The brain parenchyma itself contains no pain receptors. This is not a minor anatomical detail; it is the organising fact that explains why migraine pain is so puzzling and why brain surgery can be performed on awake patients.
Because the brain has no nociceptors, pain arising within the cranium must originate from structures that do possess them: the meninges, the large cranial blood vessels, and the peripheral trigeminal nerve terminals that innervate them. The brain is merely the organ that interprets the pain, not the tissue that generates it.
This has a direct clinical corollary. During neurosurgery, only the scalp, skull, and meninges require local anaesthetic; incision into the brain itself produces no pain sensation. The patient remains conscious because the surgical target is insensate.
The Painless Pain-Interpreter
The same principle governs migraine. The attack triggers the release of neuropeptides from trigeminal nerve endings in the meninges, producing inflammation and vasodilation. The pain signal travels centrally, but its source is extracerebral. Therefore, migraine pain is not “in the brain” in the sense of arising from brain tissue; it is in the brain only in the sense of being perceived there.
This distinction matters therapeutically. A drug that crosses the blood-brain barrier and acts on neurons is not necessarily acting at the site of pain generation. Triptans, for instance, exert their effect peripherally on meningeal vessels and trigeminal terminals, not on the cortex itself. The fact that the brain feels no pain is precisely why peripheral agents can be effective.
Dampening the Signal
The therapeutic aim is to make the meningeal nociceptors less excitable. In practice, that means reducing CGRP signalling, limiting neurogenic inflammation, and preventing meningeal vasodilation.
Why vasodilation matters
There is not a second, separate pain source. Vasodilation is part of the same peripheral trigger: dilated cranial vessels increase tension in the surrounding dura mater, which stretches nearby meningeal nociceptors. The effect is mechanical (physical stretch or tension) and chemical (local signalling molecules make the nerves easier to fire), not one nociceptor physically pressing on another.
They also promote local mediator release, which makes those endings easier to excite. The pain is then amplified centrally in the brainstem, thalamus, and cortex. So the vessel change helps create and sustain the signal, while the brain helps interpret and magnify it.
Triptans do this indirectly by suppressing CGRP release and constricting cranial vessels. Gepants block the CGRP receptor directly. Preventive therapy lowers the baseline excitability of the pathway so that the signal never reaches the threshold for pain.