Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat.

Abstract

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.