Sage Journals: Discover world-class research

Abstract

To facilitate understanding the action of antimigraine preventives the effect of topiramate on trigeminocervical activation in the cat was examined. Animals (n = 7) were anaesthetized and physiologically monitored. The superior sagittal sinus (SSS) was stimulated to produce a model of trigeminovascular nociceptive activation. Cumulative dose-response curves were constructed for the effect of topiramate at doses of 3, 5, 10, 30 and 50 mg/kg on SSS-evoked firing of trigeminocervical neurons. Topiramate reduced SSS evoked firing in a dose-dependent fashion. The maximum effect was seen over 30 min for the cohort taken together. At 3 mg/kg firing was reduced by 36 ± 13% (mean ± SEM) after 15 min. At 5 and 50 mg/kg firing was reduced by 59 ± 6% and 65 ± 14%, respectively, after 30 min. Inhibition of the trigeminocervical complex directly, or neurons that modulate sensory input, are plausible mechanisms for the action of preventives in migraine.

Keywords

migraine cluster headache preventive trigeminovascular

Introduction

Migraine is an episodic brain disorder that results in significant morbidity (1) for 10–15% of the general population (2, 3). A substantial number of patients with migraine have frequent headache (4), and it is those with more frequent headache who tend to have the most substantial disability (5). Patients with the most frequent headache are candidates for preventive treatments (6). Over the last 10 years substantial interest has arisen in the application of medicines generally used as anticonvulsants in the preventive management of migraine (7), and of cluster headache (8).

Stimulation of the superior sagittal sinus (SSS) in humans produces pain that is substantially referred to the first (ophthalmic) division of the trigeminal nerve (9). During stimulation of the superior sagittal sinus (SSS), neurons can be studied using population-based anatomical techniques, such as measurement of c-Fos with immunohistochemistry (10), or metabolic activity with 2-deoxyglucose (11), or single neurons can be more closely tracked using electrophysiological techniques (12, 13). This approach has been used to characterize agents that are effective in the acute treatment of migraine, such as the triptans (14), and agents, such as the substance P/neurokinin-1 antagonist, GR205171 (15), and the conformationally restricted triptan analogues, CP122, 288 (16) and 4991W93 (17), which were both clinically ineffective (18–20). For each class of compound the model of SSS stimulation correctly predicted the outcome of the clinical studies.

In this study we sought to explore the effects of intravenous topiramate, which has now been reported in several controlled trials (21–23) to be effective as a migraine preventive. We used the model of superior sagittal sinus stimulation and electrophysiological monitoring of single unit activity in the trigeminocervical complex of the cat in an attempt to begin to understand how topiramate may have its effect. We chose this approach based on the additional reports of topiramate's use in cluster headache (21, 24) and SUNCT (Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing) (25), given the pivotal role that the trigeminocervical complex is likely to play in all three.

This work was presented in preliminary form at the American Academy of Neurology, Honolulu, Hawai, 2 April 2003 (26).

Methods

All studies reported were conducted and terminated under general anaesthesia in accordance with a project licence issued by the Home Office of the United Kingdom under the Animals (Scientific Procedures) Act, 1986. Cats (n = 7) weighing 2.64 ± 0.27 kg (mean ± SD), not selected by age or sex, were anaesthetized with α-chloralose (60 mg/kg i.p. Sigma, St Louis, MO, USA) and prepared for physiological monitoring. Isoflurane (Merial Animal Health, Essex, UK; 0.5 – 3% in a 40% oxygen/air carrier gas mixture) was administered from an anaesthetic machine (Ohmeda-BOC Healthcare, Steeton, UK) during surgical procedures and then discontinued during experimental protocols. Catheters were placed in femoral arteries for arterial blood sampling and continuous measurement of blood pressure (DTXplus transducer, Ohmeda, Madison, WI; PM-1000 amplifier, CWE Inc., Ardmore, PA, USA). Catheters were also placed in femoral veins allowing fluid (saline for intravenous infusion BP 0.9% w/v, Baxter Healthcare, Norfolk, UK) and drug administration. Supplementary doses of α-chloralose in 2-hydroxypropyl-β-cyclodextrin (Sigma) were given i.v. at a rate of 5–10 mg/kg per h (27). The cats were intubated after local anaesthesia with 2% (w/v) lidocaine hydrochloride (Intubeaze, Arnolds, Shrewsbury, UK) and fixed in a stereotaxic frame (Kopf Instruments, Tujunga, CA, USA).

