The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater

Abstract

1We describe the actions of GR43175, a 5-hydroxytryptamine1 (5-HT,)-like receptor agonist, on neurogenically-mediated plasma protein extravasation within an important pain-sensitive intracranial tissue, the dura mater. 2 GR43175 markedly attenuated extravasation of '25I-albumin from blood vessels within ipsilateral dura mater when administered to rats (100 pgkg-1) fifteen minutes before unilateral electrical trigeminal stimulation (1.2 mA, 5Hz, Sims, S min.); the ratio (stimulated/unstimulated sides) decreased from 1.81 to 1.23, P < 0.005).3 GR43175 (l00pgkg-1, i.v., rats; 30pgkg-, i.v., guinea-pigs) decreased the leakage of radiolabelled albumin from 163% to 119% (P < 0.005, guinea-pig) or from 174 to 118% (P < 0.05, rat) above vehicletreated controls when injected ten minutes before systemic capsaicin treatment (0.5 or 1 umol kg-1, i.v.).4 GR43175 (30-300pgkg-1) did not block plasma protein extravasation within extracranial tissues of rats and guinea-pigs innervated by the trigeminal nerve (conjunctiva, eyelid and lip).5 The protein leakage which followed the i.v. administration of 5-HT (1 ymol kg 1) or neuropeptides which mediate neurogenic plasma extravasation, substance P (0.3 nmol kg-1 or 1 nmol kg 1) and neurokinin A (1 nmol kg-'), was not blocked by GR43175 (100, 300pgkg-1) despite the presence of leakage in amounts equivalent to that following neurogenic stimulation.6 GR43175 (l00gkg-1) decreased bradykinin (1Opmolkg-')-induced extravasation from 142 to 115% above vehicle-treated animals (P < 0.05). 7 These results demonstrate an important action of GR43175 on neurogenic mechanisms in dural blood vessels. Since the ergot alkaloids possess a similar profile of drug activity, it is suggested that drugs useful in the treatment of acute vascular headaches may share a similar mechanism of action.

Release of immunoreactive substance P in the brain stem upon stimulation of the cranial dura mater with low pH – inhibition by the serotonin (5‐HT1) receptor agonist CP 93,129

“…CP 93,129 at this dose signi®cantly reduced the neurogenic plasma extravasation in the dura mater encephali of the rat (Matsubara et al, 1991) which is known to depend on the activation of NK-1 receptors by substance P and (possibly) neurokinin A (Markowitz et al, 1987;Buzzi & Moskowitz, 1990). CP 93,129 at this dose also reduced the c-fos expression in the spinal trigeminal nucleus of the rat evoked by injection of autologous blood into the cisterna magna as a noxious stimulus (Nozaki et al, 1992).…”

Fisiopatologia da enxaqueca

“…Tal conclusão parece, porém, simplista. Existem receptores 5-HT 1D pré-juncionalmente, nas fibras trigeminais, cuja ativação resulta no bloqueio da inflamação neurogênica (Fig 2) 31 . Isto abre a interessante possibilidade do sumatriptan atuar na crise enxaquecosa por vias não relacionadas à vasoconstricção 32 .…”

Triptans in clinical practice: the basic scientist’s point of view

“…As an animal model of migraine, NI is induced in rat dura mater and other trigeminally innervated cephalic tissues, by either systemic administration of capsaicin (the pungent ingredient of hot pepper which is able to depolarize sensory fibers, or to abolish their functions when given to neonate animals) or by stimulating trigeminal sensory fibers by electrical stimuli [2]. Systemic administration of substance P is also able to induce tissue edema without direct involvement of sensory fibers [1].…”

“…Biochemical studies are therefore needed to better understand how triptans work and to design new abortive or preventive drugs. extracranial rat tissues [1], the experimental model for NI development has been used in the last decade to predict efficacy in aborting migraine pain of other compounds with activity on 5-HT1B/1D receptors. Briefly, NI represents vasodilatation and plasma protein extravasation that follows release of vasoactive peptides such as CGRP, SP and NKA from nerve endings upon activation of sensory fibers.…”