CACNA1A Cav2.1 gain of function, ATP1A2 astrocytic Na+/K+-ATPase loss of function and SCN1A Nav1.1 gain of function in familial hemiplegic migraine; K2P potassium channel dysfunction and endothelial dysfunction in migraine with aura; no identified molecular lesion in common migraine, where the trigger node is a population-level susceptibility rather than a named defect. The two halves of the chain are sourced differently. The cortical and spreading-depolarization half of the chain rests on genetic mouse models (PMID:15003170, PMID:21731499), so its evidence is MODEL_ORGANISM throughout and graded INDIRECT: the step from a mouse CSD threshold to a human attack is an inference this module does not assert. The step from spreading depolarization to trigeminal activation is the contested one. That edge carries a REFUTE item quoting PMID:40498799 on recent clinical data that challenge aura causing headache in patients, beside the SUPPORT item from the same essay for the animal-model result. PMID:21731499's introduction says independently that the role of CSD in migraine headache is still debated; that sentence is not quoted as an evidence item, because a statement that a question is open takes no direction on it. A conformer should not read the edge as settled. The nociceptor node keeps GO:0048265 response to pain rather than a term under GO:0019233 sensory perception of pain, because Migraine and Migraine_with_Aura already bind GO:0048265 on the very nodes that conform here; moving the module off it would put the module and two of its three conformers on different terms, which is a judgement about those entries rather than about this module. No node asserts a vasodilation measurement. GO:0042311 vasodilation is bound on the neuropeptide node because the cited review describes CGRP release onto the meningeal vasculature, but none of the cited abstracts quantifies meningeal vessel calibre during an attack, and the older view that vasodilation is itself the source of the pain is not claimed here. The module is deliberately silent on the premonitory and postdromal phases, on hypothalamic and brainstem involvement, and on the episodic-to-chronic transition. Those are real parts of migraine biology and none of them is a conserved step in this chain; an entry curating them should model them in its own pathophysiology rather than stretching a node here. Do NOT create a `Migraine Neurovascular Mechanism` Disease entry: this is a mechanism module, and the diseases that instantiate it are `Migraine`, `Migraine_with_Aura` and `Familial_Hemiplegic_Migraine`.
Cortical Hyperexcitability Lowering the Spreading Depolarization Threshold
trigger
Raised glutamatergic drive, impaired astrocytic clearance of glutamate and potassium, or an interneuron firing defect leaves the cortical network closer to the threshold at which a self-propagating depolarization can be ignited. The node is about the lowered threshold, not about any one molecular lesion; conformers substitute their own.
Downstream
-
Cortical Spreading Depolarization
A lowered threshold is what permits the wave to be ignited and to propagate faster.
Show evidence (1 reference)
"Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability."
States the node directly: susceptibility to spreading depolarization is attributed to cortical hyperexcitability. Measured in a knockin mouse carrying the human FHM1 R192Q allele.
Cortical Spreading Depolarization
amplifier
A slowly propagating wave of near-complete neuronal and glial depolarization crossing the cortex, followed by prolonged suppression of activity. It is the accepted correlate of the aura.
Used by disorders
Migraine
as Cortical Spreading Depression
Downstream
-
Trigeminovascular Nociceptor Activation
The depolarizing wave and the ionic and inflammatory environment it leaves behind activate meningeal trigeminal afferents. This is the contested step of the chain: the two evidence items below quote the same essay in opposite directions, the animal-model result for the edge and the recent clinical data against it in patients.
Show evidence (2 references)
"The pivotal role of cortical spreading depression (CSD) as a mechanism underlying aura has been widely supported by a large body of studies."
Establishes spreading depolarization as the mechanism of the aura.
"Neuroimaging examination suggests that migraine aura is associated to cortical spreading depression (CSD), a short-lasting, intense wave of neuronal and glial cell depolarization."
Supplies the node's physical description, a short intense wave of neuronal and glial depolarization, and its human imaging correlate.
Trigeminovascular Nociceptor Activation
central effector
Activation, and then mechanical sensitization, of the trigeminal primary afferents innervating the meninges and their vessels. This is the key conformance target: the step at which a cortical electrophysiological event becomes nociceptive traffic, and the one every conformer shares whatever lowered its own threshold upstream. Activation and sensitization are separable at this node, and the cited work shows they have different mechanisms.
Used by disorders
Migraine
as Trigeminovascular Activation
Downstream
-
Meningeal Neuropeptide Release and Neurogenic Vasodilation
Activated afferents release CGRP and related neuropeptides from their peripheral terminals.
Show evidence (3 references)
"Activation and sensitization of meningeal afferents play a key role in migraine headache, but the underlying mechanisms remain unclear."
Establishes the node as the pivotal step in migraine headache, and that its mechanism is open.
"Broad-spectrum P2X receptor inhibition, selective blockade of the P2X7 receptor, and its related Pannexin 1 channel suppressed CSD-evoked afferent mechanical sensitization but did not affect the accompanying afferent activation response."
Dissociates the node's two components pharmacologically, which is why the description keeps activation and sensitization distinct.
"mediates the mechanical sensitization of meningeal afferents, which contributes to migraine pain by exacerbating the headache during normally innocuous physical activities"
Names the peripheral half of this node, mechanical sensitization of the meningeal afferents, and its clinical signature: headache worsened by ordinarily innocuous activity.
Meningeal Neuropeptide Release and Neurogenic Vasodilation
effector
CGRP and related neuropeptides released from peripheral trigeminal terminals act on the meningeal vasculature and on neighbouring afferents, producing vasodilation and a neurogenic inflammatory milieu that keeps the afferents firing. The module does not claim that the vasodilation is itself the source of the pain; see the notes.
Downstream
-
Central Trigeminal Sensitization
Sustained peripheral neuropeptide signalling and afferent traffic drive the second-order neurons into a sensitized state.
Show evidence (1 reference)
"Release of CGRP from the peripheral terminals initiates a cascade of events that include increased synthesis of nitric oxide and sensitization of the trigeminal nerves."
Describes what the released neuropeptide does locally, including the feedback onto the afferents.
Central Trigeminal Sensitization
consequence
Amplified synaptic transmission in the second-order trigeminal neurons, which outlasts the peripheral drive and is the substrate of the allodynia and of pain on ordinarily innocuous movement that characterize an established attack.
Show evidence (2 references)
"progresses from peripheral sensitization of the primary afferent TG neurons to central sensitization of TNC second-order neurons and ultimately to central sensitization of third-order neurons in the thalamus."
States the node's own compartment: sensitization of the second-order neurons of the trigeminal nucleus caudalis, downstream of the peripheral afferent sensitization the node above carries.
"As the migraine attack progresses, cutaneous allodynia develops in the periorbital area, signaling central sensitization of convergent TNC neurons and an increased resistance to the efficacy of triptans."
Supplies the allodynia this node's description asserts, and ties it to central sensitization of convergent TNC neurons in patients during an attack.