Meningeal Vasodilatation Research Articles

Role of pituitary adenylate cyclase-activating polypeptide in nociception and migraine.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are widely distributed at different levels of the pain-processing pathway. Its action at the peripheral sensory nerve terminals has been found to be divergent; it can exert both pro- and anti-nociceptive effects, depending on the mode of administration (local or systemic) and the mechanism of the pain process (acute or chronic, inflammatory or neuropathic). In the central nervous system it exerts mainly neuronal excitation, leading to increased nociceptive signalling. Since the clinical data strongly suggest the involvement of PACAP in the pathophysiology of migraine, special emphasis is placed on examinations of its role and the mechanisms of activation of the trigeminovascular system. The intravenous administration of PACAP to migraineurs induces migraine-like headache and extracranial arterial dilatation. Furthermore, an increased PACAP concentration has been detected in the peripheral blood of patients during a migraine attack. Animal experiments have also revealed that PACAP elicits peripheral and central sensitization of the neuronal elements of the trigeminovascular system and evokes meningeal vasodilatation. This review summarizes data relating to the expression of PACAP and its receptors, and the main effects and mechanisms in the nociceptive pathways, with special emphasis on migraine. It is clear that PACAP plays an excitatory role in migraine, but its target and signalling pathways have not yet been elucidated due to the lack of non-peptide, selective agonists and antagonists. Identification of its up- and downstream regulations and receptorial molecular mechanisms might open up future perspectives for the development of novel analgesic drugs.

Intraganglionic signaling as a novel nasal-meningeal pathway for TRPA1-dependent trigeminovascular activation by inhaled environmental irritants.

Headache is the most common symptom associated with air pollution, but little is understood about the underlying mechanism. Nasal administration of environmental irritants activates the trigeminovascular system by a TRPA1-dependent process. This report addresses questions about the anatomical pathway involved and the function of TRP channels in this pathway. TRPV1 and TRPA1 are frequently co-localized and interact to modulate function in sensory neurons. We demonstrate here that resiniferatoxin ablation of TRPV1 expressing neurons significantly reduces meningeal blood flow responses to nasal administration of both TRPV1 and TRPA1 agonists. Accordingly resiniferatoxin also significantly reduces TRPV1 and CGRP immunostaining and TRPV1 and TRPA1 message levels in trigeminal ganglia. Sensory neurons of the trigeminal ganglia innervate the nasal epithelium and the meninges, but the mechanism and anatomical route by which nasal administration evokes meningeal vasodilatation is unclear. Double retrograde labeling from the nose and meninges reveals no co-localization of fluorescent label, however nasal and meningeal labeled cells are located in close proximity to each other within the trigeminal ganglion. Our data demonstrate that TRPV1 expressing neurons are important for TRPA1 responses in the nasal-meningeal pathway. Our data also suggest that the nasal-meningeal pathway is not primarily by axon reflex, but may instead result from intraganglionic transmission.

Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel

Although feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene-related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously that are known to trigger migraine or cluster headache attacks, such as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew’s antimigraine effect derives from its ability to target TRPA1. We found that parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, parthenolide desensitizes the TRPA1 channel and renders peptidergic TRPA1-expressing nerve terminals unresponsive to any stimulus. This effect of parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by parthenolide inhibits CGRP release from trigeminal neurons and CGRP-mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of parthenolide.

The ‘headache tree’ via umbellulone and TRPA1 activates the trigeminovascular system

