Inflammation in Migraine…or Not…: A Critical Evaluation of the Evidence

Andrew Charles MD; Sinifunanya E. Nwaobi MD, PhD; Peter Goadsby MD, PhD


Headache. 2021;61(10):1575-1578. 

In This Article

What do we Mean by Inflammation?

In the context of migraine, the term inflammation is currently used in three ways. The first is "traditional" inflammation, which is still reasonably characterized by four principal signs described by Celsus in the first century: rubor (redness), calor (heat), tumor (swelling), and dolor (pain). Loss of function may be included as an additional symptom of acute or chronic inflammation. A wide variety of molecular, chemical, and cellular mediators of inflammation have been identified including cytokines, eicosanoids, histamine, and bradykinin, among others. Cellular mediators of traditional inflammation include leukocytes, mast cells, and cells of injured tissues.

"Neurogenic inflammation" describes the release of neuropeptides and other inflammatory mediators from peripheral nerves. The functional consequences of neurogenic inflammation are increased vascular permeability and vasodilation. The neurogenic inflammation response is mediated primarily by substance P, whereas calcitonin gene-related peptide (CGRP) may facilitate associated vasodilation while not being primarily "inflammatory."

A more recently defined third type of inflammation is "neuroinflammation." This term has been used variably but generally describes localized changes in cellular gene expression and in some cases morphology in neural tissue in the setting of injury or insult. These changes have been described particularly in glial cells, and molecular or histological markers of "glial cell activation" are commonly reported as evidence of neuroinflammation. Neuroinflammation may also include increased vascular permeability, leukocyte infiltration, and increased production and release of cytokines.

One source of confusion regarding the potential role of inflammation in migraine is ambiguity regarding what can reasonably be described as inflammation. Does release of a single "inflammatory" peptide or cytokine qualify as inflammation, or should a coordinated chemical and cellular change be required? For example, is CGRP release alone sufficient to indicate inflammation? Is pain alone a sufficient symptomatic indicator, or should an increase in vascular permeability or vasodilation be required? To address these questions, it is helpful to consider the evidence.