Jackson/Foley urethral catheters (3/4 fg; Rocket Veterinary Products, Washington, UK; SIMS Portex, Kent, UK) were inserted to drain cat bladders, providing more even temperature regulation, more stable control of blood pressure through control of bladder distension, and monitoring of urine output. Core temperature was monitored and maintained between 37–39°C using a rectal thermistor probe and a low-electromagnetic-noise-emitting homeothermic heater blanket system (Harvard Apparatus, Holliston, MA, USA). Cats were ventilated with a 40% oxygen/air mixture (Harvard Apparatus), end-tidal CO₂ was continuously monitored and maintained between 2–4% (CAPSTAR-100 carbon dioxide analyser; CWE Inc., Ardmore, PA, USA). Heart rate was monitored by electrocardiogram (CT-1000; CWE Inc.) and derived from blood pressure changes. The depth of anaesthesia was monitored periodically throughout the experiment by testing for sympathetic (pupillary and cardiovascular) responses to noxious stimulation and withdrawal reflexes in the absence of neuromuscular blockade.

Surgery

Midline craniotomies (20-mm diameter) and C₁/C₂ laminectomies were performed allowing access to the superior sagittal sinus (SSS) and the area for recording neuronal activity in spinal cords. SSSs were isolated by dissecting the dura and falx cerebri adjacent to them over approximately 15 mm. Small polyethylene sheets were inserted under the isolated sinuses, laid over the outlying dura, and tucked under the edges of the craniotomy. To prevent dehydration and to provide additional electrical insulation to the cortex, a circular polypropylene dam was sealed to the bone around the craniotomy with dental acrylic (Vertex, Zeist, the Netherlands) and filled with liquid paraffin (BDH Laboratory Supplies, Poole, UK). The likelihood of possible artefacts from arterial pulsation and respiratory movement (such as movement of the electrode from recording sites) was reduced by: bilateral pneumothoraces, held patent with polypropylene tubes; immobilization of the spine by clamping a thoracic spinous process to the stereotaxic frame; clamping the C₁ transverse processes to auxiliary ear bar holders on the frame, and clamping the remaining caudal portion of the dorsal C₂ spinous process to the frame.