The California bay laurel or Umbellularia californica (Hook. & Arn.) Nutt., is known as the 'headache tree' because the inhalation of its vapours can cause severe headache crises. However, the underlying mechanism of the headache precipitating properties of Umbellularia californica is unknown. The monoterpene ketone umbellulone, the major volatile constituent of the leaves of Umbellularia californica, has irritating properties, and is a reactive molecule that rapidly binds thiols. Thus, we hypothesized that umbellulone stimulates the transient receptor potential ankyrin 1 channel in a subset of peptidergic, nocioceptive neurons, activating the trigeminovascular system via this mechanism. Umbellulone, from µM to sub-mM concentrations, selectively stimulated transient receptor potential ankyrin 1-expressing HEK293 cells and rat trigeminal ganglion neurons, but not untransfected cells or neurons in the presence of the selective transient receptor potential ankyrin 1 antagonist, HC-030031. Umbellulone evoked a calcium-dependent release of calcitonin gene-related peptide from rodent trigeminal nerve terminals in the dura mater. In wild-type mice, umbellulone elicited excitation of trigeminal neurons and released calcitonin gene-related peptide from sensory nerve terminals. These two responses were absent in transient receptor potential ankyrin 1 deficient mice. Umbellulone caused nocioceptive behaviour after stimulation of trigeminal nerve terminals in wild-type, but not transient receptor potential ankyrin 1 deficient mice. Intranasal application or intravenous injection of umbellulone increased rat meningeal blood flow in a dose-dependent manner; a response selectively inhibited by systemic administration of transient receptor potential ankyrin 1 or calcitonin gene-related peptide receptor antagonists. These data indicate that umbellulone activates, through a transient receptor potential ankyrin 1-dependent mechanism, the trigeminovascular system, thereby causing nocioceptive responses and calcitonin gene-related peptide release. Pharmacokinetics of umbellulone, given by either intravenous or intranasal administration, suggest that transient receptor potential ankyrin 1 stimulation, which eventually results in meningeal vasodilatation, may be produced via two different pathways, depending on the dose. Transient receptor potential ankyrin 1 activation may either be caused directly by umbellulone, which diffuses from the nasal mucosa to perivascular nerve terminals in meningeal vessels, or by stimulation of trigeminal endings within the nasal mucosa and activation of reflex pathways. Transient receptor potential ankyrin 1 activation represents a plausible mechanism for Umbellularia californica-induced headache. Present data also strengthen the hypothesis that a series of agents, including chlorine, cigarette smoke, formaldehyde and others that are known to be headache triggers and recently identified as transient receptor potential ankyrin 1 agonists, utilize the activation of this channel on trigeminal nerves to produce head pain.

Pituitary adenylate cyclase-activating polypeptide plays a key role in nitroglycerol-induced trigeminovascular activation in mice

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors (PAC1, VPAC) are present in sensory neurons and vascular smooth muscle. PACAP infusion was found to trigger migraine-like headache in humans and we showed its central pro-nociceptive function in several mouse pain models. Nitroglycerol (NTG)-induced pathophysiological changes were investigated in this study in PACAP gene-deleted (PACAP−/−) and wildtype (PACAP+/+) mice. Chemical activation of the trigeminovascular system was induced by 10mg/kg i.p. NTG. Light-aversive behavior was determined in a light–dark box, meningeal microcirculation by laser Doppler blood perfusion scanning and the early neuronal activation marker c-Fos with immunohistochemistry. NTG-induced photophobia both in the early (0–30min) and late phases (90–120min) due to direct vasodilation and trigeminal sensitization, respectively, was significantly reduced in PACAP−/− mice. Meningeal blood flow increased by 30–35% during 4h in PACAP+/+ mice, but only a 5–10% elevation occurred from the second hour in PACAP−/− ones. The number of c-Fos expressing cells referring to neuronal activation in the trigeminal ganglia and nucleus caudalis significantly increased 4h after NTG in PACAP+/+, but not in PACAP−/− animals. Similar PAC1 receptor immunostaining was detected in both groups, which did not change 4h after NTG treatment. PACAP-38 (300μg/kg, i.p.) produced photophobia similarly to NTG and 30% meningeal vasodilatation for 30min in PACAP+/+, but not in PACAP−/− mice. It significantly increased neural activation 4h later in the trigeminal ganglia of both groups, but in the nucleus caudalis of only the PACAP+/+ mice.We provide the first experimental results that PACAP is a pivotal mediator of trigeminovascular activation/sensitization and meningeal vasodilation related to migraine.

Pituitary Adenylate Cyclase-Activating Polypeptide plays an important role in nitroglycerol-induced trigeminovascular activation in mice

