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PubMed1993

The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats.

Both clinical and physiological consideration of migraine suggests that the pathophysiology of the syndrome is intimately linked to the trigeminal innervation of the cranial vessels, the trigeminovascular system. Studies were conducted in cats and humans to examine the interaction of these systems with the effective acute antimigraine drugs dihydroergotamine and sumatriptan. In the animal studies cats were anesthetized and prepared for routine physiological monitoring as well as for blood sampling from the external jugular veins. Cerebral blood flow was monitored continuously using laser Doppler flowmetry and the effect of trigeminal ganglion stimulation on both cerebral blood flow and jugular vein peptide levels determined prior to and after administration of either sumatriptan or dihydroergotamine. Stimulation of the trigeminal ganglion led to a frequency-dependent increase in cerebral blood flow, with a mean maximum of 43 +/- 9% at a stimulus frequency of 20 per second. There was a marked reduction in these responses by some 50% after administration of either sumatriptan or dihydroergotamine. Trigeminal ganglion stimulation at a frequency of 5 per second also led to a release into the cranial circulation of calcitonin gene-related peptide (CGRP), with the level rising from 67 +/- 3 to 82 +/- 5 pmol/liter on the side of stimulation. These increases were also markedly antagonized by both sumatriptan and dihydroergotamine. Human studies were conducted as part of the overall evaluation of sumatriptan for the treatment of acute migraine. In 7 of 8 patients responding to subcutaneous sumatriptan administration, elevated CGRP levels (60 +/- 8 pmol/liter) were normalized, with the headache being relieved (40 +/- 8 pmol/liter).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1987

Influence of loperamide on the internal anal sphincter in the opossum.

The objective of this study was to examine the influence of the commonly used antidiarrheal agent loperamide on the internal anal sphincter of anesthetized opossums. Loperamide caused a rise in internal anal sphincter pressures, and a decrease in the rectal distention-induced internal anal sphincter relaxation. To define the mechanism of decrease in the rectal distention response of the internal anal sphincter, we examined the effects of sacral efferent nerve stimulation, local intramural stimulation, and ganglionic stimulant (which acts at the postganglionic inhibitory neuron). Loperamide caused a significant decrease in the internal anal sphincter relaxation caused by sacral nerve stimulation, but not in that caused by local intramural stimulation and nicotine. These effects of loperamide on the internal anal sphincter were antagonized by naloxone. These findings suggest that the therapeutic effects of loperamide on the internal anal sphincter as an antidiarrheal agent are due to a rise in the tone of the sphincter and the inhibition of its relaxation in response to rectal distention. Both of these actions are mediated by activation of opioid receptors. The inhibition of internal anal sphincter relaxation induced by rectal distention (which mimicks recto-anal reflex) is due to inhibition of release of neurotransmitter from the preganglionic sacral nerve fibers.

Anal Canal↗

PubMed2000

Heme oxygenase activity in the internal anal sphincter: effects of nonadrenergic, noncholinergic nerve stimulation.

BACKGROUND & AIMS: To date, the exact role of carbon monoxide (CO) in the nonadrenergic, noncholinergic (NANC) relaxation is not known. This is partly related to the lack of an appropriate method to measure heme oxygenase (HO) activity in the gastrointestinal tissues. METHODS: HO activity of the opossum internal anal sphincter (IAS) smooth muscle was determined using a newly developed assay system that used radiolabeled hemin as a substrate. Enzyme activity of the IAS tissues was measured in the basal state, after electric field stimulation (EFS), ganglionic stimulant dimethyl diphenyl piperazinium iodide (DMPP), and neuropeptide vasoactive intestinal polypeptide (VIP). The presence and localization of HO was examined by Western blot analysis and immunocytochemistry. RESULTS: NANC nerve stimulation of the IAS smooth muscle by EFS (0.25-5 Hz), DMPP, and VIP caused a significant increase in the HO activity of the IAS. The increase in HO activity by EFS was inhibited by the HO inhibitor Tin protoporphyrin (1 x 10(-4) mol/L). Both HO-1 and HO-2 were present in the IAS tissue extracts, and both enzymes were localized in the neurons of the myenteric plexus. The method for HO activity determination used in the present study was found to be reliable and reproducible. CONCLUSIONS: The data suggest that the HO pathway may have a role in neurally mediated relaxation of the IAS. The exact site of involvement and the source of HO activity, however, remains to be determined.

