Ramadan NM.
The link between glutamate and migraine.
CNS Spectr. 2003 Jun;8(6):446-9.
"Migraine pain-relay centers, including the trigeminal ganglion, trigeminal nucleus caudalis, and thalamus, contain glutamate-positive neurons, and glutamate activates the trigeminal nucleus caudalis. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, and central sensitization. Glutamate receptor-subtype antagonists are effective in preclinical models of migraine, and in the clinic. These preclinical and clinical observations argue for a strong link between migraine and the glutamatergic system, a link that is important to further characterize in an effort to better understand migraine mechanisms and deliver effective therapies." [Abstract]

Alam Z, Coombes N, Waring RH, Williams AC, Steventon GB.
Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache.
J Neurol Sci. 1998;156(1):102-6.
"Plasma amino acids were analysed in patients with migraine with (9) and without (80) aura, in patients with tension headache (14) and in controls (62). The neuroexcitatory amino acids glutamic acid, glutamine, glycine, cysteic acid and homocysteic acid were elevated in migraine patients while total thiols (cysteine/cystine) were reduced. Patients with tension headache had values which were similar to those of controls. Tryptophan was elevated in migraine patients without aura only. Studies on two patients showed that the raised resting excitatory amino acid levels became still further elevated during a migraine attack. These results show that high concentrations of neurotransmitter amino acids occur normally in migraine patients and suggest that this profile may be a contributory factor in migraine attacks. Tension headache, however, has different biochemical parameters." [Abstract]

Cananzi AR, D'Andrea G, Perini F, Zamberlan F, Welch KM.
Platelet and plasma levels of glutamate and glutamine in migraine with and without aura.
Cephalalgia. 1995 Apr;15(2):132-5.
"We evaluated plasma and platelet glutamate and glutamine levels in migraine with and without aura during headache-free periods and compared the results with those of normal controls. The plasma and platelet levels of glutamine in migraine with and without aura were normal. Migraine without aura patients had higher glutamate levels in plasma, and normal platelet levels. In migraine with aura patients, glutamate levels were high in platelets, but not in plasma. This suggests different profiles of excitatory amino acid metabolism in migraine with and without aura." [Abstract]

Ferrari MD, Odink J, Bos KD, Malessy MJ, Bruyn GW.
Neuroexcitatory plasma amino acids are elevated in migraine.
Neurology. 1990 Oct;40(10):1582-6.
"To investigate the role of glutamic (Glu) and aspartic acid (Asp) in migraine, we measured the plasma amino acids in migraine patients with and without aura, between and during attacks, and compared the profiles with the plasma amino acid profiles of tension headache patients and healthy controls. Between attacks, migraineurs (notably with aura) had substantially higher plasma Glu and Asp levels than did controls and tension headache patients. In addition, patients with migraine without aura showed low plasma histidine levels. During migraine attacks, Glu (and to a lesser extent Asp) levels were even further increased. The results suggest a defective cellular reuptake mechanism for Glu and Asp in migraineurs, and we hypothesize a similar defect at the neuronal/glial cell level, predisposing the brain of migraineurs to develop spreading depression." [Abstract]

Castillo J, Martinez F, Leira R, Prieto JM, Lema M, Noya M.
[Changes in neuroexcitatory amino acids during and between migraine attacks]
Neurologia. 1994 Feb;9(2):42-5.
"We studied changes in plasma levels of neuroexcitatory amino acids during and between migraine attacks in 16 patients with migraine without aura, 11 with aura and 21 controls. Glutamic acid levels between attacks were 1.027 +/- 0.60 and 0.890 +/- 0.41 mg/dl in migraine patients without and with aura, respectively; during attacks the levels were 0.535 +/- 0.23 and 0.601 +/- 0.20 for the same patients. The concentration of glutamic acid in the control group was 0.980 +/- 0.64 mg/dl. Aspartic acid levels between attacks in patients without and with aura were 0.179 +/- 0.04 and 0.167 +/- 0.03 mg/dl. Concentrations during attacks were 0.129 +/- 0.02 and 0.119 +/- 0.02 mg/dl for the same patients. Plasma levels of aspartic acid for controls were 0.146 +/- 0.03 mg/dl. We found no significant variations in neuroexcitatory amino acids between migraine attacks in patients with an without aura; changes took place only during attacks, possibly related to the mechanisms of the spreading depression process." [Abstract]