Stimulation and recording

Isolated SSSs were gently lifted onto a pair of bipolar platinum hook electrodes connected to a stimulus isolation unit (SIU5A; Grass Instruments, West Warwick, RI). To activate primary trigeminal afferents, SSSs were supramaximally stimulated with stimulus-isolated (Grass SIU) square wave pulses from a Grass S88 stimulator (250 µs, 0.3 – 0.5 Hz) after neuromuscular blockade with gallamine triethiodide (Concord Pharmaceuticals, Essex, UK; initially 5–10 mg/kg i.v. and maintained with 5–10 mg/kg per h). The dura mater above the recording regions on the surface of the spinal cord was reflected after a midline incision and held to the edges of the laminectomy with N-butyl-cyanoacrylate, further stabilizing movement of the cord in this sling-like arrangement. Extracellular recordings were made using tungsten electrodes (TM33A20; World Precision Instruments, Sarasota, FL). Recording electrode impedances were typically 0.8 – 2.1 MΩ when measured at 1 kHz in 0.9% saline. After local removal of the pia mater the electrodes were lowered into the cord substance caudal to the C₂ roots in the area of the dorsal root entry zone. The electrodes were advanced or retracted in the cord substance in 5 µm steps using an ultra low drift (<1 µm/h) LSS-100 microelectrode positioner system consisting of a piezoelectric motor (IW-711; Lateral Stability Option (±0.2 µm lateral motion), Burleigh Instruments, Harpenden, UK) and ultra-low-noise controller (6000ULN) attached to a heavy-duty micromanipulator (Kopf 1760–61). Tissue culture grade agar 3% (w/v) (Sigma) in pyrogen free saline (Baxter Healthcare) was set over the exposed cord after electrode insertion to further reduce cardiovascularly related movements. Signal from the recording electrode attached to a high impedance headstage preamplifier (NL100AK; Neurolog, Digitimer, Herts, UK) was fed via an AC preamplifier (Neurolog NL104, gain ×1000) through filters (Neurolog NL125; bandwith approximately 300 Hz to 20 kHz) and a 50 Hz noise eliminator (Humbug, Quest Scientific, North Vancouver, BC, Canada) to a second stage amplifier (Neurolog NL106) providing variable gain (×20 −×90). This signal (total gain approximately × 20 000 −×90 000) was fed to a gated amplitude discriminator (Neurolog NL201) and analogue-to-digital converter (Cambridge Electronic Design, Cambridge, UK) to a Pentium II (Intel, Santa Clara, CA, USA) microprocessor-based personal computer (DELL Latitude CPi; Berkshire, UK) where the signal was processed and stored. Filtered and amplified electrical signals from action potentials were fed to a loudspeaker via a power amplifier (Neurolog NL120) for audio monitoring and displayed on analogue and digital storage oscilloscopes (Goldstar, LG Precision, Korea; Metrix Electronics, Watford, UK) to assist the isolation of single unit activity from adjacent cell activity and noise.

In order to record the response of single units to stimulation, poststimulus histograms were constructed on-line and saved to disk. During experiments, electrophysiological data, blood pressure, heart rate, core temperature and end-tidal CO₂ were processed and recorded on VHS magnetic tape (Pulse Code Modulator; Vetter, Rebersburgh, PA, USA) and local hard disk for documentation and latter review.

The position of the recording electrodes was controlled by use of a heavy-duty stereotaxic micropositioner (Kopf 1760–61) with reference to the mid-point of the C₂ dorsal roots. Together with the depth of the recording electrode tip with respect to the surface of the spinal cord at the dorsal root entry zone, as determined by the distance travelled display on the ULN6000 pizoelectric motor controller (Burleigh Instruments), this provided the coordinates of the recording sites. The location of selected recording sites was marked by thermocoagulation via an electrolytic lesion (20–50 µA, 10–30 s or 20 mA, 5 s; DCLM5 constant current lesion maker; Grass Instruments). Animals were euthanased with sodium pentobarbital (400 mg), followed by KCl (10% w/v; 5 ml). After termination of experiments the sections of spinal cord containing the recording sites were removed, fixed with neutral buffered 10% formalin, stored in phosphate buffered 30% sucrose, pH 7.4 until sunk and sectioned (40 µm; HM500 OM cryostat microtome, Microm Laborgeräte, Walldorf, Germany). Electrolytic lesion marks were located after cresyl violet (Sigma) Nissl staining. The position of the recording sites within the cord were determined from histologically identified lesion marks or by reference to the coordinates of recording electrode positions where lesion marks were not recovered.

Receptive fields

Cells responding to superior sagittal sinus (SSS) stimulation were characterized as receiving low threshold mechanoreceptor (LTM) input if they responded to non-noxious input, such as brush or stroke, on cutaneous receptive fields on the face or forepaws. They were characterized as nociceptive specific (NS) if they responded to noxious mechanical stimuli, such as pinch or pricking with a needle, or wide dynamic range (WDR), if they responded to both (28). These cells usually had an increased firing rate in response to noxious stimuli.

Test compound

Topiramate (Johnson & Johnson PRD, Raritan, NJ, USA) was administered i.v. to each cat in a cumulative log-dose manner at 1–3 h intervals at 3, 5, 10, 30 and 50 mg/kg in saline for injection BP (5–15 ml; Phoenix Pharma, Gloucester, UK).

