Differential effects of 5-HT1B/1D receptor agonists on neurogenic dural plasma extravasation and vasodilation in anaesthetized rats.
These studies compared the effects of the 5-HT1B/1D receptor agonists sumatriptan, CP-122 288 ((R)-N-methyl-[3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl] methanesulphonamide succinate) and CP-93 129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one dihydrochloride) on neurogenic dural extra-vasation and vasodilation in anaesthetized rats. Dural extravasation, evoked by high intensity (1.2 mA) stimulation of the trigeminal ganglion, was measured using the radioactive plasma marker 125I-labelled bovine serum albumin. Dural vasodilation produced by lower intensity (50-300 microA) stimulation of trigeminal fibres, was measured through a closed cranial window using intravital microscopy. All compounds inhibited dural extravasation (rank order of potency: CP-122 288 > > sumatriptan > CP-93 129) and dural vasodilation (rank order of potency: CP-93 129 > > sumatriptan = CP-122 288). Comparison of the potency of these compounds with their potencies in an in vitro functional model, agonist-induced [35S]GTP gamma S binding, suggests that blockade of dural extravasation was consistent with an action at rat 5-HT1D receptors, but activity at another, unknown, "extravasation receptor" could also be involved. In contrast, inhibition of dural vasodilation was consistent with an action at rat 5-HT1B receptors. We suggest that in our preparations, production of dural vasodilation involves activation of trigeminal A delta-fibres whereas production of dural extravasation involves activation of trigeminal C-fibres. The differential effects of compounds on dural extravasation and vasodilation may therefore be due to the different receptor subtypes involved and to the selective localization of these subtypes on different populations of trigeminal sensory fibre.
Shepherd
S L
SL
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K. sara_shepheard@merck.com
Williamson
D J
DJ
Beer
M S
MS
Hill
R G
RG
Hargreaves
R J
RJ
D000768:Anesthesia, General; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D004388:Dura Mater / Q000187:drug effects / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D001798:Blood Proteins; D011725:Pyridines; D011758:Pyrroles; D011759:Pyrrolidines; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; C085263:CP 122288; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018170:Sumatriptan