Antidromic Vasodilatation Research Articles

Somatosensory regulation of resting muscle blood flow and physical therapy.

Somatosensory stimulation can affect skeletal muscle blood flow (MBF) at rest in anesthetized animals via pressor reflex response or antidromic and local vasodilation. Increase in MBF due to reflex pressor response occurs generally in the skeletal muscles of the entire body, while antidromic and local vasodilation are limited to the peripheral stimulation site. Since increased MBF improves several disorders (muscle stiffness, pain, etc.), it is reasonable to further explore the effective use of somatic stimulation in physical therapies, such as massage, acupuncture, anma, and shiatsu or acupressure, in treating skeletal muscle disorders.

Nociceptors in the skin: fire-raisers to be kept at bay?

Nociceptors in the skin: fire-raisers to be kept at bay?

Comments on the review article ‘Antidromic vasodilatation and the migraine mechanism’ by Geppetti et al. in the Journal of Headache and Pain 2012; 13:103–111

The authors reviewed the role of antidromic vasodilatation in migraine, and concluded that the weight of evidence shows that the concept of antidromic vasodilatation in migraine cannot be discarded [1]. Unfortunately they included references that they wrongly claimed mitigate against the concept, weakening their position unnecessarily. In the section entitled ‘Neurogenic vasodilatation in migraine’, they state that Graham and Wolff’s proposal that the headache phase of migraine is associated with dilatation of the superficial temporal artery, was subsequently challenged by failure to measure significant vasodilatation during migraine (a) using Doppler flowmetry [2], and (b) using magnetic resonance angiography [3]. In fact in neither of these studies were the terminal branches of the external carotid artery studied. Zwetsloot studied the only middle cerebral artery and not the extracranial vessels, and Schoonman studied the intracranial vessels, and the last 10 mm of the external carotid before it divides into its terminal branches. This section of the external carotid artery has never been implicated in migraine, and is therefore irrelevant in any discussion of Graham and Woolf’s proven theory. The authors also cite the ‘lack of correlation between the degree of vasodilatation and the severity of headache’ as possibly challenging Woolf’s theory. Both studies that they cite, however, were on headache induced in healthy volunteers [4, 5], and not in migraineurs. Graham and Woolf’s findings relate to the temporal arteries in migraineurs, and should not be compared to the findings in non-migraineurs. The conclusion of Geppetti et al. that the concept of antidromic vasodilatation is valid is strengthened when the incorrect references are removed from the equation.

Antidromic vasodilatation and the migraine mechanism

Despite the fact that an unprecedented series of new discoveries in neurochemistry, neuroimaging, genetics and clinical pharmacology accumulated over the last 20 years has significantly increased our current knowledge, the underlying mechanism of the migraine headache remains elusive. The present review article addresses, from early evidence that emerged at the end of the nineteenth century, the role of ‘antidromic vasodilatation’ as part of the more general phenomenon, currently defined as neurogenic inflammation, in the unique type of pain reported by patients suffering from migraine headaches. The present paper describes distinctive orthodromic and antidromic properties of a subset of somatosensory neurons, the vascular- and neurobiology of peptides contained in these neurons, and the clinical–pharmacological data obtained in recent investigations using provocation tests in experimental animals and human beings. Altogether, previous and recent data underscore that antidromic vasodilatation, originating from the activation of peptidergic somatosensory neurons, cannot yet be discarded as a major contributing mechanism of the throbbing head pain and hyperalgesia of migraine.

