Comparison of the effects of sumatriptan and the NK1 antagonist CP-99,994 on plasma extravasation in dura mater and c-fos mRNA expression in trigeminal nucleus caudalis of rats

S. L. Shepheard, D. J. Williamson, J. Williams, R. G. Hill, R. J. Hargreaves

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Abstract

Dural plasma extravasation produced by electrical stimulation of the trigeminal ganglion was measured in rats and the concomitant expression of c-fos mRNA produced in the trigeminal nucleus caudalis (NtV) was measured using in situ hybridization techniques. The non-peptide NK1 receptor selective antagonist CP-99,994 (1-3000 μg kg-1) and the 5HT1D receptor agonist sumatriptan (1-1000 μg kg-1) reduced dural plasma extravasation dose-dependently with ID50s of 52 μg kg-1 and 30 μg kg-1 respectively. CP-99,994 (1000 μg kg-1), a compound known to have good brain penetration, decreased c-fos mRNA expression in the NtV by 37 ±7% without disruption of the blood brain barrier (BBB). Sumatriptan (1000 μg kg-1), known to be poorly brain penetrant, had no significant effect on c-fos mRNA expression in the NtV unless the BBB was disrupted by infusion of a hyperosmolar mannitol solution after which sumatriptan decreased c-fos mRNA expression by 65 ±11%. The results suggest that brain penetrant NK1 receptor antagonists may have anti-migraine effects peripherally through blockade of dural extravasation and centrally by inhibition of nociceptive pathways. Furthermore the data indicates that the anti-migraine action of sumatriptan must be predominantly peripherally mediated, be it via inhibition of plasma extravasation or direct vasoconstriction, since it had little effect on the activation of neurones in the NtV unless the BBB was disrupted.

Original languageEnglish (US)
Pages (from-to)255-261
Number of pages7
JournalNeuropharmacology
Volume34
Issue number3
DOIs
StatePublished - Mar 1995

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Keywords

  • 994
  • CP-99
  • c-fos mRNA
  • dural extravasation
  • migraine
  • sumatriptan

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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