The understanding of the pathophysiology of migraine is advancing rapidly. The current state of knowledge suggests that a primary neuronal dysfunction leads to a sequence of changes intracranially and extracranially that account for migraine, including the four phases of premonitory symptoms, aura, headache, and postdrome. The once popular vascular theory of migraine, which suggested that migraine headache was caused by the dilatation of blood vessels, while the aura of migraine resulted from vasoconstriction, is no longer considered viable. Vasodilatation, if it occurs at all during spontaneous migraine attacks, is probably an epiphenomenon resulting from instability in the central neurovascular control mechanism.

Migraine and headache both seem to be linked to cortical spreading depression. Cortical spreading depression is a self-propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex. This phenomenon is hypothesized to cause the aura of migraine, activate trigeminal nerve afferents and alter blood-brain barrier permeability by activating and upregulating matrix metalloproteinase. The activation of the trigeminal afferents causes inflammatory changes in the pain-sensitive meninges that generate the headache of migraine through central and peripheral reflex mechanisms. The likely molecular cascade of events by which pain sensitive trigeminal afferent neurons are activated by cortical spreading depression involves the opening of neuronal pannexin-1 megachannels and subsequent activation of caspase-1, followed by the release of the proinflammatory mediators, activation of nuclear factor kappa-B in astrocytes, and transduction of the inflammatory signal to trigeminal nerve fibers around pial vessels.

This way it can be explained that cortical spreading depression is linked to prolonged activation of trigeminal nociception which generates the pain in migraine headaches. It has been suggested that migraine without aura may be caused by the occurrence of cortical spreading depression in areas of the brain (eg, cerebellum) where depolarization is not consciously perceived.

The pathophysiology of migraine involves activation of the trigeminovascular system, which consists of small caliber pseudounipolar sensory neurons that originate from the trigeminal ganglion and upper cervical dorsal roots. Stimulation of the trigeminal ganglion results in release of vasoactive neuropeptides, including substance P, calcitonin gene-related peptide, and neurokinin A. Release of these neuropeptides is associated with the process of neurogenic inflammation. The two main components of this sterile inflammatory response are vasodilation (calcitonin gene-related peptide is a potent vasodilator) and plasma protein extravasation. Neurogenic inflammation is thought to be important in the prolongation and intensification of the pain of migraine. Elevated levels of vasoactive neuropeptides have been found in the cerebrospinal fluid of patients with chronic migraine, suggesting chronic activation of the trigeminovascular system in these patients. Neurogenic inflammation may lead to the process of sensitization.

Sensitization refers to the process in which neurons become increasingly responsive to nociceptive and non-nociceptive stimulation: response thresholds decrease, response magnitude increases, receptive fields expand, and spontaneous neuronal activity develops. Peripheral sensitization in the primary afferent neurons and central sensitization within second order neurons in the trigeminal nucleus caudalis and higher order neurons in the central nervous system are thought to play a role within individual migraine attacks and, perhaps, even in the transformation of episodic migraine to chronic migraine. Sensitization is likely responsible for many of the clinical symptoms of migraine, including the throbbing quality of the pain, the worsening of pain with coughing, bending, or sudden head movements (as is often observed during the postdrome), hyperalgesia (increased sensitivity to painful stimuli), and allodynia (pain produced by normally non-noxious stimulation).

The calcitonin gene-related peptide (CGRP) may also play a role in migraine pathophysiology. CGRP is a 37 amino acid neuropeptide that is expressed in trigeminal ganglia nerves and is a potent vasodilator of cerebral and dural vessels. CGRP may mediate trigeminovascular pain transmission from intracranial vessels to the central nervous system, as well as the vasodilatory component of neurogenic inflammation.