COMPARISON OF THE EFFECTS OF SUMATRIPTAN AND THE NK1 ANTAGONIST CP-99,994 ON PLASMA EXTRAVASATION IN DURA-MATER AND C-FOS MESSENGER-RNA EXPRESSION IN TRIGEMINAL NUCLEUS CAUDALIS OF RATS

Dural plasma extravasation produced by electrical stimulation of the t rigeminal ganglion was measured in rats and the concomitant expression of c fos mRNA produced in the trigeminal nucleus caudalis (NtV) was m easured using in situ hybridization techniques. The non-peptide NK1 re ceptor selective antagonist CP-99,994 (1-3000 mu g kg(-1)) and the 5HT (1D) receptor agonist sumatriptan (1-1000 mu g kg(-1)) reduced dural p lasma extravasation dose-dependently with ID(50)s of 52 mu g kg(-1) an d 30 mu g kg(-1) respectively. CP-99,994 (1000 mu g kg(-1)), a compoun d known to have good brain penetration, decreased c-fos mRNA expressio n in the NtV by 37 +/- 7% without disruption of the blood brain barrie r (BBB). Sumatriptan (1000 mu g kg(-1)), known to be poorly brain pene trant, had no significant effect on c-fos mRNA expression in the NtV u nless the BBB was disrupted by infusion of a hyperosmolar mannitol sol ution after which sumatriptan decreased c-fos mRNA expression by 65 +/ - 11%. The results suggest that brain penetrant NK1 receptor antagonis ts may have anti-migraine effects peripherally through blockade of dur al extravasation and centrally by inhibition of nociceptive pathways. Furthermore the data indicates that the anti-migraine action of sumatr iptan must be predominantly peripherally mediated, be it via inhibitio n of plasma extravasation or direct vasoconstriction, since it had lit tle effect on the activation of neurones in the NtV unless the BBB was disrupted.