P.J. Goadsby

Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides

External jugular vein blood was sampled in the anesthetized cat during electrical stimulation of the superior sagittal sinus (SSS), and the levels of calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), substance P (SP) and neuropeptide Y (NPY) were measured with sensitive radioimmunoassays. CGRP levels rose by 85% and VIP levels by 300% while there was no change in SP or NPY levels in the same samples. These data provide the first evidence that activation of the trigeminovascular system, by selective stimulation of nociceptive craniovascular afferents, causes releases of vasodilator peptides and further implicates this system in the pathophysiology of migraine.

Brainstem Influences on the Cephalic Circulation: Experimental Data From Cat and Monkey of Relevance to the Mechanism of Migraine

SYNOPSIS

Neuropeptides in Migraine and Cluster Headache

The cerebral circulation is invested by a rich network of neuropeptide Y (NPY) and noradrenaline containing sympathetic nerve fibers in arteries, arterioles and veins. However, the nerve supply of vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) containing fibers is sparse. While noradrenaline and NPY cause vasoconstriction, VIP, SP and CGRP are potent vasodilators. Stimulation of the trigeminal ganglion in cat and man elicits release of SP and CGRP. Subjects with spontaneous attacks of migraine show release of CGRP in parallel with headache. Cluster headache patients have release of CGRP and VIP during bouts. Treatment with sumatriptan aborts headache in migraine and cluster headache as well as the concomitant peptide release.

Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation.

Electrical stimulation at 1-200/s of the locus coeruleus in 12 Macaca nemestrina monkeys caused a frequency-dependent drop in vascular resistance in the extracerebral circulation which was twice as great on the side stimulated. Accompanying this dilatation of the extracerebral vasculature was a frequency-dependent rise in internal carotid vascular resistance, usually seen only on the side ipsilateral to stimulation. This constrictor response was maximal at low frequencies of stimulation and minimal at higher frequencies. Neither the dilator nor constrictor responses were affected by sectioning of the vagus nerve or sympathetic trunk in the neck. The simultaneous occurrence of intracranial vasoconstriction and extracranial vasodilatation has not been demonstrated previously, and bears a remarkable resemblance to the vascular changes of migraine.

PACAP, a VIP-like Peptide: Immunohistochemical Localization and Effect upon Cat Pial Arteries and Cerebral Blood Flow

Pituitary adenylate cyclase activating peptide (PACAP) is a vasoactive intestinal polypeptide (VIP)–like peptide recently isolated from ovine hypothalami. Nerve fibers containing PACAP immunoreactivity were present in the adventitia and the adventitia-media border of cat cerebral arteries. Double immunostaining revealed that PACAP-immunoreactive nerve fibers constituted a sub-population of the VIP-containing fibers. PACAP effected a concentration-dependent relaxation of feline middle cerebral arteries that had been precontracted with prostaglandin F2α. The maximum relaxation, 24 and 34% of precontraction, was achieved with PACAP-38 and PACAP-27, respectively, at a concentration of 10−6 M. In cats anesthetized with α-chloralose, intracerebral microinjection of PACAP effected a moderate increase in cerebral blood flow. The maximal increase (18.6 ± 6%) was observed following the injection of 5 μg PACAP.

Oral sumatriptan in acute migraine

The efficacy in acute migraine of oral sumatriptan was assessed in a double-blind, randomised, placebo-controlled, crossover study of 61 patients (mean age 39 [SD 10] years). 41 completed treatment of four attacks, two with sumatriptan 100 mg and two with placebo. The response rate (reduction in headache from moderate or severe to mild or absent at 2 h) was 51% (45/89) with sumatriptan and 10% (9/93) with placebo (p less than 0.01); rescue medication was needed at 2 h in 41% and 88%, respectively. Of 28 patients headache-free at 24 h, 11 (39%) had recurrent headache within 24 h. There were no substantial side-effects. Thus, sumatriptan is an effective well-tolerated treatment for acute migraine attacks.

Neuropeptides in the cerebral circulation: relevance to headache

The article briefly describes the innervation of the human cerebral circulation by nerve fibers containing neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gent-related peptide (CGRP). The neuropeptides in human cerebral arteries were characterized by radioimmunoassay in combination with HPLC. These neuropeptides mediate contraction (NPY) and dilatation (VIP, SP, CGRP). In conjunction with spontaneous attacks of migraine or cluster headache, release of CGRP is seen. With the associated symptoms of nasal congestion and rhinorrhea, VIP is released. Successful treatment may abort the peptide release in parallel with disappearance of headache.

Extracranial vasodilatation mediated by vasoactive intestinal polypeptide (VIP)

Pooled antisera to vasoactive intestinal polypeptide were used to block neurogenic extracranial vasodilatation elicited from either brainstem (locus coeruleus) or pterygopalatine ganglion stimulation in the cat. Vasodilatation was not inhibited by sham immune sera, or by antisera to bradykinin or substance P. The efferent pathway for vasodilatation from the locus coeruleus traverses the facial nerve (greater superficial petrosal branch) and the pterygopalatine and otic ganglia. Its blockade demonstrates a novel action of a peptide transmitter in the expression of a central neurogenic response.

Comparative effects of stimulation of the trigeminal ganglion and the superior sagittal sinus on cerebral blood flow and evoked potentials in the cat

The superior sagittal sinus (SSS) and the trigeminal ganglion (Vg) of anesthetized cats were stimulated electrically and field potentials in the upper cervical spinal cord and regional cerebral blood flow were recorded. Stimulation of the entire ganglion produced smaller field potential changes in two regions (medioventral area (MVA); dorsolateral area (DLA] of the upper spinal cord than did stimulation of the sagittal sinus (Vg/SSS response ratio = 17% for the MVA and 48% for the DLA). Stimulation of the trigeminal ganglion increased blood flow in only the frontal and parietal cortices (+93% and +33%), whereas stimulation of the sinus produced both larger changes in these areas (+137% and +139%) and also produced changes in regional cerebral blood flow in the thalamus (+122%).

Stimulation of the Trigeminal ganglion increases flow in the extracerebral but not the cerebral circulation of the monkey

The trigeminal ganglion of 9 anesthetized paralysed artificially ventilated Macaca nemestrina monkeys was electrically stimulated with frequencies varying from 0.2 to 200 Hz. This stimulation led to a frequency-dependent decrease in external carotid resistance but no significant change in internal carotid resistance was recorded. The response is probably mediated as previously described in the cat, i.e. predominantly through the greater superficial petrosal branch of the facial nerve and a small proportion through antidromic activation of the trigeminal system. Elucidation of the physiological and pharmacological mechanisms underlying such a response may aid in a better understanding of the pathophysiology of vascular headache.