Fig. 2

CSD activates trigeminal nociceptors around pial and dural vessels as well as meningeal macrophages and dendritic cells within 6–20 min in rodents [17]. Mast cell degranulation also contributes to the sterile meningeal inflammatory response. These inflammatory cells are in close proximity to the meningeal nociceptor fibers (pial nociceptive fibers and their axon collaterals around dural vessels) and may contribute to sustained stimulation and sensitization of nociceptors after initial activation, causing hours to days lasting headache. Blood-brain barrier (BBB) impermeable drugs such as anti-CGRP antibodies and sumatriptan can reach dural nociceptors located outside the BBB unlike pial nociceptors under the pial membrane. This figure is produced using Servier Medical Art (http://www.servier.com)