1 Calcitonin gene-related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists a-CGRP-(8-37) and BIBN4096BS. 2 Cats were anaesthetised with a-chloralose, and using halothane during surgical preparation. A craniotomy and C 1 /C 2 laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for microiontophoresis of test substances.3 Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25-30 Hz by microiontophoresis of L-glutamate (n ¼ 43 cells). 4 Microiontophoresis of a-CGRP excited seven of 17 tested neurons. 5 BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by L-glutamate, demonstrating a non-presynaptic site of action for CGRP. a-CGRP-(8-37) inhibited a similar proportion of units (five of nine cells). 6 Intravenous BIBN4096BS resulted in a dose-dependent inhibition of trigeminocervical SSS-evoked activity (ED 50 31 mg kg -1 ). The maximal effect observed within 30 min of administration. 7 The data suggest that there are non-presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache.

We conclude that central dopamine-containing neurons may play a role in modulating trigeminovascular nociception; these neurons offer an important target that will expand our understanding of migraine and may offer new directions for therapy.

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To facilitate understanding the action of antimigraine preventives the effect of topiramate on trigeminocervical activation in the cat was examined. Animals (n = 7) were anaesthetized and physiologically monitored. The superior sagittal sinus (SSS) was stimulated to produce a model of trigeminovascular nociceptive activation. Cumulative dose-response curves were constructed for the effect of topiramate at doses of 3, 5, 10, 30 and 50 mg/kg on SSS-evoked firing of trigeminocervical neurons. Topiramate reduced SSS evoked firing in a dose-dependent fashion. The maximum effect was seen over 30 min for the cohort taken together. At 3 mg/kg firing was reduced by 36 +/- 13% (mean +/- SEM) after 15 min. At 5 and 50 mg/kg firing was reduced by 59 +/- 6% and 65 +/- 14%, respectively, after 30 min. Inhibition of the trigeminocervical complex directly, or neurons that modulate sensory input, are plausible mechanisms for the action of preventives in migraine.

Migraine is a common and debilitating condition. Its treatment has received considerable attention in recent times with the introduction into clinical use of the 5HT1B/1D agonist sumatriptan. It is known from human studies that the intracranial blood vessels and dura mater are important pain-producing structures since mechanical or electrical stimulation of these vessels, such as the superior sagittal sinus, causes pain. We have developed a model of craniovascular pain by stimulating the superior sagittal sinus and monitoring trigeminal neuronal activity using electrophysiological techniques. Cats were anaesthetized with alpha-chloralose (60 mg/kg, intraperitoneally), paralysed (gallamine 6 mg/kg, intravenously) and ventilated. The superior sagittal sinus was accessed and isolated for electrical stimulation by a mid-line circular craniotomy. The region of the dorsal surface of C2 spinal cord was exposed by a laminectomy and an electrode placed for recording evoked activity from sinus stimulation and spontaneous activity of the same cells. The electrode was a custom-made seven barrel glass microelectrode with the central barrel containing a tungsten recording wire. Signals were amplified and monitored on-line using a custom-written sampling program. Cells were recorded that were activated by electrical stimulation of the sinus and were also spontaneously activated. Cells fired with latencies consistent with A delta and C fibres, generally firing three or four times per stimulus (0.3 Hz, 250 microseconds duration, 100 V) delivered to the sinus. Both evoked and spontaneous firing could be inhibited by iontophoresis of ergometrine (9/10 cells), sumatriptan (2/3 cells) and zolmitriptan (9/15 cells) but not by saline (3/10 cells). These data are the first demonstration of inhibition of second order trigeminal neurons by direct local application of 5HT1B/1D agonists. Although intravenous administration of these compounds has demonstrated inhibition of sinus evoked firing in previous studies, it is not possible using the intravenous route to be clear at which anatomical site inhibition is taking place, whereas microiontophoresis offers a clear locus of action. These data demonstrate that the second order trigeminal nucleus synapse in the brainstem and upper cervical cord is the most likely site of action for brain penetrant anti-migraine drugs of the 5HT1B/1D class.