**2. Complex neurovascular interactions in primary headaches: migraine as a pathophysiological model**

Primary headaches share many similarities, primarily trigeminovascular activation. While migraine is the most studied of all primary headaches, from both a clinical and a preclinical perspective, there have been advances in our understanding of the pathophysiology of tension‐ type headache and the trigeminal autonomic cephalalgias, through a combination of clinical studies and preclinical animal models.

Migraine is a complex primary brain disorder that involves a cascade of events that lead to recurrent inappropriate activations of the trigeminocervical pain system. As any other pain, it is perceived differently by each patient. Conceived as an alarm system of the body, the pain may become, at some point, an aggressor factor of the own body by the reflex reactions that it can trigger. It is well known that the pain perception is dependent not only on the intensity of the stimulus, but also on a multitude of genetic, psychological associated factors (emotional state and attention), on anterior experiences, memories, associations with facts of life, and comorbidities. The stimulation of the nociceptors in teguments, vessels, and joints leads the stimulus on known sensitive paths toward the parietal cortex, but a series of regulating neural mechanisms intervene both at the cortical level and on the route of the stimulus, trying to adapt the perception of the pain sensation to the individual body homeostasis. Which are those structures and whether they can be influenced represent the concern of scientists for decades.

The meningeal vessels have a motor and sensitive innervation by the trigeminal terminations (ophthalmic branches for the anterior and posterior compartment, the cervical C2, C3 nerve roots, with sympathetic fibers from the paravertebral sympathetic chain‐contributing for the posterior part), which, in the end, establish connections with the secondary trigeminal neurons from the caudal trigeminal nucleus. Trigeminal nucleus is made up of the spinal portion in the converging information about pain and temperature and the pontine region with tactile information. The dendrites of the bipolar neurons from Gasser ganglia receive input from the pain receptors of dura mater and craniofacial structures, but also from the vascular wall and they direct it to trigeminal nucleus, thalamus, and contralateral parietal cortex (and in the same time collateral projections also target mesencephalic nuclei), including the dorsal reticular nucleus (DRt), the rostral ventral medulla (RVM), and the midbrain periaqueductal gray (PAG) [12–14].

The motor component of the cerebrovascular system implies an extrinsic innervation of the meningeal vessels, from the cervical (sympathetical), otic, sphenopalatin, and trigeminal ganglia (parasympathetical) and an intrinsic innervation for the small intraparenchimatous vessels, derived from brain stem nuclei such as locus coeruleus [15].

Cerebral blood flow (CBF) is regulated by vasomotor, chemical, metabolic, and neurogenic mechanisms, but under normal physiological conditions neurogenic control has little influence on cerebral autoregulation as other methods of control are dominant [16].

There is considerable experimental literature to document that stimulation of trigeminal afferents can result in cranial autonomic outflow, the trigeminal–autonomic reflex.

From the time of the stimulation of the nociceptive endings until the perception of the pain sensation, the transmission of the signal is modified by a series of mechanisms with the final aim of improving the painful sensation.
