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New Directions in Migraine Pathophysiology: The Glymphatic System and PACAP

Cuciureanu DI, Bistriceanu CE, Vulpoi GA, Constantinescu V, Blajuta DL, Nădejde AM, Antochi F, Roceanu AM

Life (Basel, Switzerland), 2026

Abstract

Migraine severely impacts the quality of life of young adults. During the past few years, many studies have been done regarding the pathophysiology of this condition. There has been intense debate regarding CGRP, but research is still underway about the glymphatic system and PACAP. This review provides an overview of the current literature in this area of migraine pathophysiology. The inflammatory mediators and neuropeptides that activate trigeminovascular pathways can be accumulated during migraine attacks as a result of a failure of glymphatic clearance. Neuroinflammation, CGRP, CSD, and sleep have all been linked to the glymphatic system and migraine. In this article, we also discuss the latest hypotheses regarding the PACAP pathway in the neurophysiology of migraine. Additionally, recent research suggests that glymphatic dysfunction could enhance PACAP-mediated signaling. This article will explore possible correlations between these mechanisms and migraine pathophysiology.

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