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.
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 micrograms kg-1) and the 5HT1D receptor agonist sumatriptan (1-1000 micrograms kg-1) reduced dural plasma extravasation dose-dependently with ID50S of 52 micrograms kg-1 and 30 micrograms kg-1 respectively. CP-99,994 (1000 micrograms 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 micrograms 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.
Shepheard
S L
SL
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
Williamson
D J
DJ
Williams
J
J
Hill
R G
RG
Hargreaves
R J
RJ
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D004388:Dura Mater / Q000187:drug effects / Q000378:metabolism*; D004558:Electric Stimulation; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D017403:In Situ Hybridization; D008297:Male; D015288:Neurokinin A / Q000037:antagonists & inhibitors*; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018170:Sumatriptan / Q000494:pharmacology*; D012668:Trigeminal Ganglion / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*
D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D012333:RNA, Messenger; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D015288:Neurokinin A; D018170:Sumatriptan