Statistical analysis

Physiological parameters and results are indicated as mean ± SEM. Inhibition of SSS-evoked trigeminal activation data were compared using an ANOVA with repeated measures (SPSS, v.11). Significance was assessed at the P < 0.05 level.

Results

Animals from which data is reported had cardio-respiratory parameters that were normal for the anaesthetized cat. Blood gas parameters were measured at intervals throughout the experiment and were within normal limits for an α-chloralose anaesthetized cat: arterial blood pH 7.34 ± 0.06 and pCO₂ 3.47 ± 0.64 kPa. Urine output was 5.10 ± 2.01 ml/h.

Localization and neuronal characteristics

Extracellular recordings were made and data collected from 7 neurons in the trigeminocervical complex of cats (11). Cells were located +3 mm rostral to −1 mm caudal to the midpoint of the C₂ rootlets, 0–150 µm lateral to the dorsal root entry zone at a depth of approximately −650 µm to around −3000 µm below the (dorsal) cord surface (Fig. 1). Cells responded to electrical sagittal sinus stimulation with latencies consistent with Aδ fibres, typically 8–10 ms. Cells received wide dynamic range or nociceptive specific mechanoreceptor input from cutaneous V_I or V_II receptive fields on the face, or cutaneous receptive fields on forepaws, or both.

Figure 1

Localization of recording sites. A transverse section through the spinal cord at the level of C₂ is represented. Lesions marking recording sites were identified histologically as recovered (•) or reconstructed (○) sites. Although the positions of the recorded units are mapped to only one side of the cord in the figure, they represent results obtained from both the left-hand-side and right-hand-side of the spinal cord. Scale bar represents a distance of 1 mm in both directions.

Intravenous administration

Intravenous administration of topiramate resulted in a dose dependent inhibition of superior sagittal sinus evoked trigeminocervical nucleus activity. Topiramate usually had a near maximal effect by 30 min (Fig. 2). Topiramate 5 mg/kg at 30 min reduced firing by 50 ± 6% of predrug controls. Maximal effects were observed with 50 mg/kg when firing was reduced to 80 ± 8% at 60 min (Fig. 3).

Figure 2

Dose-dependent inhibition of superior sagittal sinus evoked trigeminocervical nucleus activity by intravenous topiramate. Post-stimulus histograms illustrating the inhibition by intravenous topiramate at 30 min after administration. Note the short latency artefact from the stimulus indicating 100 stimuli per histogram. (a) Baseline control and Topiramate at (b) 3 mg/kg i.v., (c) 5 mg/kg and (d) 10 mg/kg.

Figure 3

Dose- and time-dependent inhibition of superior sagittal sinus evoked trigeminocervical nucleus activity by intravenous topiramate. Combined data indicating time- and dose-dependent inhibition by intravenous topiramate. At lower doses inhibition is variable, but at the higher doses 30 and 50 mg/kg a clear dependency can be seen. ▪ 5 mins, ░ 10 mins, ▨ 15 mins, □ 30 mins, 60 mins.

Discussion

This study demonstrates a robust inhibitory effect for topiramate on trigeminovascular nociceptive neurons activated by stimulation of the superior sagittal sinus. The effect was dose-dependent, and was maximal within an hour. It is clear that inhibition of trigeminovascular neurons activated by a nociceptive stimulus has been predictive of acute antimigraine activity (16, 29). However, the question of the action of preventive medicines in this model has not hitherto been tested. Recent results with controlled trials showing a robust effect of topiramate as a preventive agent in migraine (22, 23), and the compound's broad spectrum of neuropharmacological action and variable effects at different plasma concentrations (30), makes it a reasonable choice with which to explore this question.

Topiramate has several mechanisms of action that include inhibition of glutamatergic excitatory amino acid transmission, inhibition of voltage-gated calcium channels, augmentation of GABAergic mechanisms, fast Na⁺ channel inhibition and carbonic anhydrase inhibition. These effects are likely to arise from allosteric influences on these receptor/channel protein complexes and may involve changes in their phosphorylation state (31). A number of these mechanisms are known to be at play in the trigeminal nucleus. These include glutamatergic, voltage-gated calcium channel and GABAergic mechanisms. Fast Na⁺ channel and carbonic anhydrase related mechanisms are not clearly described for the trigeminovascular system.

