John W. Duckworth

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

SYNOPSIS

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%).

Low frequency stimulation of the locus coeruleus reduces regional cerebral blood flow in the spinalized cat

Regional cerebral blood flow (RCBF) was studied during low frequency (15/s) and high frequency (50/s) electrical stimulation of the locus coeruleus (LC) in the alpha-chloralose-anesthetized cat using the freely diffusible tracer [14C]iodoantipyrine and regional brain dissection. The responses were determined in animals spinalized at the C1/C2 level to eliminate systemic effects of pontine stimulation such as alterations in blood pressure and heart rate. The spinalization, itself, did not alter resting RCBF or reactivity to hypercapnia. Low frequency stimulation reduced regional cerebral blood flow in the cortex, basal ganglia and white matter of the corpus callosum. The reductions in RCBF were maximal (35%) in the occipital cortex whereas no changes were seen in the colliculi. No changes were seen in any brain areas with high frequency stimulation. The relevance of this brainstem effect on cerebral blood flow to pathological states such as stroke and migraine is discussed.

The Anatomy and Physiology of the Vertebral Nerve in Relation to Cervical Migraine

The anatomy of the vertebral nerve was investigated in humans and in monkeys. The effect of stimulation of the vertebral nerve and the cervical sympathetic trunk in the monkey was studied. The vertebral nerves in man and monkey represent a series of deep grey rami communicantes which form intersegmental neural arcades around the vertebral artery between C7 and C3. Above C3 the vertebral artery is accompanied by direct branches from the C1–3 ventral rami. Electrical stimulation of either the vertebral nerve or the cervical sympathetic trunk had a minimal effect on vertebral blood flow. In contrast, sympathetic stimulation had pronounced effects on carotid flow and resistance. Anatomically and physiologically there are no grounds to support the hypothesis that irritation of the “vertebral nerve” is the pathogenetic mechanism of cervical migraine.

Internal and external carotid vascular responses to vasoactive agents in the monkey

Internal and external carotid blood flows in anesthetized monkeys were measured simultaneously using electromagnetic flowmeters. Complete dose-response relationships were established for the effects of intracarotid infusion of several humoral agents implicated in migraine. Both the internal and external carotid vasculatures were constricted by serotonin and prostaglandin F2 α and dilated by bradykinin, histamine, and acetylcholine. Noradrenalin and adrenaline constricted the external carotid vasculature but had little direct effect in the internal carotid territory. Prostaglandin E1 dilated the external carotid vasculature. Low doses of prostaglandin E1 produced dilation in the internal carotid circulation, but with higher doses there was a paradoxical abolition of this effect.

Effects of methyserrgide, pizotifen and ergotamine in the monkey cranial circulation

Internal and external carotid vascular resistances were measured, in anaesthetized monkeys, to asses the direct cranial vascular effects of i.v. methysergide, pizotifen and ergotamine, and their effects on the cranial vascular responses to the constrictors 5-hydroxytryptamine and noradrenaline and the dilators histamine, prostaglandin E1 and bradykinin. Methysergide reduced responses to 5-HT, and tended to potentiate the external carotid responses to noradrenaline. Pizotifen blocked responses to histamine; it tended to reduce internal carotid responses to 5-HT, but it potentiated external carotid 5-HT responses. Ergotamine reduced responses to 5-HT and noradrenaline, but this was probably related to its cranial vasoconstrictor effects, especially in the external carotid circulation. Methysergide induced weak transient cranial vasoconstriction and pizotifen had no direct effects. These findings may be relevant to the therapeutic actions of these drugs in migraine, since the doses used approximated to those used clinically.

Complement and immune complex studies in migraine.

SYNOPSIS

Low pharmacological responsiveness of the vertebro-basilar circulation in Macaca nemestrina monkeys.

We have examined the responsiveness of the vertebro-basilar circulation of the anesthetized Macaca nemestrina monkey to vasoactive agents infused directly into the artery. Infusion of noradrenaline caused a slight increase in vertebral arterial resistance. This constriction was less than that seen in previous experiments with either the internal or vertebral arterial resistance. This constriction was less than that seen in previous experiments with either the internal or external carotid arteries. In the presence of vasodilatation caused by inhalation of a CO2-rich gas mixture, this constriction became a dilatation. Serotonin was without significant effect on the vertebral arterial bed. Bradykinin, histamine and prostaglandin E1 all produced slight dilatation, with bradykinin being the most potent. In all cases the concentration required to produce an effect on the vasculature was much greater in the vertebral circulation than it is in the internal carotid and extracerebral circulations. We conclude that the intact vertebro-basilar circulation is much less sensitive to vasoactive agents than experiments with isolated segments of these arteries would indicate and that therefore these agents are unlikely to play a significant part in the pathogenesis of vertebro-basilar migraine.

EFFECTS OF HISTAMINE H1 AND H2-RECEPTOR ANTAGONISTS IN THE CRANIAL CIRCULATION OF THE MONKEY

1. The effects of the histamine H2‐receptor antagonists, metiamide and cimetidine, and the Hi‐receptor antagonist, mepyramine, on cranial vasodilator and systemic vasodepressor responses to histamine have been investigated in anaesthetized monkeys.

Effects of low doses of clonidine in the monkey cranial circulation.

Migraine therapy using low doses of clonidine has been based on the proposal that clonidine directly inhibits vascular smooth muscle reactivity. In anaesthetized monkeys in which internal and external carotid vascular resistances were measured, the only significant effects of clonidine administered acutely (0.5 and 2 microgram x kg-1 i.v.) or chronically (2 microgram x kg-1 i.m. daily for 7 days) on cranial vascular responses to the constrictors noradrenaline and 5-hydroxytryptamine, and the dilators histamine, prostaglandin E1 and bradykinin, were small potentiations of some of the responses. Acute clonidine initially increased blood pressure and constricted the cranial vasculature, then induced hypotension without involvement of the cranial circulation. It also decreased the external carotid vasoconstrictor response to low frequency cervical sympathetic nerve stimulation. The low chronic dose of clonidine had no hypotensive effect. The pressor response to common carotid occlusion was inhibited by both acute and chronic clonidine. These experiments thus provide no evidence that clonidine inhibits cranial vascular reactivity at doses equivalent to those used in migraine.