Event Abstract Back to Event Pituitary Adenylate Cyclase-Activating Polypeptide plays an important role in nitroglycerol-induced trigeminovascular activation in mice A. Markovics1*, A. Lashgarara1, E. Szőke1, K. Sándor1, B. Tuka2, V. Kormos1, J. Tajti2, J. Szolcsányi1, B. Gaszner3, D. Reglődi3, H. Hashimoto4 and Z. Helyes1 1 University of Pécs, Department of Pharmacology and Pharmacotherapy, Hungary 2 University of Szeged, Department of Neurology, Hungary 3 University of Pécs, Department of Anatomy, Hungary 4 Osaka University, Graduate School of Pharmaceutical Sciences, Japan Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its receptors are present in sensory neurones and vascular smooth muscle. Its infusion triggers migraine-like headache in humans. Therefore, we aimed at examining the effects of PACAP in nitroglycerol (NG)-induced light-aversive behavior, meningeal vasodilatation and c-Fos expression in the trigeminal nucleus and ganglia using gene-deleted mice (PACAP-/-). Significantly reduced light-aversive behaviour was detected in the modified light-dark box in PACAP-/- mice both in the early phase (0-30 min) due to the acute vasodilating effect of NG (10 mg/kg i.p.) and in the late phase (90-120 min) when the trigeminal system is sensitized. NG produced significant (30-35%) biphasic increase of meningeal blood flow measured by laser Doppler imaging in anaesthesized mice with a second peak starting 170 minutes after its injection. In contrast, in PACAP-/- mice NG did not alter microcirculation in the first 2 h-period and exerted only a minor increase later. Exogenous PACAP (300 mg/kg i.p.) produced 30% meningeal flow increase. C-Fos expression in the trigeminal ganglia and nucleus caudalis was also significantly smaller in PACAP-/- mice. PACAP has both direct and indirect vasodilating effects on the brain surface, and also activates the trigeminovascular system involved in migraine. Exploration of its mechanism and targets might open interesting future perspectives in novel anti-migraine therapy. Keywords: Neurophysiology, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Neurophysiology Citation: Markovics A, Lashgarara A, Szőke E, Sándor K, Tuka B, Kormos V, Tajti J, Szolcsányi J, Gaszner B, Reglődi D, Hashimoto H and Helyes Z (2011). Pituitary Adenylate Cyclase-Activating Polypeptide plays an important role in nitroglycerol-induced trigeminovascular activation in mice. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00174 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. A. Markovics, University of Pécs, Department of Pharmacology and Pharmacotherapy, Pécs, Hungary, adri.markovics@yahoo.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers A. Markovics A. Lashgarara E. Szőke K. Sándor B. Tuka V. Kormos J. Tajti J. Szolcsányi B. Gaszner D. Reglődi H. Hashimoto Z. Helyes Google A. Markovics A. Lashgarara E. Szőke K. Sándor B. Tuka V. Kormos J. Tajti J. Szolcsányi B. Gaszner D. Reglődi H. Hashimoto Z. Helyes Google Scholar A. Markovics A. Lashgarara E. Szőke K. Sándor B. Tuka V. Kormos J. Tajti J. Szolcsányi B. Gaszner D. Reglődi H. Hashimoto Z. Helyes PubMed A. Markovics A. Lashgarara E. Szőke K. Sándor B. Tuka V. Kormos J. Tajti J. Szolcsányi B. Gaszner D. Reglődi H. Hashimoto Z. Helyes Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation

The TRPA1 receptor is a member of the transient receptor potential (TRP) family of ion channels expressed in nociceptive neurons. TRPA1 receptors are targeted by pungent compounds from mustard and garlic and environmental irritants such as formaldehyde and acrolein. Ingestion or inhalation of these chemical agents causes irritation and burning in the nasal and oral mucosa and respiratory lining. Headaches have been widely reported to be induced by inhalation of environmental irritants, but it is unclear how these agents produce headache. Stimulation of trigeminal neurons releases CGRP and substance P and induces neurogenic inflammation associated with the pain of migraine. Here we test the hypothesis that activation of TRPA1 receptors is the mechanistic link between environmental irritants and peptide-mediated neurogenic inflammation. Known TRPA1 agonists and environmental irritants stimulate CGRP release from dissociated rat trigeminal ganglia neurons and this release is blocked by a selective TRPA1 antagonist, HC-030031. Further, TRPA1 agonists and environmental irritants increase meningeal blood flow following intranasal administration. Prior dural application of the CGRP antagonist, CGRP8–37, or intranasal or dural administration of HC-030031, blocks the increases in blood flow elicited by environmental irritants. Together these results demonstrate that TRPA1 receptor activation by environmental irritants stimulates CGRP release and increases cerebral blood flow. We suggest that these events contribute to headache associated with environmental irritants.

Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study

Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study

Reply to: Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3T magnetic resonance angiography study

Reply to: Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3T magnetic resonance angiography study

