Perivascular neurotransmitters: Regulation of cerebral blood flow and role in primary headaches

Abstract

In order to understand the nature of the relationship between cerebral blood flow (CBF) and primary headaches, we have conducted a literature review with particular emphasis on the role of perivascular neurotransmitters. Primary headaches are in general considered complex polygenic disorders (genetic and environmental influence) with pathophysiological neurovascular alterations. Identified candidate headache genes are associated with neuro- and gliogenesis, vascular development and diseases, and regulation of vascular tone. These findings support a role for the vasculature in primary headache disorders. Moreover, neuronal hyperexcitability and other abnormalities have been observed in primary headaches and related to changes in hemodynamic factors. In particular, this relates to migraine aura and spreading depression. During headache attacks, ganglia such as trigeminal and sphenopalatine (located outside the blood-brain barrier) are variably activated and sensitized which gives rise to vasoactive neurotransmitter release. Sympathetic, parasympathetic and sensory nerves to the cerebral vasculature are activated. During migraine attacks, altered CBF has been observed in brain regions such as the somatosensory cortex, brainstem and thalamus. In regulation of CBF, the individual roles of neurotransmitters are partly known, but much needs to be unraveled with respect to headache disorders.

Calcitonin gene-related peptide and disease activity in cluster headache

“…Higher PACAP38 levels in episodic CH patients in active phase compared to chronic patients could theoretically reflect marked parasympathetic activation, but as VIP was unchanged, this interpretation remains speculative. To notice, we found no correlation between hours since last attack and baseline VIP or PACAP38 levels, as would be expected given the short half-lives (min) of VIP and PACAP38 35 . Infusion of CGRP induced an increase in VIP, but not PACAP38, and development of an attack was associated with a decrease in VIP.…”

Serotonin and Neuropeptides in Blood From Episodic and Chronic Migraine and Cluster Headache Patients in Case‐Control and Case‐Crossover Settings: A Systematic Review and Meta‐Analysis

“…It would aid in (1) definition of subgroup strata, (2) characterization of factors needed in the definition and (3) calculation of correlations between signaling molecules. Correlations between signaling molecules might be important in the development of signaling molecule subgroup profiles since multiple studies only report a slight change 5 …”

“…Analyses of biomarkers in blood samples have previously been used to gather information about the nervous system 4 . The biological rationale behind identification of blood‐derived biomarkers in migraine and CH includes: (1) Sensitization and activation of ganglia during headache attacks in humans and hyperexcitable neurons in primary headache patients, 5 (2) electrical stimulation of trigeminal ganglia from rats potentially inducing neuropeptide release of, for example, calcitonin gene‐related peptide (CGRP), neurokinin A (NKA), pituitary adenylate cyclase‐activating peptide 38 (PACAP‐38), and substance P (SP) 6,7 and (3) perivascular nerve endings being identified on the cerebral vasculature and found to originate from uni‐ and bilateral ganglia 8‐10 . Observational case‐control and case‐crossover human studies have sought to explore signaling molecule levels in blood from migraine and CH headache patients – often focusing on 1 or 2 markers.…”

“…The results varied between studies and individuals 16‐18 . An in‐depth overview of the involvement of the signaling molecules in the primary headache pathophysiology can be found in our recent review, Frederiksen et al, 5 which created the foundation for the design of the current study.…”

Phase Contrast MRI Suggests an Internal Carotid Vascular Tone Alteration in Migraines

“…meninges. 4,5 Cortical spreading depression (CSD) is a slowly propagating depolarization of neurons and astrocytes leading to a loss of ion homeostasis, change in synaptic response, and an altered vascular response. This occurs in two steps: an increase followed by a decrease of cerebral blood flow (CBF).…”