Anal Canal↗

PubMed1998

Dynamic sympathetic regulation of left ventricular contractility studied in the isolated canine heart.

We investigated the dynamic sympathetic regulation of left ventricular end-systolic elastance (Ees) using an isolated canine ventricular preparation with functioning sympathetic nerves intact. We estimated the transfer function from both stellate ganglion stimulation to Ees and ganglion stimulation to heart rate (HR) for both left and right ganglia by means of the white noise approach and transformed those transfer functions into corresponding step responses. The HR response was much larger with right sympathetic stimulation than with left sympathetic stimulation (4.3 +/- 1.4 vs. 0.7 +/- 0.6 beats . min-1 . Hz-1, P < 0.01). In contrast, the Ees responses without pacing were not significantly different between left and right sympathetic stimulation (0.72 +/- 0.34 vs. 0.76 +/- 0. 42 mmHg . ml-1 . Hz-1). Fixed-rate pacing significantly decreased the Ees response to right sympathetic stimulation (0.53 +/- 0.43 mmHg . ml-1 . Hz-1, P < 0.01), but not to left sympathetic stimulation (0.67 +/- 0.32 mmHg . ml-1 . Hz-1, not significant). Although the mechanism by which the sympathetic nervous system regulates cardiac contractility is different depending on whether the left or right sympathetic nerves are activated, this difference does not affect the apparent response of Ees to dynamic sympathetic stimulation.

Animals↗

PubMed1983

Effect of shakuyaku-kanzoh-toh, a prescription composed of shakuyaku (Paeoniae Radix) and kanzoh (Glycyrrhizae Radix) on guinea pig ileum.

The actions of shakuyaku-kanzoh-toh (SK), a prescription of the traditional Chinese medicine, on an isolated guinea pig ileum were studied by comparing those of shakuyaku (S) (peony root, Paeoniae Radix) and kanzoh (K) (licorice root, Glycyrrhizae Radix). SK, S and K suppressed the neurogenic contractions of ileum induced by electrical stimulation and ganglionic stimulating agents such as DMPP and nicotine. Although S did not influence acetylcholine (ACh)-induced contraction of ileum, K inhibited ACh-induced contraction to the same extent as the neurogenic contraction. Also SK inhibited ACh-induced contraction but its inhibition was smaller than the inhibition of the neurogenic contraction. SK and K inhibited 40 mM KCl-induced contraction of ileum and the specific binding of 3H-QNB on muscarinic receptors in ileum, but S at 3 X 10(-4) and 10(-3) g/ml, which were enough to suppress the neurogenic contraction of ileum, did not inhibit them. These results suggest that the inhibitory actions of S and K on the neurogenic contraction are due to an inhibition of ACh release from cholinergic nerve and an inhibition of ACh action on ileum smooth muscle, respectively, and that the inhibitory actions of SK are responsible for both inhibitions by S and K. The inhibitions of ACh action by SK and K are presumed to be due to inhibitions of ACh binding on muscarinic receptors and of contractile machinery of smooth muscle.

Acetylcholine↗

PubMed1979

[Sympathetic control on salivary secretion by the parotid gland in rabbit. II. Effects upon the gland submitted to a weak parasympathetic stimulation (author's transl)].

Superior cervical ganglion stimulation significantly increases both, flow and amylase activity of saliva. Stimulation provokes two markedly different periods of flow: during the first half, flow is very high and differs significantly from the flow of the second half which closely resembles the one previous to stimulation. Alpha-adrenergic blocking agents, when administered intravenously, abolish the hypersecretion induced by sympathetic stimulation; beta-adrenergic blocking agents do not. These facts strengthen the hypothesis that alpha-adrenoceptors are most important in fluid secretion. The infusion of epinephrine acts similarly on cervical ganglion stimulation, but it differs because of its more diffuse effects and deeper cardiovascular alterations. Isoproterenol, after a long latency period, slightly increases salivary flow, which seemingly indicates that beta-adrenoceptors are involved in the fluid secretory processes although in a lesser degree than alpha-adrenoceptors.

Adrenergic alpha-Antagonists↗

PubMed1992

Amide, urea, and carbamate analogues of the muscarinic agent [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride.