Tongue angioedema in vivo: Antagonist response of anti-inflammatory drugs

Introduction. The toxicity of Dieffenbachia picta, an ornamental plant, arises from its ability to cause painful edema of oral mucous membranes, buccal ulcerations, and tongue hypertrophy after chewing on the stem or contact with the sap. Objectives. We compared the anti-inflammatory effect of eugenol (2-methoxy-4-(2-propenyl)phenol) to different drugs, and investigated the role of oxalate crystals in the development of the inflammation reaction. Methods. Tongue edema in live mice were measured with a digital tachymeter, 2 h after topical application (0.1 mL) or tissue injection (0.05 mL) of D. picta sap. The mice were treated by intraperitoneal or topical application of drugs, 15 min after edema induction. Vascular permeability was quantified based on abdominal skin plasma extravasation of Evans blue dye in response to intradermal administration of D. picta sap. The proteolytic assay was carried out as previously described (Kunitz M. Crystalline soybean trypsin inhibitor. General properties. J Gen Physiol 1947; 30:291–310.). Results. Arachidonate cascade antagonists and eugenol showed anti-edematogenic effects. High doses of eugenol (50 μg/kg) and sodium cromoglycate (100 mg/kg), but not a combination of the two, inhibited plasma extravasations. The sap without crystals, its methanol extract, or the ethanol-washed crystals in saline-reconstituted solution did not reproduce the tongue edema seen with the original sap. Topical application of 10% sodium bicarbonate completely abolished the tongue edema. Conclusions. The inflammatory response induced by D. picta may be due to mechanical tissue damage resulting from the physical presence of calcium oxalate crystals. We were, however, unable to exclude the possibility of an insoluble toxicity present within the sap as an etiological agent. We realized that emergency treatment should also aim to inhibit antidromic vasodilation and axon reflex flare, reducing mastocyte degranulation and release of tachykinins from nerve endings. We speculate that eugenol showed better antiedematogenic results because it seems to function not only as a classic non-steroidal anti-inflammatory drug, but also as a local anesthetic, blocking neurotransmission in the damaged tissue.

Absence of reflex somato-parasympathetic vasodilatation in human dental pulp

The neural regulation of blood flow in tooth pulp has been demonstrated that there is: (1) sympathetic adrenergic vasoconstriction; (2) alpha-adrenergic vasodilatation; (3) sympathetic cholinergic vasoactive system; and (4) antidromic vasodilator mechanisms involving the sensory nerves, including axon reflex vasodilatation. However, it is yet to be conclusively established whether reflex parasympathetic vasodilatation occurs in the dental pulp, although there have been numerous reports of the existence of reflex parasympathetic vasodilatation in the submandibular gland, nasal mucosa, tongue, lip, and gingiva in various species.

Unlocking the secrets of skin blood flow

Unlocking the secrets of skin blood flow

Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy

Six patients with chronic pain, mechanical and thermal hyperalgesia/allodynia, and cutaneous vasodilatation starting distally in their extremities, were evaluated using clinical and neurophysiological methods and microneurography. Evidence of small-fiber polyneuropathy was documented in all, but the etiology remained cryptogenic in several. Different forms of hyperexcitability were detected by microneurography in both common polymodal and mechanically insensitive C nociceptors, which explain all the somatosensory abnormalities. Signs of hyperexcitability included reduced receptor threshold (accounting for mechanical and heat allodynias), spontaneous C nociceptor discharge (explaining spontaneous "burning" pain and antidromic vasodilatation), and multiplied nociceptor responses to stimulation (accounting for hyperalgesia). The clinical and electrophysiological profiles of these patients resemble the experimental syndrome evoked by application of capsaicin to the skin. This similarity, and the striking heat dependence of the spontaneous pain, suggest that a common feature may be altered expression or modulation of vanilloid 1 receptor, provoking abnormal nociceptor discharges.

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.

Functional Evaluation of the Perivascular Innervation of the Skin of the Extremities Using Laser Doppler Flowmetry

Examination of 30 healthy subjects and 132 patients with hand denervation syndrome who were aged 16 to 30 years demonstrated that laser Doppler flowmetry is a highly effective approach to both qualitative and quantitative characterization of the nervous regulation of the microvasculature and the perivascular innervation of the skin. To study the sympathetic adrenergic perivascular innervation, it is expedient to evaluate the ratio between the neurogenic tone of afferent microvessels at rest and the decrease in microcirculation during the vasoconstrictive breath-holding test. The sensory peptidergic component of control is evaluated by electric stimulation of nociceptive afferent nerves, which causes antidromic vasodilation. The results of the study demonstrate the possibility of both concordant and discordant changes in sympathetic vascular regulation and isolated predominance of functional activity of the sympathetic or sensory peptidergic components of perivascular innervation.

