Fig. 2

Descending brainstem and cortical modulation of dural-trigeminovascular mechanisms in primary headache.  Descending projections from brainstem nuclei including the ventrolateral periaqueductal grey (vlPAG), locus coeruleus (LC) and raphe/rostral ventromedial medullary (RVM) nuclei provide modulation of noxious somatosensory dural-trigeminovascular inputs. Noxious peripheral inputs and central descending modulation are integrated within trigeminocervical (TCC) neurons, the net result of which is head pain, processed within the thalamocortical neurons. Either direct activation of preganglionic pontine superior salivatory nucleus neurons from descending hypothalamic projections, or via reflex activation of trigeminal-autonomic relay, leads to activation of the cranial parasympathetic projection, which can trigger or exacerbate the dural neuro-inflammatory cascade. Activation of cortical neurons within the somatosensory (S1) and insulae cortices, via cortical spreading depression, and direct descending projections, can also facilitate or inhibit dural-trigeminovascular responses within the TCC. In addition, CSD is thought to directly mediate a neuro-inflammatory response within the dural micro-environment to activate trigeminal primary afferent neurons that innervate the dural vasculature. CSD is proposed to activate headache by initiating a complex cascade where neurons open pannexin1 channels that activate caspase-1 and the release of pro-inflammatories such as HMGB1 and IL-1B. Following pro-IM release, NF-KB translates to the nucleus to induce COX2 and iNOS expression in astrocytes. The activated astrocytes release cytokines, prosanoids, and NO to the subarachnoid space and produce sustained activation of trigeminal nerve fibers. Trigeminal fiber collaterals produce a sterile dural inflammation that lead to mast cell degranulation and the trigeminoparasympathetic reflex causes a late and sustained medial meningeal artery dilation (see Fig. S6 in Katata et al. [79] for more details.). In the CSD rodent model, facial grimace assessments suggest the final step in the parenchymal signaling cascade outlined above produces headache