Glutamate-like immunoreactivity has been seen in tooth pulp neurons that project to the trigeminal nucleus caudalis in the rat (32). Glutaminase immunoreactivity is most dense in the nucleus caudalis when compared with other parts of the trigeminal nucleus of the rat (33). Each of N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), kainate and metabotropic glutamate receptors have been identified in the superficial laminae of the trigeminal nucleus caudalis of the rat (34) and may therefore be important for trigeminal nociceptive transmission. NMDA mediated actions have been reported in the principal sensory nucleus of the trigeminal complex in neurons involved in the jaw opening reflex (35). Microiontophoretic application of D,L-homocysteic acid onto trigeminal neurons responding to superficial pain stimuli increases their firing rate (36), and similarly, microiontophoresis of D,L-homocysteic acid onto trigeminal neurons responding to superior sagittal sinus stimulation increases their firing rate (37), as does direct iontophoresis of L-glutamate (38). While administration of the NMDA receptor antagonist, MK-801, inhibits sagittal sinus-evoked trigeminal neuronal activation, as determined electrophysiologically (39), Fos expression in the trigeminocervical complex (40), and local evoked trigeminal nucleus blood flow (41). Fos expression after meningeal irritation is inhibited by both NMDA (42) and non-NMDA (43) receptor antagonists. So some part of the effect of topiramate may involve inhibition of glutamatergic transmission within the trigeminocervical complex, which, given the pharmacology of topiramate is likely to be a non-NMDA mediated effect.

GABAergic mechanisms have been implicated in the trigeminocervical complex. Expression of the proto-oncogene c-fos as a marker of nociceptive neuronal activity within the trigeminal nucleus caudalis is reduced by valproate (44) and allopregnanolone, a neurosteroid progesterone metabolite that modulates GABA_A receptor activity through an allosteric binding site (45). Using electrophysiological methods, neurons within the trigeminocervical complex of the cat responding to a nociceptive stimulus contain two distinct populations of GABA receptors corresponding to the GABA_A and GABA_B class. Most cells are inhibited by the GABA_A agonist muscimol, an effect reversed by the GABA_A antagonist N-methylbicuculline, but not by the GABA_B antagonist 2-hydroxysaclofen (46). Many fewer units are inhibited by the GABA_B agonist baclofen (46). Taken together, the substantial GABAergic influence on trigeminovascular nociceptive neurons is mediated chiefly by GABA_A receptors. For calcium channels there is evidence in rat that P/Q-type channels may influence trigeminal neuronal activation through a GABAergic mechanism (47). In cat we have recently demonstrated P/Q-, N- and L-type voltage-gated calcium channel modulation of trigeminocervical neurons (48), that mirror peripheral trigeminovascular neurons that are modulated by P/Q- and N-type voltage-gated calcium channels (49). In a mechanistic sense an effect of topiramate on voltage-gated channels would be attractive in the context of viewing migraine as a channelopathic disorder (50).

Would one expect inhibition of trigeminal neurons to be associated with preventive effects in primary headache? In recent times responses of trigeminal neurons have been used to characterize possible actions of acute antimigraine compounds (14, 29). As presented here, the observations of reduced transmission to second order trigeminovascular neurons after stimulation of the superior sagittal sinus in the presence of topiramate given intravenously does not necessarily indicate an action in the trigeminocervical complex. Human brain imaging of acute migraine has demonstrated important regions in the midbrain and pons to be activated in both episodic (51, 52) and chronic migraine (53). Indeed one region that would be consistent with these data is involvement of the periaqueductal grey matter that can inhibit trigeminovascular neuronal traffic (54, 55), with a P/Q voltage gated calcium channel component in rat (56). Topiramate may therefore have an action at a site distant to the trigeminocervical complex, a question that requires further study.