Reduction in parasympathetic reflex vasodilatation following stereotaxic ear-bar insertion: importance of reduced afferent input

As in our previous report, when cats were fitted with stereotaxic ear-bars ‘type A’ animals (26 out of 41) still exhibited a parasympathetic reflex lip blood flow (LBF) increase in response to lingual nerve stimulation, while in ‘type B’ animals (the remaining 15) it was greatly reduced or abolished. We compared (in both magnitude and in their sensitivity to hexamethonium, 10 mg/kg, i.v.) the LBF responses evoked by electrical stimulation of various sites within the reflex arc (lingual nerve, trigeminal ganglion, spinal trigeminal nucleus (Vsp)) in type A and type B animals to examine where the suppressive effect of ear-bar insertion might be exerted (using artificially ventilated, cervically vago-sympathectomized cats deeply anesthetized with α-chloralose and urethane). After ear-bar insertion: (a) in type A animals, stimulation of both lingual nerve and Vsp evoked a similar, hexamethonium-sensitive LBF increase; (b) in type B animals (in which lingual-nerve stimulation evoked no LBF increase), Vsp stimulation evoked a hexamethonium-sensitive LBF increase; (c) in both type A and type B animals, trigeminal ganglion stimulation consistently elicited an LBF increase (abolished by hexamethonium in type A, but reduced by only 50% in type B). These results suggest (i) that abolition of the lingual nerve-induced parasympathetic reflex vasodilatation by ear-bar insertion is due to reduced afferent traffic (in peripheral trigeminal or facial nerves) rather than to a damaged efferent output, and (ii) this effect in type B animals seems somehow to allow an antidromic (hexamethonium-insensitive) vasodilatation to occur on trigeminal ganglion stimulation.

Calcitonin gene-related peptide produces skeletal muscle and nerve vasodilation following antidromic stimulation of unmyelinated afferents in the dorsal root in rats

In anesthetized rats, the contribution of calcitonin gene-related peptide (CGRP) to antidromic vasodilation of skeletal muscle blood flow (MBF) and nerve blood flow (NBF) following electrical stimulation of afferents in the dorsal roots was investigated by measuring the biceps femoris MBF and sciatic NBF using laser Doppler flowmetry. Increases in MBF and NBF were observed following repetitive antidromic electrical stimulation of unmyelinated C fibers in the ipsilateral dorsal roots between the L3 and L5 segments and between the L3 and S1 segments, respectively, without significant changes in systemic arterial blood pressure. The increases occurred during and several minutes after the end of 10–30-s stimulation. The responses were totally abolished by topical application of hCGRP (8–37), a CGRP receptor antagonist. It is concluded that antidromic vasodilation in biceps femoris muscles and the sciatic nerve following stimulation of unmyelinated C afferents in the dorsal roots is independent of systemic blood pressure and is mediated essentially by CGRP. It is suggested that this CGRP-related antidromic vasodilation may be important in the clinical improvement of skeletal MBF and NBF produced by physical therapy, e.g. acupuncture.

Neurogenic inflammation. I. Basic mechanisms, physiology and pharmacology

Activation of sensory unmyelinated neurons by noxious stimuli evokes the release of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. These neuropeptides and subsequently released mediators cause a local oedema, hyperaemia and an erythema which extends beyond the site of stimulation (so-called flare response). Since these inflammatory signs depend on the function and integrity of peripheral sensory nervous systems, the response has been termed neurogenic inflammation. Due to the fact that nearly all tissues in mammals including humans are innervated by afferent sensory neurons, this neurogenic inflammation can occur ubiquitously throughout the body. Albeit first evidence showing that sensory neurons contribute to the inflammatory signs, described as antidromic vasodilatation, axon reflex, triple response, neurogenic inflammation, elicited at the level of tissue that they innervate was first obtained more than one hundred years ago, it was in the last two decades that inflammation caused by the release of neuropeptides from afferent nerve endings was recognised as a physiologically and pathologically relevant process. A large number of exogenous and endogenous substances and autacoids may stimulate or sensitise sensory nerve endings, thus simultaneously producing pain and nociceptive responses, as well as neurogenic inflammation. On the basis of recent research a variety of pharmacological substances and antagonists of putative mediators have been identified to modulate or suppress neurogenic inflammation, thus providing a rationale for therapeutical strategies for various diseases in which neurogenic inflammation is suggested to be involved. Among them, capsaicin and other newly developed agonists and antagonists at the vanilloid receptor have attracted particular attention, since they were found to be capable of desensitizing nociceptive nerve structures and thus of preventing development of neurogenic inflammation or even of abolishing an ongoing inflammatory process.

Light and electron microscopic study of the distribution of substance P-immunoreactive fibers and neurokinin-1 receptors in the skin of the rat lower lip.

