Introduction likely that they are due to release of nitric oxide NO

Brain Research 887 2000 203–210 www.elsevier.com locate bres Interactive report 1 Activation of trigeminovascular neurons by glyceryl trinitrate Geoffrey Andrew Lambert , Cathy Donaldson, Peter Michael Boers, Alessandro Stefano Zagami Institute of Neurological Sciences , The Prince Henry and Prince of Wales Hospitals, University of New South Wales, Little Bay NSW 2036, Australia Accepted 12 September 2000 Abstract The effect of intra-carotid arterial infusions of glyceryl trinitrate GTN, a substance known to precipitate headache, including migraine, upon the spontaneous activity of trigeminal neurons with craniovascular input was studied in cats. Second-order craniovascular neurons which received sensory input from the superior sagittal sinus were recorded in the trigeminal nucleus caudalis. Infusions of GTN were administered via a catheter inserted retrogradely into the common carotid artery through the lingual artery. Infusions of GTN 100 mg 21 21 21 kg min in a volume of 2 ml min increased the mean basal discharge rate of all second-order neurons to 239647 of control. GTN produced a fall in mean blood pressure, but there was no correlation between this fall and the changes in discharge rate. GTN infusions sensitised neurons to the effects of electrical stimulation of the superior sagittal sinus, but not to subsequent GTN infusions. Infusions of similar volumes of vehicle did not alter the discharge rate of neurons. We conclude that GTN activates craniovascular sensory pathways at a site at, or peripheral to, the second-order neuron and that such an action may account for at least the acute-onset headache induced by GTN.  2000 Elsevier Science B.V. All rights reserved. Theme : Sensory systems Topic : Pain modulation: pharmacology Keywords : Glyceryl trinitrate; Trigeminal; Vascular headache

1. Introduction likely that they are due to release of nitric oxide NO

from the GTN donor molecules. Glyceryl trinitrate GTN, nitroglycerin was first syn- Glyceryl trinitrate administration leads to an immediate thesised in 1846 by Sobrero who immediately observed throbbing headache in nearly all subjects [12,19]. In that it produced a ‘migraine’ when he tasted it [29]. It was susceptible subjects, GTN reliably triggers a cluster head- used as a homeopathic remedy for headache two years ache like pain [4]. In migraineurs, it also produces a later [7] and for angina and hypertension later in the delayed headache highly reminiscent of the spontaneous nineteenth century [19]. Alfred Nobel observed that work- migraine headaches which these people suffer. These ers in dynamite factories where the active principal, effects have been attributed to a selective action of GTN nitroglycerin, was incorporated into the explosive, suffered on extracranial and intracranial blood vessels, principally from chronic migraine-like headaches at work and angina- the dural arteries and large penetrating cerebral arteries, like problems on their vacations [19]. The therapeutic and mainly through the formation of NO [22]. It is tempting to side effects were thought to be due to the nitrate [20], as assume that the immediate headache is a consequence of they were shared by other organic nitrates [23], but it is the vasodilator action of GTN, but both it and the delayed headache might be due to an effect of GTN or NO on neuronal function [32]. In 1993, Olesen and co-workers demonstrated that the immediate headache induced by 1 Published on the World Wide Web on 7 November 2000. GTN could be ameliorated by prior subcutaneous injection Corresponding author. Room 136, Clinical Sciences Building, Prince of the antimigraine drug sumatriptan, which also reduced Henry Hospital, Little Bay NSW 2036, Australia. Tel.: 161-2-9382-5728; the frequency of the delayed headache [11]. In rats, fax: 161-2-9382-5127. E-mail address : g.lambertunsw.edu.au G.A. Lambert. intravenous administration of GTN leads to increased 0006-8993 00 – see front matter  2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 9 1 9 - X 204 G expression of c-fos, a marker for neuronal activation, in the supramaximal square-wave shocks 150 V, 250 ms trigeminal nucleus caudalis and several other brain nuclei duration, 0.3 Hz with a Grass S88 stimulator. [31]. This activation was suppressed by the intraperitoneal The central tungsten wire of a glass-coated tungsten administration of the non-steroidal anti-inflammatory drug electrode [18] was used to record single unit activity in the indomethacin [33], which is effective in migraine [2]. trigeminal nucleus caudalis. The electrode was placed on GTN-induced expression of c-fos in the caudal trigemi- the dorsal surface of the brainstem, 1.5–3 mm caudal to nal nucleus does not however demonstrate unequivocally the obex and 2.5–4.5 mm lateral to the midline, and whether GTN specifically activates those neurons respon- advanced to a depth of up to 2500 mm below the surface sible for dural or cerebrovascular pain processing, synaptic by means of a piezoelectric microdrive. Single unit activity activation is only inferred. The experiments we describe was amplified, filtered and displayed on an oscilloscope. here were carried out to determine whether GTN adminis- Peri-stimulus and post-stimulus histograms were compiled tered into the carotid artery of cats can produce activation and used for post-experiment analysis of the latency and of neurons which also process sensory information from firing frequency of single units. the dura. Neurons were located first by the presence of a response to the search stimulus-electrical stimulation of skin or superior sagittal sinus. Some units were tested for the presence of a cutaneous receptive field. The skin and hair

2. Materials and methods of the face were examined systematically with a variety of