A series of amide, urea, and carbamate analogues of the muscarinic (M1) ganglionic stimulant [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride (McN-A-343; 1) was prepared. The C1-methyl-substituted carbamates 8-11 were resolved into the enantiomers. In order to investigate the ganglionic stimulant activity and affinity of the new compounds we studied their ability to increase mean arterial blood pressure (MAP) in the pithed rat and their ability to displace the M1 receptor selective antagonist [3H]pirenzepine from rabbit sympathetic ganglia. The quaternary ammonium derivatives of 1, but not their corresponding tertiary amines, displayed ganglionic stimulant properties. The urea derivative 14 and the acetamide derivative 18 were almost equipotent to 1 as ganglionic agonists. In addition, 14 and 18 showed only 2- to 3-fold less affinity to ganglionic muscarinic receptors than 1. Introduction of a methyl group in the 1 position of the butynyl chain of 1 and its 4-chlorophenyl analogue increased ganglionic stimulant potency. The resulting (+/-)-9 and (+/-)-11 were the most potent analogues in this study. They were found to be partial agonists and showed 5- and 16-fold higher potency than 1, respectively, in increasing the MAP. They also displayed 6- and 18-fold higher affinity than 1 for ganglionic M1 receptors. The (S)-enantiomers of 9 and 11 were 1.5- and 4.9-fold more potent, respectively, than their antipodes as ganglionic muscarinic stimulants. The C1-methyl-substituted urea and acetamide derivatives (15 and 19) were 1.5- and 3-fold less potent than 1 and displayed several-fold lower affinity for ganglionic M1 receptors. The new quaternary analogues retained the selectivity for ganglionic muscarinic receptors since they produced weak partial agonist effects on the guinea pig ileum and showed several-fold lower nicotinic activity than 1 in the frog rectus abdominis assay.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed1981

Morphological changes in presynaptic terminals of the chick ciliary ganglion after stimulation in vivo. A stereological study showing a net loss of total membrane.

The Edinger-Westphal nucleus of one day old chicks was stimulated in vivo. This nucleus projects via the oculomotor nerve to the ciliary ganglion. The stimulation produces morphological changes in the calyciform endings located in the ciliary ganglion. There is a significant reduction of the numerical density on area of the clear and the dense core vesicles. The numerical density of the coated vesicles is low compared to that of the clear vesicles. Their density is however almost doubled by the stimulation. The vesicles, the vacuoles and the plasma membrane were quantified using stereological procedures. A net loss of total membrane was found due to the loss of organelle membrane not compensated for by an equivalent increase of the plasma membrane. These observations are discussed in terms of the theory of vesicular membrane recycling as proposed by Heuser and Reese (1973).

Animals↗

PubMed1998

Depletion of calcitonin gene-related peptide from the caudal trigeminal nucleus of the rat after electrical stimulation of the Gasserian ganglion.

Electrical stimulation of the Gasserian ganglion resulted in partial depletion of calcitonin gene-related peptide (CGRP) from ipsilateral central terminals of pseudounipolar primary sensory ganglion cells. Affected terminals exhibit decreased CGRP immunoreactivity as shown by cytophotometric densitometry of the caudal trigeminal nucleus. The decrease in CGRP immunoreactivity is statistically significant only in the medial one-third of the caudal trigeminal nucleus. Since earlier studies have shown that electrical stimulation of the Gasserian ganglion induces first accumulation then depletion of CGRP from perivascular sensory terminals in the dura mater, the present experiments suggest that CGRP is depleted also from central terminals of primary sensory trigeminal neurons, which might be of importance in the pathogenesis of migraine headache.

Animals↗

PubMed2004

Kynurenine aminotransferase in the supratentorial dura mater of the rat: effect of stimulation of the trigeminal ganglion.

Electrical stimulation of the trigeminal ganglion has been widely used as a model of nociception, characterizing migraine. This treatment is known to evoke release of neuropeptides and neurotransmitters from nerve fibers of the dura mater. On the basis of immunocytochemical investigations, we found that under normal conditions, surface membranes of Schwann cells surrounding nerve fibers in the supratentorial dura mater display kynurenine aminotransferase-immunoreaction (KAT-IR); also KAT-IR are the granules of mast cells and the cytoplasms of macrophages (histiocytes). In consequence of stimulation of the trigeminal ganglion, Schwann cells in the dura mater became conspicuously swollen while their KAT-IR decreased considerably; also KAT-IR of mast cells and macrophages decreased significantly. At the same time, nitric oxide synthase (NOS)-IR of nerve fibers in the dura mater increased, suggesting release of nitric oxide (NO), this is known to be involved in NMDA receptor activation leading to vasodilation followed by neurogenic inflammation. Because kynurenic acid (KYNA) is an antagonist of NMDA receptors, we hypothesize that KYNA and its synthesizing enzyme, KAT, may play a role in the prevention of migraine attacks.