Cutaneous antidromic vasodilatation and plasma extravasation, two phenomena that occur in neurogenic inflammation, are partially blocked by substance P (SP) receptor antagonists and are known to be mediated in part by mast cell-released substances, such as histamine, serotonin, and nitric oxide. In an attempt to provide a morphological substrate for the above phenomena, we applied light and electron microscopic immunocytochemistry to investigate the pattern of SP innervation of blood vessels and its relationship to mast cells in the skin of the rat lower lip. Furthermore, we examined the distribution of SP (neurokinin-1) receptors and their relationship to SP-immunoreactive (IR) fibers. Our results confirmed that SP-IR fibers are found in cutaneous nerves and that terminal branches are observed around blood vessels and penetrating the epidermis. SP-IR fibers also innervated hair follicles and sebaceous glands. At the ultrastructural level, SP-IR varicosities were observed adjacent to arterioles, capillaries, venules, and mast cells. The varicosities possessed both dense core vesicles and agranular synaptic vesicles. We quantified the distance between SP-IR varicosities and blood vessel endothelial cells. SP-IR terminals were located within 0.23-5.99 microm from the endothelial cell layer in 82.7% of arterioles, in 90.2% of capillaries, and in 86.9% of venules. Although there was a trend for SP-IR fibers to be located closer to the endothelium of venules, this difference was not significant. Neurokinin-1 receptor (NK-1r) immunoreactivity was most abundant in the upper dermis and was associated with the wall of blood vessels. NK-1r were located in equal amounts on the walls of arterioles, capillaries, and venules that were innervated by SP-IR fibers. The present results favor the concept of a participation of SP in cutaneous neurogenic vasodilatation and plasma extravasation both by an action on blood vessels after binding to the NK-1r and by causing the release of substances from mast cells after diffusion through the connective tissue.

Calcitonin gene-related peptide produces skeletal muscle vasodilation following antidromic stimulation of unmyelinated afferents in the dorsal root in rats.

In anesthetized rats, the contribution of calcitonin gene-related peptide (CGRP) to antidromic vasodilation of skeletal muscle blood flow (MBF) following electrical stimulation of muscle afferent was investigated by measuring biceps femoris MBF using laser Doppler flowmetry. Repetitive antidromic electrical stimulation of unmyelinated C fibers in ipsilateral dorsal roots at the 3rd-5th lumbar segments for 30 s caused an increase in MBF for 3-15 min (mean 4.5 min) without significant change in systemic arterial blood pressure. The increase in skeletal MBF started about 10 s after the onset of stimulation, and peaked at approximately 130% of the control value at about 30 s after the end of the 30 s period of stimulation. The MBF response was totally abolished by topical application of hCGRP (8-37), a CGRP receptor antagonist. It is concluded that antidromic vasodilation in skeletal muscles following stimulation of unmyelinated C afferents in dorsal roots is independent of systemic blood pressure and is mediated essentially by CGRP. It is suggested that this CGRP-related antidromic vasodilation may be important in the clinical improvement of skeletal MBF produced by physical therapy, e.g. acupuncture.

Involvement of two different mechanisms in trigeminal ganglion-evoked vasodilatation in the cat lower lip: role of experimental conditions

The present study was designed to examine the vasodilator mechanisms elicited by electrical stimulation of trigeminal ganglion (TG) in cat lower lip of the cats. When vago-sympathectomized cats were fixed into a stereotaxic frame by means of ear-bars, etc., the lip blood flow (LBF) increase evoked by lingual nerve (LN) stimulation (parasympathetic reflex response) was almost abolished in 15 out of 34 animals, but unaffected in the other 19. With the animal in the stereotaxic frame, electrical stimulation at sites within the TG evoked an LBF increase whether or not the LN stimulation-induced reflex response was intact. However, hexamethonium abolished the TG stimulation-induced LBF increase in animals whose brainstem parasympathetic reflex was intact, but reduced it by only 50% in animals whose reflex was impaired. This difference was seen in all experiments in which the electrode site was within the TG proper, regardless of its exact position. Although the underlying mechanism is unclear, these data suggest that when the TG is stimulated the LBF increase is entirely mediated via the parasympathetic reflex mechanism in animals whose brainstem reflex is intact, and that an antidromic vasodilatation occurs only in animals whose brainstem parasympathetic reflex is impaired.

