The innervation of the cranial vessels by the trigeminal nerve, the trigeminovascular system, has recently been the subject of study in view of its possible role in the mediation of some aspects of migraine. Since stimulation of the trigeminal ganglion in humans leads to facial pain and flushing and associated release of powerful neuropeptide vasodilator substances, their local release into the extracerebral circulation of humans was determined in patients who had either common or classic migraine. Venous blood was sampled from both the external jugular and cubital fossa ipsilateral to the side of headache. Plasma levels of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide were determined using sensitive radioimmunoassays for each peptide, and values for the cubital fossa and external jugular and a control population were compared. A substantial elevation of the calcitonin gene-related peptide level in the external jugular but not the cubital fossa blood was seen in both classic and common migraine. The increase seen in classic migraine was greater than that seen with common migraine. The other peptides measured were unaltered. This finding may have importance in the pathophysiology of migraine.

Both clinical and physiological consideration of migraine suggests that the pathophysiology of the syndrome is intimately linked to the trigeminal innervation of the cranial vessels, the trigeminovascular system. Studies were conducted in cats and humans to examine the interaction of these systems with the effective acute antimigraine drugs dihydroergotamine and sumatriptan. In the animal studies cats were anesthetized and prepared for routine physiological monitoring as well as for blood sampling from the external jugular veins. Cerebral blood flow was monitored continuously using laser Doppler flowmetry and the effect of trigeminal ganglion stimulation on both cerebral blood flow and jugular vein peptide levels determined prior to and after administration of either sumatriptan or dihydroergotamine. Stimulation of the trigeminal ganglion led to a frequency-dependent increase in cerebral blood flow, with a mean maximum of 43 +/- 9% at a stimulus frequency of 20 per second. There was a marked reduction in these responses by some 50% after administration of either sumatriptan or dihydroergotamine. Trigeminal ganglion stimulation at a frequency of 5 per second also led to a release into the cranial circulation of calcitonin gene-related peptide (CGRP), with the level rising from 67 +/- 3 to 82 +/- 5 pmol/liter on the side of stimulation. These increases were also markedly antagonized by both sumatriptan and dihydroergotamine. Human studies were conducted as part of the overall evaluation of sumatriptan for the treatment of acute migraine. In 7 of 8 patients responding to subcutaneous sumatriptan administration, elevated CGRP levels (60 +/- 8 pmol/liter) were normalized, with the headache being relieved (40 +/- 8 pmol/liter).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of migraine is on the cusp of a new era with the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are expected to receive approval for use in migraine headache in 2018 and 2019. CGRP-related therapies offer considerable improvements over existing drugs as they are the first to be designed specifically to act on the trigeminal pain system, they are more specific and they seem to have few or no adverse effects. CGRP receptor antagonists such as ubrogepant are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) effectively prevent migraine attacks. As these drugs come into clinical use, we provide an overview of knowledge that has led to successful development of these drugs. We describe the biology of CGRP signalling, summarize key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatment, and synthesize what is known about the role of CGRP in the trigeminovascular system. Finally, we consider how the latest findings provide new insight into the central role of the trigeminal ganglion in the pathophysiology of migraine.

Cluster headache is a rare very severe disorder that is clinically well characterized with a relatively poorly understood pathophysiology. In this study patients with episodic cluster headache fulfilling the criteria of the International Headache Society were examined during an acute spontaneous attack of headache to determine the local cranial release of neuropeptides. Blood was sampled from the external jugular vein ipsilateral to the pain before and after treatment of the attack. Samples were assayed for calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), substance P and neuropeptide Y. Attacks were treated with either oxygen inhalation, sumatriptan or an opiate. Thirteen patients were studied of whom 10 were male and three female. All had well-established typical attacks of cluster headache when blood was sampled. During the attacks external jugular vein blood levels of CGRP and VIP were raised while there was no change in neuropeptide Y or substance P. Calcitonin gene-related peptide levels rose to 110 +/- 7 pmol/l (normal: < 40) while VIP levels rose to 20 +/- 3 pmol/l (normal: < 7). Treatment with both oxygen and subcutaneous sumatriptan reduced the CGRP level to normal, while opiate administration did not alter the peptide levels. These data demonstrate for the first time in vivo human evidence for activation of the trigeminovascular system and the cranial parasympathetic nervous system in an acute attack of cluster headache. Furthermore, it is shown that both oxygen and sumatriptan abort the attacks and terminate activity in the trigeminovascular system.

The trigeminal ganglion was activated, in humans by thermocoagulation as part of the treatment of trigeminal neuralgia and in cats by electrical stimulation, and blood samples were taken from the external jugular vein for estimates of plasma levels of substance P and calcitonin gene-related peptide (CGRP). In those patients who were noted at the time of coagulation to have flushed there were marked elevations of the local (cranial) levels of both peptides. However, in the nonflushing patients no changes in the peptide levels were observed. Parallel experiments in the cat revealed that the levels of substance P-like and CGRP-like immunoreactivity were increased during electrical stimulation of the trigeminal ganglion. The observation of elevation of substance P-like and CGRP-like immunoreactivity after activation of the nociceptive afferent system of the head provides new insights into a putative role of peptides in the pathophysiology of migraine and cluster headache, and suggests new areas of possible therapeutic intervention.