Animals↗

PubMed1985

A neuronal cell surface heparan sulfate proteoglycan is required for dorsal root ganglion neuron stimulation of Schwann cell proliferation.

Axons of dorsal root ganglion neurons express on their surfaces one or more proteins which are mitogenic for Schwann cells (Salzer, J., R. P. Bunge, and L. Glaser, 1980, J. Cell Biol., 84:767-778). Incubation of co-cultures of dorsal root ganglion neurons and Schwann cells with 4-methylumbelliferyl-beta-D-xyloside, an inhibitor of proteoglycan biosynthesis, decreases the mitogenic response of the Schwann cell by over 95%. The effect of the beta-D-xyloside has been localized to the neurons; pretreatment of neurons but not of Schwann cells with the inhibitor causes a marked reduction of the mitogenic response. In addition, Schwann cells treated with beta-D-xyloside are still mitogenically responsive to soluble Schwann cell mitogens (cholera toxin and glial growth factor). Neurons treated with heparitinase and membrane vesicles prepared from heparitinase-treated neurons show diminished mitogenicity for Schwann cells, while other proteoglycan lyases have no effect. We conclude that a cell surface heparan sulfate proteoglycan is a component of the Schwann cell mitogen present on the surface of dorsal root ganglion neurons.

Animals↗

PubMed1996

Optic nerve glia secrete a low-molecular-weight factor that stimulates retinal ganglion cells to regenerate axons in goldfish.

The ability of lower vertebrates to regenerate an injured optic nerve has been widely studied as a model for understanding neural development and plasticity. We have recently shown that, in goldfish, the optic nerve contains two molecules that stimulate retinal ganglion cells to regenerate their axons in culture: a low-molecular-weight factor that is active even at low concentrations (axogenesis factor-1) and a somewhat less active polypeptide of molecular weight 10,000-15,000 (axogenesis factor-2). Both are distinct from other molecules described previously in this system. The present study pursues the biological source and functional significance of axogenesis factor-1. Earlier studies have shown that cultured goldfish glia provide a highly favorable environment for fish or rat retinal ganglion cells to extend axons. We report that the glia in these cultures secrete high levels of a factor that is identical to axogenesis factor-1 in its chromatographic properties and biological activity, along with a larger molecule that may coincide with axogenesis factor-2. Axogenesis factor-1 derived from either goldfish glial cultures or optic nerve fragments is a hydrophilic molecule with an estimated molecular weight of 700-800. Prior studies have reported that goldfish retinal fragments, when explanted in organ culture, only extend axons if the ganglion cells had been "primed" to begin regenerating in vivo for one to two weeks. However, axogenesis factor-1 caused the same degree of outgrowth irrespective of whether ganglion cells had been induced to regenerate new axons in vivo. Moreover, ganglion cells primed to begin regenerating in vivo continued to extend axons in culture only when axogenesis factor-1 was present. In summary, this study shows that glial cells of the goldfish optic nerve secrete a low-molecular-weight factor that initiates axonal regeneration from retinal ganglion cells.

Animals↗

PubMedDate not supplied

Neuropeptide Y (NPY) and the pig heart: release and coronary vasoconstrictor effects.

The effects of electrical stimulation of the stellate ganglia on the arterio-venous concentration differences of neuropeptide Y (NPY)-like immunoreactivity (LI) over the pig heart were studied in vivo in relation to changes in heart rate and left ventricular pressure. Furthermore, the effects of NPY on coronary vascular tone were analysed in vivo and in vitro. Stellate ganglion stimulation at a high frequency (10 Hz) caused a clear-cut, long lasting increase in plasma levels of NPY-LI in the coronary sinus compared to the aorta, suggesting release of this peptide from sympathetic terminals within the heart. The stimulation-evoked overflow of NPY-LI from the heart was enhanced about 3-fold by alpha-adrenoceptor blockade using phenoxybenzamine, suggesting that NPY release is under prejunctional inhibitory control by noradrenaline (NA). Combined alpha- and beta-adrenoceptor blockade abolished most of the positive inotropic response of the heart upon stellate ganglion stimulation, while a considerable positive chronotropic effect remained. After guanethidine treatment, stellate ganglion stimulation still produced a small positive inotropic and chronotropic effect on the heart. The stimulation evoked NPY overflow was markedly reduced by guanethidine indicating an origin from sympathetic nerve terminals. Injection of NPY into the constantly perfused left anterior descending artery in vivo caused a long lasting, adrenoceptor antagonist resistant increase in perfusion pressure, suggesting coronary vasoconstriction. NPY contracted coronary arteries in vitro via a nifedipine-sensitive mechanism. NA dilated coronary vessels both in vivo and in vitro via beta-adrenoceptor activation. It is concluded that sympathetic nerve stimulation increases overflow of NPY-LI from the heart suggesting release from cardiac nerves in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Evidence for a neurotransmitter role of glutamate in guinea pig myenteric plexus neurons.