In conclusion, we have demonstrated inhibition of trigeminovascular nociceptive neuronal activity with topiramate after superior sagittal sinus stimulation. The effect is dose- and time-dependent, and robust across experiments. Models of trigeminal activation may permit insights into the mode or, in concert with local administration techniques, the site of action of preventive antimigraine compounds.

Footnotes

Acknowledgements

The authors thank Paul Hammond for technical assistance. This work has been supported by the Johnson & Johnson Pharmaceutical Research and Development, LLC. PJG is a Wellcome Senior Research Fellow.

References

Menken

Munsat

Toole

JF.

The global burden of disease study — implications for neurology. Arch Neurol 2000; 57: 418–20.

Lipton

Stewart

Diamond

Reed

Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001; 41: 646–57.

Rasmussen

Olesen

Symptomatic and nonsymptomatic headaches in a general population. Neurology 1992; 42: 1225–31.

Lipton

Scher

Kolodner

Liberman

Steiner

Stewart

WF.

Migraine in the United States. Epidemiology and patterns of health care use. Neurology 2002; 58: 885–94.

Von Korff

Stewart

Simon

Lipton

RB.

Migraine and reduced work performance: a population-based diary study. Neurology 1998; 50: 1741–5.

Silberstein

Lipton

Goadsby

PJ.

Headache in Clinical Practice, 2nd edn. London: Martin Dunitz, 2002.

Silberstein

Rosenberg

Multispecialty consensus on diagnosis and treatment of headache. Neurology 2000; 54: 1553.

Dodick

Rozen

Goadsby

Silberstein

SD.

Cluster headache. Cephalalgia 2000; 20: 787–803.

Feindel

Penfield

McNaughton

The tentorial nerves and localization of intracranial pain in man. Neurology 1960; 10: 555–63.

10.

Kaube

Keay

Hoskin

Bandler

Goadsby

PJ.

Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical cord following stimulation of the superior sagittal sinus in the cat. Brain Res 1993; 629: 95–102.

11.

Goadsby

Zagami

AS.

Stimulation of the superior sagittal sinus increases metabolic activity and blood flow in certain regions of the brainstem and upper cervical spinal cord of the cat. Brain 1991; 114: 1001–11.

12.

Hoskin

Kaube

Goadsby

PJ.

Central activation of the trigeminovascular pathway in the cat is inhibited by dihydroergotamine. A c-Fos and electrophysiology study. Brain 1996; 119: 249–56.

13.

Cumberbatch

Hill

Hargreaves

RJ.

Rizatriptan has central antinociceptive effects against durally evoked responses. Eur J Pharmacol 1997; 328: 37–40.

14.

Goadsby

PJ.

The pharmacology of headache. Prog Neurobiol 2000; 62: 509–25.

15.

Goadsby

Hoskin

Knight

YE.

Substance P blockade with the potent and centrally acting antagonist GR205171 does not effect central trigeminal activity with superior sagittal sinus stimulation. Neuroscience 1998; 86: 337–43.

16.

Goadsby

Hoskin

KL.

Differential effects of low dose CP122,288 and eletriptan on Fos expression due to stimulation of the superior sagittal sinus in cat. Pain 1999; 82: 15–22.

17.

Storer

Akerman

Connor

Goadsby

PJ.

4991W93, a potent blocker of neurogenic plasma protein extravasation, inhibits trigeminal neurons at 5-hydroxytryptamine (5-HT_1B/1D) agonist doses. Neuropharmacology 2001; 40: 911–7.

18.

18. Connor

Bertin

Gillies

Beattie

Ward

The

, 205171 Clinical Study Group.Clinical evaluation of a novel, potent, CNS penetrating NK₁ receptor antagonist in the acute treatment of migraine. Cephalalgia 1998; 18: 392.

19.

19. Roon

Olesen

Diener

Ellis

Hettiarachchi

Poole

, No acute antimigraine efficacy of CP-122,288, a highly potent inhibitor of neurogenic inflammation: results of two randomized, double-blind, placebo-controlled clinical trials. Ann Neurol 2000; 47: 238–41.

