New brain-to-nerve signaling mechanism reveals potential path to migraine pain

The rapid influx of cerebral spinal fluid (CSF) and protein solutes released during cortical spreading depression (CSD) in the brain activates neurons to trigger aural migraine headaches, according to a new mouse study. The findings identify a novel non-synaptic signaling mechanism between the brain and peripheral sensory system important for migraine. They also suggest potential pharmacological targets for treating the painful disorder. Migraine with aura, or an aural migraine, is a distinct headache disorder that can include sensory disturbances, such as hearing- or vision-related symptoms that precede onset of headache pain. During the aura phase, it is believed that waves of CSD are spontaneously triggered in the cerebral cortex or cerebellum, which, in turn, lead to activation of pain receptors (nociceptors) in the peripheral nervous system (PNS). Previous research has suggested that CSD events release small molecules through the CSF that activate sensory nerve endings in the external tissues of the CNS (central nervous system), “outside” of the blood-brain barrier. These nerve endings are not exposed to CSF. How pathological CSD events in the cortex trigger the activation of peripheral nociceptors outside the brain remains poorly understood. Using a combination of proteomic, histological, imaging, and functional approaches in a mouse model of classical migraine, Martin Rasmussen and colleagues identified a signaling pathway between the CNS and PNS at the trigeminal ganglion. Unlike more distal parts of the CNS, the proximal zone of the trigeminal ganglion lacks a tight nerve barrier, allowing CSF and the signaling molecules released during CSD events to enter and interact with trigeminal cells. Rasmussen et al. found that CSD alters 11% of the CSF proteome, with up-regulation of proteins that directly activate receptors in the trigeminal ganglion, including calcitonin gene-related peptide (CGRP). “Although this work provides some of the strongest data to date for a role of the glymphatic system in migraine, there is much to discover about the foundational role that fluid and solute transport play in neurobiological processes, suggesting that the journey toward understanding the role that glymphatic function and dysfunction play in a wide range of neurological and psychiatric conditions has only just begun,” write Andrew Russo and Jeffery Iliff in a related Perspective.