Over the past 300 years, the migraine field has been dominated by two main theories-the vascular theory and the central neuronal theory. The success of vasoconstrictors such as ergotamine and the triptans in treating acute migraine bolstered the vascular theory, but evidence is now emerging that vasodilatation is neither necessary nor sufficient to induce a migraine attack. Attention is now turning to the core migraine circuits in the brain, which include the trigeminal ganglia, trigeminal nucleus, medullary modulatory regions, pons, periaqueductal gray matter, hypothalamus and thalamus. Migraine triggers are likely to reflect a disturbance in overall balance of the circuits involved in the modulation of sensory activity, particularly those with relevance to the head. In this Review, we consider the evidence pointing towards a neuronal mechanism in migraine development, highlighting the role of calcitonin gene-related peptide (CGRP), which is found in small to medium-sized neurons in the trigeminal ganglion. CGRP is released during migraine attacks and can trigger migraine in patients, and CGRP receptor antagonists can abort migraine. We also examine whether other drugs, such as triptans, might exert their antimigraine effects via their actions on the neuronal circuit as opposed to the intracranial vasculature.

"Differential distribution of calcitonin gene-related peptide (CGRP) and CGRP receptor components (CLR and RAMP1) in the human trigeminal ganglion."Neuroscience, 2010, Jun 2 http://dx.doi.org/10.1016/j.neuroscience.2010.05.016Access to the published version may require journal subscription.Published with permission from: Elsevier Antibodies against purified CLR and RAMP1 proteins were produced and characterized for this study. Trigeminal ganglia were obtained at autopsy from adult subjects and sections from rat trigeminal ganglia were used to compare the immunostaining pattern. The number of cells expressing CGRP, CLR and RAMP1, respectively, were counted. In addition, the glial cells of trigeminal ganglion, particularly the satellite glial cell, were studied to understand a possible relation.We observed immunoreactivity for CGRP, CLR and RAMP1, in the human trigeminal ganglion: 49% of the neurons expressed CGRP, 37% CLR and 36% RAMP1. Co-localization of CGRP and the receptor components was rarely found. There were no CGRP immunoreactions in the glial cells; however some of the glial cells displayed CLR and RAMP1 immunoreactivity. Similar results were observed in rat trigeminal ganglia.We report that human and rat trigeminal neurons store CGRP, CLR and RAMP1, however, CGRP and CLR/RAMP1 do not co-localize regularly but are found in separate neurons. Glial cells also contain the CGRP receptor components but not CGRP. Our results indicate, for the first time, the possibility of CGRP signaling in the human trigeminal ganglion involving both neurons and satellite glial cells. This suggests a possible site of action for the novel CGRP receptor antagonists in migraine therapy.

Distribution studies disclosed that all major cerebral arteries and cortical arterioles of the cat were invested with fme varicose nerve fibers that contained calcitonin generelated peptide (CGRP)-like immunoreactivity; the trigeminal ganglia likewise contained CGRP immunoreactivity. Sequential immunostaining with antibodies to CGRP and to substance P (SP) revealed identical distributions of these two peptides in trigeminal ganglia and cerebrovascular nerve fibers, suggesting that CGRP and SP are colocalized in these nerves. CGRP completely disappeared from ipsilateral blood vessels after unilateral section of the trigeminal nerve. Exogenous CGRP was a potent relaxant of feline middle cerebral arteries in vitro (maximum relaxation, 10.5 ± 1.5 mN; concentration eliciting half-maximal response, 9.6 ± 1.3 nM). Perivascular microapplication of CGRP to individual cortical arterioles of chloralose-anesthetized cats provoked dose-dependent dilatations (maximum increase in diameter, 38 ± 5%; concentration eliciting half-maximal response, '-3 nM). CGRP was signifiw cantly more potent than SP as a cerebrovascular dilator, both in vitro and in situ. Chronic division of the ipsilateral trigeminal nerve in cats did not modify the magnitude of arteriolar responses to perivascular microapplication of either vasoconstrictor or vasodilator agents, but the duration of vasoconstrictor responses to norepinephrine (0.1 mM) or alkaline solutions (pH 7.6) was significantly increased. The cerebrovascular trigeminal neuronal system, in which CGRP is the most potent vasoactive constituent, may participate in a reflex or local response to excessive cerebral vasoconstriction that restores normal vascular diameter.Local cerebral blood flow is normally adjusted to meet local demands for energy generation that is almost exclusively met by the oxidative catabolism of glucose. The vasoactive products of cellular metabolism, with perivascular hydrogen ions, potassium ions, and adenosine being the most favored candidates, have long been considered primarily responsible for this dynamic regulation of cerebral blood flow (1). Cerebral blood vessels are, however, invested by nerve fibers that contain diverse neurotransmitters [norepinephrine, acetylcholine, 5-hydroxytryptamine, vasoactive intestinal polypeptide, peptide histidine isoleucine, neuropeptide Y, substance P (SP) and such]. Although these agents have direct vasomotor effects upon cerebral blood vessels, the explicit function of any of these perivascular neuronal systems in cerebrovascular regulation remains obscure (2, 3).The neuropeptide, calcitonin gene-related peptide (CGRP), has recently been identified from structural analysis of the products of calcitonin gene expression. Alternative processing of RNA transcribed from the calcitonin gene leads to the production, in neuronal tissue, of a 37-amino acid peptide, CGRP (4,5). CGRP-like immunoreactivity is present in many regions of the central nervous system (most notably the spinal cord, medullary and pontine nuclei, amygdala, a...