20.

Earl

McDonald

Lowy

, 4991 W93 Investigator Group. Efficacy and tolerability of the neurogenic inflammation inhibitor, 4991W93, in the acute treatment of migraine. Cephalalgia 1999; 19: 357.

21.

Silberstein

Karim

Kamin

Jordan

Hulihan

Topiramate prophylaxis in patients suffering from migraine without aura: results from a randomized, double-blind, placebo-controlled trial. Eur J Neurol 2002; 9 (Suppl. 2): 44.

22.

Brandes

Jacobs

Neto

Bhattacharaya

Topiramate in the prevention of migraine headache: a randomized, double-blind, placebo-controlled, parallel study (MIGR-002). Neurology 2003; 60 Suppl 1: A238.

23.

Mathew

Schmitt

Jacobs

Neto

Topiramate in migraine prevention (MIGR-001): effect on migraine frequency. Neurology 2003; 60 Suppl 1: A336.

24.

Wheeler

Carrazana

EJ.

Topiramate-treated cluster headache. Neurology 1999; 53: 234–6.

25.

Matharu

Boes

Goadsby

PJ.

SUNCT syndrome: prolonged attacks, refractoriness and response to topiramate. Neurology 2002; 58: 1307.

26.

Storer

Goadsby

PJ.

Topiramate inhibits trigeminovascular traffic in the cat: a possible locus of action in the prevention of migraine. Neurology 2003; 60 Suppl 1: A238–A239.

27.

Storer

Butler

Hoskin

Goadsby

PJ.

A simple method, using 2-hydroxypropyl-β-cyclodextrin, of administering α-chloralose at room temperature. J Neurosci Meth 1997; 77: 49–53.

28.

Dostrovsky

Sessle

BJ.

Functional properties of neurons in cat trigeminal subnucleus caudalis (medullary dorsal horn). I. Responses to oral-facial noxious and nonnoxious stimuli and projections to thalamus and subnucleus oralis. J Neurophysiol 1981; 45: 173–92.

29.

De Vries

Villalón

Saxena

PR.

Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy. Eur J Pharmacol 1999; 375: 61–74.

30.

Rosenfeld

WE.

Topiramate: a review of the preclinical, pharmacokinetic, and clinical data. Clin Ther 1997; 19: 1294–308.

31.

Shank

Gardocki

Streeter

Maryanoff

BE.

An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 2000; 41 Suppl 1: S3–S9.

32.

Clements

Magnusson

Hautman

Beitz

AJ.

Rat tooth pulp projections to spinal trigeminal subnucleus caudalis are glutamate-like immunoreactive. J Comp Neurol 1991; 309: 281–8.

33.

Magnusson

Larson

Madl

Altschuler

Beitz

AJ.

Co-localization of fixative-modified glutamate and glutaminase in neurons of the spinal trigeminal nucleus of the rat: an immunohistochemical and immunoradiochemical analysis. J Comp Neurol 1986; 247: 477–90.

34.

Tallaksen-Greene

Young

Penney

Beitz

AJ.

Excitatory amino acid binding sites in the trigeminal principal sensory and spinal trigeminal nuclei of the rat. Neurosci Lett 1992; 141: 79–83.

35.

Boucher

Pollin

Azérad

Microinfusions of excitatory amino acid antagonists into the trigeminal sensory complex antagonize the jaw opening reflex in freely moving rats. Brain Res 1993; 614: 155–63.

36.

Bouhassira

Le Bars

Villanueva

Heterotopic activation of Aδ and C fibres triggers inhibition of trigeminal and spinal convergent neurons in the rat. J Physiol 1987; 389: 301–17.

37.

Storer

Goadsby

PJ.

Microiontophoretic application of serotonin (5HT)_1B/1D agonists inhibits trigeminal cell firing in the cat. Brain 1997; 120: 2171–7.

38.

Storer

Connor

Goadsby

PJ.