Involvement of Nitric Oxide in Parasympathetic and Antidromic Vasodilatations in Cat Lower Lip

The involvement of nitric oxide (NO) in the lower lip vasodilatations mediated via parasympathetic and antidromic mechanisms was examined in alpha-chloralose/urethane-anesthetized cats, with the two types of blood flow responses being recorded separately (by laser Doppler flowmeter) from the two sides of the lower lip. The central cut end of the lingual nerve (LN) or the peripheral cut end of the inferior alveolar nerve (IAN) was electrically stimulated to elicit parasympathetic or antidromic vasodilatation, respectively, in the lower lip. N(G)-nitro-L-arginine methyl ester (L-NAME), but not N(G)-nitro-D-arginine methyl ester (D-NAME) (each at 30 mg/kg), markedly reduced the increases in lip blood flow evoked by stimulation, the reduction being to a similar degree irrespective of whether LN or IAN was stimulated. Pretreatment with L-arginine did not prevent the L-NAME-induced attenuation of either type of vasodilatation. In conclusion, these results suggest that synthesized NO may have a common site of action in antidromic and parasympathetic vasodilator pathways to the cat lower lip.

Functional roles played by the sympathetic supply to lip blood vessels in the cat.

In the anesthetized cat we used laser-Doppler flowmetry to investigate the part played by cervical superior sympathetic trunk (CST) fibers in the control of blood vessels in an orofacial area (the lower lip). The blood flow increase (antidromic vasodilatation) elicited by inferior alveolar nerve (IAN) stimulation was not affected by ongoing repetitive CST stimulation over the frequency range examined (0.2-10 Hz), although reflex parasympathetic vasodilatation was attenuated. The vasoconstrictor responses elicited by IAN stimulation in some preparations were reduced in a frequency-dependent manner (at 0.2-1 Hz) during ongoing CST stimulation (and replaced by vasodilator responses). The vasoconstrictor response evoked directly by brief CST stimulation was attenuated, but not transformed to a vasodilator response, by ongoing CST stimulation. Thus in the cat lower lip 1) sympathetic stimulation attenuated one type of vasodilator response (parasympathetic-mediated vasodilatation), but not another (antidromic vasodilatation), and 2) ongoing sympathetic (CST) stimulation at low frequencies (<1 Hz) prevented further sympathetic-mediated vasoconstriction.

Effects of nociceptin and nocistatin on antidromic vasodilatation in hairless skin of the rat hindlimb in vivo.

1. We tested whether nociceptin (NCE), the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor, and nocistatin (NST), which reverses central NCE effects when applied intrathecally (i.t.), affect small-diameter afferent fibre-mediated vasodilatation in rat hairless skin. 2. Female Wistar rats were vagotomized. Ongoing sympathetic vasoconstrictor activity was abolished by bilateral section of the lumbar sympathetic trunk between ganglia L2 and L3. Sensory axons were selectively stimulated in the dorsal root L5 by 20 electrical impulses supramaximal for activating C-fibres at 1 Hz. Blood flow was measured on the plantar skin of the left hind paw in the L5 dermatome using laser Doppler flowmetry. 3. NCE injected intravenously (i.v.) as single boluses (1, 10 and 100 nmol kg(-1) 7 - 8 min before dorsal root stimulation (n=6) dose-dependently decreased blood pressure and local vascular resistance and suppressed antidromic vasodilatation maximally by 47% (P<0.01). When NCE was injected 2 min before stimulation (n=3), antidromic vasodilatation was reduced by 64% after NCE (1 nmol kg-1) and totally, or almost totally, abolished after the two higher doses. 4. NST (1 - 100 nmol kg(-1) i.v., n=6) was without significant effect on blood pressure and cutaneous vascular resistance. Applied 5 (n=6) or 2 min (n=3) before stimulation it also did not affect antidromic vasodilatation. NST (100 nmol kg(-1) i.v.) applied shortly before an equimolar dose of NCE did not antagonize NCE effects on vascular resistance, blood pressure and antidromic vasodilatation (n=4). 5. In conclusion, NCE inhibits antidromic vasodilatation, a component of neurogenic inflammation, in rat skin while NST is without effect. NST, at the small-diameter sensory ending, is not an effective antagonist of NCE.

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.