Longitudinal muscle-myenteric plexus strips of the guinea pig ileum were used to investigate a possible transmitter role of glutamate (Glu) in the enteric nervous system. Glu was released from this nerve muscle preparation by high K(+)-depolarization in a Ca2(+)-dependent manner, by electrical field stimulation and by the ganglionic stimulant dimethylphenylpiperazinium which indicates its neural origin. Contractions of the longitudinal muscle evoked by electrical stimulation of the myenteric nerves or by Glu, were significantly reduced by the N-methyl-D-aspartate (NMDA)-receptor antagonist FR115427 (9 and 18 microM), whereas contractions induced by histamine were unaffected. The results show that the amino acid Glu is likely to play an excitatory neurotransmitter role via NMDA receptors in the myenteric plexus of the guinea pig.

Animals↗

PubMed1975

Nature of the vagal inhibitory innervation to the lower esophageal sphincter.

The purpose of the present study was to investigate the nature of the vagal inhibitory innervation to the lower esophageal sphincter in the anesthetized opossum. Sphincter relaxation with electrical stimulation of the vagus was not antagonized by atropine, propranolol, phentolamine, or by catechloamine depletion with reserpine. A combination of atropine and propranolol was also ineffective, suggesting that the vagal inhibitory influences may be mediated by the noncholinergic, nonadrenergic neurons. To determine whether a synaptic link with nicotinic transmission was present, we investigated the effect of hexamethonium on vagal-stimulated lower esophageal sphincter relaxation. Hexamethonium in doses that completely antagonized the sphincter relaxation in response to a ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), did not block the sphincter relaxation in response to vagal stimulation at 10 pulses per second, and optimal frequency of stimulation. A combination of hexamethonium and catecholamine depletion was also ineffective, but hexamethonium plus atropine markedly antagonized sphincter relaxation (P less than 0.001). Moreover, 4-(m-chlorophenyl carbamoyloxy)-2-butyltrimethylammonium chloride (McN-A-343), a muscarinic ganglionic stimulant, also caused relaxation of the lower esophageal sphincter. We suggest from these results that: (a) pthe vagal inhibitory pathway to the sphincter consists of preganglionic fibers which synapse with postganglionic neurons: (b) the synaptic transmission is predominantly cholinergic and utilizes nicotinic as well as muscarinic receptors on the postganglionic neuron, and; (c) postganglionic neurons exert their influence on the sphincter by an unidentified inhibitory transmitter that is neither adrenergic nor cholinergic.

Animals↗

PubMed1989

'Non-chronotropic' mechanisms on withdrawal of efferent vagal stimulation in anesthetized dogs.