Cerebral or meningeal vasodilatation does not occur during migraine headaches

Cerebral or meningeal vasodilatation does not occur during migraine headaches

Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study

Migraine headache is widely believed to be associated with cerebral or meningeal vasodilatation. Human evidence for this hypothesis is lacking. 3 Tesla magnetic resonance angiography (3T MRA) allows for repetitive, non-invasive, sensitive assessment of intracranial vasodilatation and blood flow. Nitroglycerine (NTG) can faithfully induce migraine attacks facilitating pathophysiological studies in migraine. Migraineurs (n = 32) randomly received NTG (IV 0.5 microg/kg/min for 20 min; n = 27) or placebo (n = 5; for blinding reasons). Using 3T MRA, we measured: (i) blood flow in the basilar (BA) and internal carotid arteries (ICA) and (ii) diameters of the middle meningeal, external carotid, ICA, middle cerebral, BA and posterior cerebral arteries at three timepoints: (a) at baseline, outside an attack; (b) during infusion of NTG or placebo and (c) during a provoked attack or, if no attack had occurred, at 6 h after infusion. Migraine headache was provoked in 20/27 (74%) migraineurs who received NTG, but in none of the five patients who received placebo. The headache occurred between 1.5 h and 5.5 h after infusion and was unilateral in 18/20 (90%) responders. During NTG (but not placebo) infusion, there was a transient 6.7-30.3% vasodilatation (P < 0.01) of all blood vessels. During migraine, blood vessel diameters were no different from baseline, nor between headache and non-headache sides. There were no changes in BA and ICA blood flow during either NTG infusion or migraine. In contrast to widespread belief, migraine attacks are not associated with vasodilatation of cerebral or meningeal blood vessels. Future anti-migraine drugs may not require vasoconstrictor action.

Loss of capsaicin-induced meningeal neurogenic sensory vasodilatation in diabetic rats

Neuropathic alterations of sensory nerves involved in the mediation of neurogenic inflammation of the meninges may contribute to the increased incidence of headaches in diabetics. In the rat, activation of capsaicin-sensitive nociceptors, which express the transient receptor potential vanilloid type 1 (TRPV1) receptor, induces meningeal vasodilatation, a significant component of neurogenic inflammation, through the release of calcitonin gene-related peptide (CGRP). This study examines the effects of streptozotocin-induced diabetes on TRPV1 receptor-mediated neurogenic sensory vasodilatation, CGRP release and nerve fiber density in the rat dura mater. In a cranial window preparation, epidural application of capsaicin (10 −7 M) produced distinct vasodilatory responses in control animals as measured by laser Doppler flowmetry. In diabetic rats, capsaicin-induced vasodilatation was reduced or even abolished 6, but not 2 or 4 weeks after diabetes induction. In contrast, vasoconstriction, a non-neurogenic response to capsaicin at a higher concentration (10 −5 M), was not altered in diabetic rats. The vasodilatory effects of histamine (10 −5 M), acetylcholine (10 −4 M) and CGRP (10 −5 M) were similar in control, diabetic and insulin-treated diabetic animals. In diabetic rats, a significant decrease in the capsaicin-evoked release of CGRP and reduction in the density of TRPV1-immunoreactive (IR) nerves were demonstrated. Treatment of the diabetic rats with insulin restored both the vasodilatory response and the capsaicin-induced CGRP release toward control values. In conclusion, this study revealed a marked impairment of meningeal TRPV1-IR nerves in streptozotocin diabetic rats by showing reduced neurogenic sensory vasodilatation, decreased capsaicin-evoked CGRP release and reduction in the number of TRPV1-IR nerve fibers of the dura mater. The findings suggest that capsaicin-sensitive afferents may play an important role in meningeal nociceptor function and their dysfunction, e.g. due to a limited removal of inflammatory mediators and/or tissue metabolites from the meningeal tissue, may contribute to the enhanced incidence of headaches in diabetics.

Calcitonin gene–related peptide does not excite or sensitize meningeal nociceptors: Implications for the pathophysiology of migraine

Migraine is among the most common types of pain, but its mechanisms are poorly understood. A growing body of evidence points to a critical role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine headache. During migraine, CGRP is thought to be released from peripheral endings of perivascular meningeal nociceptors primary and to promote vasodilatation. A current hypothesis suggests that peripheral CGRP and its related meningeal vasodilatation results in activation and sensitization, leading to the generation of migraine headache. However, direct evidence supporting this idea is lacking. Here, using electrophysiological, extracellular, single-unit recording combined with laser-Doppler flowmetry measurements of dural blood flow (DBF), we examined whether CGRP and meningeal vasodilatation promote activation or sensitization of meningeal nociceptors. Changes in (DBF), ongoing discharge, and responsiveness to mechanical stimulation of the dura were studied after either topical administration or intravenous infusion of rat alpha-CGRP in anesthetized rats. Both topical and systemic administration of CGRP caused a significant increase in dural blood flow; however, neither method of CGRP administration resulted in activation or sensitization of meningeal nociceptors. The results of this study suggest that CGRP effects in the meninges, including meningeal vasodilatation, are not sufficient to activate or sensitize meningeal nociceptors.

