Migraine as an inflammatory disorder

Inflammation is a localized response designed to protect tissues against infection, injury, or disease. The inflammatory response acts to destroy, dilute, or wall off (sequester) both the injurious agent and the injured area. The production and release of chemical agents by cells in the affected tissue result in the four well-known signs of Celsus: pain (dolor), heat (calor), redness (rubor), and swelling (tumor), to which Galen later added loss of function (functio laesa). Histologically, inflammation is characterized by a complex series of events. These include the following: dilatation of arterioles, capillaries, and venules, with increased permeability and blood flow; exudation of fluids, including plasma proteins; and leukocyte migration into the inflammatory focus.

Although pain and inflammation usually go hand in hand, migraine has not classically been considered an inflammatory disease, possibly because it is not obviously associated with heat, redness, and swelling. Instead, a vascular etiology was proposed on the basis of a report that ergotamine tartrate alleviates pain and reduces the amplitude of temporal artery pulsation in migraineurs,¹ a small but significantly increased risk for strokes,² association with vascular malformations,³ and genetic disorders such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).⁴ For most of the twentieth century, the prevailing theory of migraine held that pain results from an abnormal dilatation of intracranial blood vessels, leading to mechanical excitation of sensory fibers that innervate these vessels. This “vascular” theory, however, has never been validated. No differences in blood flow velocity exist in vertebral and middle cerebral arteries during and outside migraine attacks,⁵ and a consistent relationship between vessel caliber, cerebral blood flow, and headache has not been established.⁶

In recent years, accumulating evidence has shifted the emphasis away from vascular smooth muscle and toward mechanisms related to inflammation within cephalic …