Spreading Depression Triggers Headache by Activating Neuronal Panx1 Channels

TLDR

The initial phase of migraine development is poorly understood, yet a pathway that alarms the organism with headache when neurons are stressed may exist. The study aims to describe a novel signaling pathway linking stressed neurons to trigeminal afferents during cortical spreading depression, a putative trigger of migraine aura and headache. CSD induces neuronal Pannexin1 megachannel opening, caspase‑1 activation, HMGB1 release, and NF‑κB activation in astrocytes, which may sustain trigeminal afferent activation through parenchymal inflammatory cascades reaching the glia limitans. Inhibiting this cascade eliminated CSD‑induced trigeminovascular activation, dural mast cell degranulation, and headache.

Abstract

The initial phase in the development of a migraine is still poorly understood. Here, we describe a previously unknown signaling pathway between stressed neurons and trigeminal afferents during cortical spreading depression (CSD), the putative cause of migraine aura and headache. CSD caused neuronal Pannexin1 (Panx1) megachannel opening and caspase-1 activation followed by high-mobility group box 1 (HMGB1) release from neurons and nuclear factor κB activation in astrocytes. Suppression of this cascade abolished CSD-induced trigeminovascular activation, dural mast cell degranulation, and headache. CSD-induced neuronal megachannel opening may promote sustained activation of trigeminal afferents via parenchymal inflammatory cascades reaching glia limitans. This pathway may function to alarm an organism with headache when neurons are stressed.