Withdrawal of the efferent vagal tone to the heart is an important factor of the increase of cardiac output (CO) and arterial blood pressure (ABP) in several conditions, such as exercise, emotion, postural changes. Vagal withdrawal enhances cardiovascular performance both by increasing heart rate (HR) and by other mechanisms, which were globally named 'non-chronotropic mechanisms'. The nature of these non-chronotropic mechanisms was studied in open-chest dogs under morphine-chloralose anesthesia. After cutting the cervical vagi and all the branches of the stellate ganglia except for the ansae subclaviae, the animals were prepared for recording HR, ABP, CO and left ventricular pressure (LVP). The experiments started during control vagal stimulations and consisted either in turning the vagal stimulators off (STOP), or in raising HR by atrial placing without withdrawing vagal stimulation (PACE), or in turning the vagal stimulators off while keeping HR constant by atrial pacing since the control vagal stimulation (STPA). Thus, STOP, PACE and STPA produced withdrawal of all vagal effects, of the chronotropic effects and of the non-chronotropic effects, respectively. Non-chronotropic mechanisms were evaluated both as the effects of STPA and as the difference between the effects of STOP and PACE. Experiments were repeated during stellate ganglion stimulation and during simultaneous atrio-ventricular pacing, to evaluate the role of vagosympathetic interactions and of atrial contractility. CO increased by 25% after STOP, by 20% after PACE and by 5% after STPA in the absence of sympathetic stimulation and by 30% after STOP, by 20% after PACE and by 10% after STPA during sympathetic stimulation. Stellate ganglion stimulation doubled non-chronotropic effects probably by potentiating vagal effects on myocardial contractility: after STPA the maximum LVdP/dt increased by 2% without sympathetic stimulation and by 7% with sympathetic stimulation. In all conditions, the increases in ABP after STOP, PACE and STPA were small and not statistically different between STOP and PACE. Simultaneous atrio-ventricular pacing in the absence of sympathetic stimulation nearly abolished non-chronotropic mechanisms, since CO increased to about the same extent both with STOP and with PACE. It is concluded that non-chronotropic mechanisms on vagal withdrawal consist mainly in the enhancement of atrial contractility and in the release of vagal restraint on the sympathetic effects upon the ventricles.

Analysis of Variance↗

PubMed1996

[Influence of stellate ganglion block and electrical stimulation of the stellate ganglion on bilateral brachial arterial blood flow--is stellate ganglion block effective either unilaterally or bilaterally?].

The purpose of this study was to investigate the influence of the stellate ganglion block (SGB), stellate ganglion electrical stimulation (SGES) and stellate ganglionectomy on bilateral arterial blood flows (BAF). Sixteen mongrel dogs were divided into two groups; a SGB group (n = 8) and a SGES group (n = 8). Anesthesia was induced with pentobarbital 25 mg.kg-1 and the animals were mechanically ventilated to maintain proper PaO2 (90-100 mmHg) and PaCO2 (35-40 mmHg). After a thoracotomy, the SGB with 0.5% mepivacaine 1.0 ml was performed in the SGB group. SGES was performed at a strength of 12 volts, and at a frequency of 50 Hz, applied for 15 minutes and then 15 minutes after the SGES, stellate ganglionectomy was performed in SGES group. In the SGB group, BAF in the blocked side increased significantly but BAF in the contralateral side decreased significantly after SGB. In the SGES group, bilateral BAF decreased significantly (Lt > Rt) and after the stellate ganglionectomy, bilateral BAF increased more than after SGES. These results suggest that the SGB may not be effective on the contralateral side under normal conditions, but under the conditions of sympathetic stimulation, the SGB may be effective on the contralateral side.

Animals↗

PubMed1991

Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and dihydroergotamine.

Neurogenic plasma extravasation, endothelial cell activation (increase in vesicle number and vacuole formation), platelet aggregation and adhesion, and mast cell degranulation occur selectively in post-capillary venules of the dura mater following electrical trigeminal ganglion stimulation, and are mediated by release of neuropeptides from perivascular unmyelinated C fibres. Pre-treatment with the antimigraine drugs dihydroergotamine and sumatriptan, two drugs that bind with high affinity to 5-HT1B/1D receptors, markedly attenuated plasma protein extravasation induced by electrical trigeminal ganglion stimulation. Trigeminal stimulation increased plasma calcitonin gene-related peptide levels in rat superior sagittal sinus. Pre-treatment with dihydroergotamine and, to a lesser extent, sumatriptan, attenuated this increase. Both drugs reduced morphological changes in post-capillary venules and mast cells within dura mater following electrical trigeminal ganglion stimulation. Plasma protein extravasation was selectively blocked in dura mater (but not in extracranial tissues) by pre-treatment with those receptor agonists showing a rank order of potency suggesting a 3-HT1B/1D interaction (5-CT greater than 5-BT greater than DHE greater than sumatriptan greater than 8-OH-DPAT). Pre-treatment with 5-HT2 and 5-HT3 antagonists was not effective. Taken together, these data are consistent with the interpretation that putative 5-HT-1B/1D receptors located on sensory fibres are coupled to inhibition of peptide release and blockade of neurogenic inflammation. An important therapeutic action of ergot alkaloids and sumatriptan in migraine headaches is so defined.

Animals↗