Sensory nitrergic meningeal vasodilatation and non-nitrergic plasma extravasation in anaesthesized rats

The aim of the present study was to evaluate the role of nitric oxide (NO) of sensory neural origin in neurogenic inflammatory response in the trigeminovascular system. Antidromic vasodilatation and plasma extravasation in response to electrical stimulation (15 V, 5 Hz, 0.5 ms, 100 impulses) of the trigeminal ganglion were investigated in the dura mater and nasal mucosa/upper eyelid by laser Doppler flowmetry and [ 125I]-labelled bovine serum albumin, respectively. Electrical stimulation of the trigeminal ganglion of rats elicited a reproducible ipsilateral enhancement of both meningeal and nasal mucosal blood flow. N ω-nitro- l-arginine ( l-NNA; 4, 8, and 16 mg/kg, i.v.), a nonselective inhibitor of nitric oxide synthase (NOS), inhibited antidromic vasodilatation both in the dura mater (15.86±2.05%, 22.82±2.51%, and 36.28±4.37%) and nasal mucosa (35.46±8.57%, 58.72±9.2%, and 89.99±8.94%) in a dose-dependent manner. Specific inhibitors of neuronal NOS, 7-nitroindazole (7-NI; 20 mg/kg, i.v.) and 3-bromo-7-nitroindazole (3Br-7NI; 10 mg/kg, i.v.) were administered to assess the possible role of NO released from the trigeminal sensory fibres. The meningeal vasodilatation was inhibited by both 3Br-7NI and 7-NI (63.36±7.7% and 49±6.5%, respectively). The nasal hyperaemic response was also reduced by 3Br-7NI (78.26±8.7%). Plasma extravasation in the dura mater and upper eyelid evoked by electrical stimulation of the trigeminal ganglion (25 V, 5 Hz, 0,5 ms, 5 min), expressed as extravasation ratios (ERs) of the stimulated vs. nonstimulated sides, was 1.80±0.8 and 4.63±1.24, respectively. This neurogenic oedema formation was not inhibited by neither l-NNA nor 3Br-7NI. It is concluded that neural nitrergic mechanisms are involved in the meningeal vasodilatation evoked by electrical stimulation of the trigeminal ganglion.

MIGRAINE PATHOPHYSIOLOGY

MIGRAINE PATHOPHYSIOLOGY

Capsaicin-insensitive sensory-efferent meningeal vasodilatation evoked by electrical stimulation of trigeminal nerve fibres in the rat.

1. Antidromic vasodilatation and plasma extravasation to stimulation of the trigeminal ganglion or its perivascular meningeal fibres was investigated by laser-Doppler flowmetry and 125I-labelled bovin serum albumin in the dura mater and in exteroceptive areas (nasal mucosa, upper eyelid) of anaesthetized rats pretreated with guanethidine and pipecuronium. 2 Trigeminal stimulation at 5 Hz for 20 s elicited unilateral phasic vasodilatation in the dura and lasting response in the nasal mucosa. Resiniferatoxin (1-3 microg kg(-1) i.v.), topical (1%) or systemic capsaicin pretreatment (300 mg kg(-1) s.c. plus 1 mg kg(-1) i.v.) did not inhibit the meningeal responses but abolished or strongly inhibited the nasal responses. Administration of vinpocetine (3 mg kg(-1) i.v.) increased both basal blood flow and the dural vasodilatation to perivascular nerve stimulation. 3. Dural vasodilatation to trigeminal stimulation was not inhibited by the calcitonin gene-related peptide-1 receptor (CGRP-1) antagonist hCGRP8-37 (15 or 50 microg kg(-1) i.v), or the neurokinin-1 receptor antagonist RP 67580 (0.1 mg kg(-1) i.v.) although both antagonists inhibited the nasal response. Neither mucosal nor meningeal responses were inhibited by atropine (5 mg kg(-1) i.v.), hexamethonium (10 mg kg(-1) i.v.) or the vasoactive intestinal polypeptide (VIP) antagonist (p-chloro-D-Phe6-Leul7)VIP (20 microg kg(-1) i.v.). 4. Plasma extravasation in the dura and upper eyelid elicited by electrical stimulation of the trigeminal ganglion was almost completely abolished in rats pretreated with resiniferatoxin (3 microg kg(-1) i.v.). 5. It is concluded that in the rat meningeal vasodilatation evoked by stimulation of trigeminal fibres is mediated by capsaicin-insensitive primary afferents, while plasma extravasation in the dura and upper eyelid and the vasodilatation in the nasal mucosa are mediated by capsaicin-sensitive trigeminal fibres.