Microiontophoretic application of 4991W93 inhibits trigeminocervical neurons. Cephalalgia 1999; 19: 314.

39.

Storer

Goadsby

PJ.

Trigeminovascular nociceptive transmission involves N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors. Neuroscience 1999; 90: 1371–6.

40.

Classey

Knight

Goadsby

PJ.

The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical complex following superior sagittal sinus stimulation in the cat. Brain Res 2001; 907: 117–24.

41.

Goadsby

Classey

JD.

Glutamatergic transmission in the trigeminal nucleus assessed with local blood flow. Brain Res 2000; 875: 119–24.

42.

Mitsikostas

Sanchez del Rio

Waeber

Moskowitz

Cutrer

FM.

The NMDA receptor antagonist MK-801 reduces capsaicin-induced c-fos expression within rat trigeminal nucleus caudalis. Pain 1998; 76: 239–48.

43.

Mitsikostas

Sanchez del Rio

Waeber

Huang

Cutrer

Moskowitz

MA.

Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis. Br J Pharmacol 1999; 127: 623–30.

44.

Cutrer

Limmroth

Ayata

Moskowitz

MA.

Attenuation by valproate of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin. Br J Pharmacol 1995; 116: 3199–204.

45.

Cutrer

Moskowitz

MA.

The actions of valproate and neurosteroids in a model of trigeminal pain. Headache 1996; 36: 579–85.

46.

Storer

Akerman

Goadsby

PJ.

Characterization of opioid receptors that modulate nociceptive neurotransmission in the trigeminocervical complex. Br J Pharmacol 2003; 138: 317–24.

47.

Richter

Ebersberger

Mikulik

Schaible

HG.

P/Q-type channels in the brainstem regulate activity of neurons with input from the dura by controlling GABA release from inhibitory interneurons. Program no. 349.13. Abstract Viewer. Washington DC. Society for Neuroscience, 2002 , [WWW document]. URL http://sfn.scholarone.com

48.

Shields

Storer

Akerman

Goadsby

PJ.

Post-synaptic high threshold Voltage Dependent Calcium Channels (VDCC) modulate trigeminovascular nociceptive transmission in the TrigeminoCervical Complex (TCC). Cephalalgia 2003; 23: 726–7.

49.

Akerman

Williamson

Goadsby

PJ.

Voltage-dependent calcium channels are involved in neurogenic dural vasodilatation via a presynaptic transmitter release mechanism. Br J Pharmacol 2003; 140: 558–66.

50.

Goadsby

Lipton

Ferrari

MD.

Migraine — current understanding and treatment. N Eng J Med 2002; 346: 257–70.

51.

51. Weiller

May

Limmroth

Jüptner

Kaube

Schayck

V, Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1: 658–60.

52.

Bahra

Matharu

Buchel

Frackowiak

RSJ

Goadsby

PJ.

Brainstem activation specific to migraine headache. Lancet 2001; 357: 1016–7.

53.

Matharu

Bartsch

Ward

Frackowiak

RSJ

Weiner

Goadsby

PJ.

Central neuromodulation in chronic migraine with implanted suboccipital stimulators. Neurology 2003; 60 Suppl 1: A404–A405.

54.

Knight

Bartsch

Goadsby

PJ.

Trigeminal antinociception induced by bicuculline in the periaqueductal gray (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat. Neurosci Lett 2003; 336: 113–6.

55.

Knight

Goadsby

PJ.

The periaqueductal grey matter modulates trigeminovascular input: a role in migraine?

Neuroscience 2001; 106: 793–800.

56.

Knight

Bartsch

Kaube

Goadsby

PJ.

P/Q-type calcium channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine?

J Neurosci 2002; 2 2: RC213 (1–6).

Topiramate Inhibits Trigeminovascular Neurons in the Cat

Abstract

Keywords

Introduction

Methods

Surgery

Stimulation and recording

Receptive fields

Test compound

Statistical analysis

Results

Localization and neuronal characteristics

Intravenous administration

Discussion

Footnotes

Acknowledgements

References