Fig. 1

Anatomy and PACAP-mediated cranial trigeminal-autonomic mechanisms mediating dural-trigeminovascular activation. Cranial autonomic symptoms are thought to be mediated, in part, by activation of the trigeminal-autonomic reflex; a reflex connection from the trigeminal nucleus caudalis (TNC; grey neuron), via the superior salivatory nucleus (SuS; green diamond), which provides an autonomic parasympathetic projection to the cranial vasculature. This is predominantly through the greater petrosal nerve (green neuron) and its relay with the sphenopalatine ganglion (SPG), but also via the facial (VIIth cranial) nerve (sky blue neuron). Descending projections from hypothalamic nuclei (red and yellow neurons) including the posterior (PH), paraventricular (PVN), lateral (LH), dorsomedial (DMH) and pre-optic hypothalamic nuclei (PON), to the TCC (red projections) and SuS (yellow projections) neurons, are thought to modulate and control both trigeminovascular nociceptive transmission (purple network of neurons) and parasympathetic (green) autonomic projections to the cranial vasculature that result indirectly or directly, respectively, in cranial autonomic symptoms ipsilateral to head pain. Cranial autonomic symptoms, and activation of the cranial autonomic projection, are thought to modulate or even trigger activation of dural neuro-inflammatory mechanisms, which mediate dural trigeminovascular activation resulting in headache in primary headache. Activation of preganglionic SuS neurons stimulates the release of various neurotransmitter (light blue dots), including PACAP-38, VIP, neuropeptide (NPY), acetylcholine (ACh), and nitric oxide (NO) from nerve terminals of postganglionic parasympathetic neurons in the SPG. Their release is thought to mediate meningeal vasodilation and dural mast cell degranulation (brown dots), the production of COX-1 from mast cells and COX-2 from macrophage, causing the local release of inflammatory mediators, together capable of activating pial and dural branches of the trigeminal nerve. The presence of mRNA and/or protein for VPAC1/2 and PAC1 receptors in human/rat middle meningeal arteries, trigeminal ganglia and trigeminal nucleus caudalis (TNC), and sphenopalatine ganglia (SPG), mast cells and macrophages, suggest PACAP signaling mechanisms are involved in mediating cranial autonomic symptoms, but also in mediating dural neuro-inflammatory mechanisms that contribute to dural trigeminovascular activation. CGRP, calcitonin gene-related peptide; SP, substance P; NKA, neurokinin A; VMH, ventromedial hypothalamus; SON, supra-optic nerve, TG, trigeminal ganglion, SCG, superior cervical ganglion, PAG, periaqueductal gray; LC, locus coeruleus; RVM, rostral ventromedial medulla