Rothrock JF, Mar KR, Yaksh TL, Golbeck A, Moore AC.
Cerebrospinal fluid analyses in migraine patients and controls.
Cephalalgia. 1995 Dec;15(6):489-93.
"To investigate the role of central neurotransmitters in the pathogenesis of migraine, we measured cerebrospinal fluid (CSF) levels of certain amino acids (glycine, taurine, glutamine) and metabolites of biogenic amines (5-hydroxyindoleacetic acid and homovanillic acid) in 38 migraine patients and compared them with the levels from 10 headache-free controls. The levels of taurine, glycine and glutamine were significantly higher in the migraine patients (p < 0.0001 for taurine and glycine; p < 0.0009 for glutamine); there were no significant differences among the three migraine subgroups (infrequent migraine, frequent migraine and transformed migraine). In seven patients subsequently treated with divalproex sodium, CSF taurine levels decreased significantly from pretreatment baseline values. These data support the concept that migraine is at least in part a disorder of central neurotransmission." [Abstract]

Martinez F, Castillo J, Rodriguez JR, Leira R, Noya M.
Neuroexcitatory amino acid levels in plasma and cerebrospinal fluid during migraine attacks.
Cephalalgia. 1993 Apr;13(2):89-93.
"A current hypothesis for migraine suggests that neuroexcitatory amino acids may participate in the triggering of attacks. To investigate this possibility we measured glutamic and aspartic acid level in plasma and cerebrospinal fluid (CSF) of patients with common and classic migraine during attacks, making comparisons with controls suffering stress. Plasma levels of amino acids in migraine patients were lower than in controls. CSF concentrations of glutamic acid were higher in migraineurs than in controls. Our results suggest an excess of neuroexcitatory amino acids in the CNS of migraine patients during attacks, possibly favoring a state of neuronal hyperexcitability." [Abstract]

D'Andrea G, Cananzi AR, Joseph R, Morra M, Zamberlan F, Ferro Milone F, Grunfeld S, Welch KM.
Platelet glycine, glutamate and aspartate in primary headache.
Cephalalgia. 1991 Sep;11(4):197-200.
"Platelet levels of glutamic and aspartic acid and glycine were measured in patients with migraine with aura, migraine without aura, tension headache and cluster headache. High levels of these amino acids were found in patients with migraine with aura compared to normal subjects and other headache groups. During headache, glutamate levels further increased in migraine with aura patients. These findings may have relevance to the neurological symptoms of migraine with aura." [Abstract]

D'Eufemia P, Finocchiaro R, Lendvai D, Celli M, Viozzi L, Troiani P, Turri E, Giardini O.
Erythrocyte and plasma levels of glutamate and aspartate in children affected by migraine.
Cephalalgia. 1997 Oct;17(6):652-7.
"In this study we determined plasma and erythrocyte amino acids in children affected by migraine, in order to evaluate glutamate and aspartate metabolism in the pathogenesis of this disorder. Fifteen children with migraine with aura (mean age +/- SD = 10.3 +/- 1.56), 19 children with migraine without aura (mean age +/- SD = 10.4 +/- 1.48) and 16 healthy normal controls (mean age +/- SD 10.6 +/- 1.53) were investigated. In both migraine groups there were significantly lower plasma glutamate and aspartate levels and significantly higher erythrocyte/plasma concentration (E/P) ratios of these amino acids with respect to the controls. Erythrocyte aspartate concentrations were significantly elevated in migraine children compared to the controls, while erythrocyte glutamate concentrations showed no significant differences between groups. Similar results were observed in both migraine groups. These results seem to suggest the presence of a higher activity of the erythrocytes' glutamate/aspartate transport system that could reflect a similar alteration at the neuronal/glial cell level in the CNS. Our study suggests an imbalance of the excitatory amino acid turnover in the pathogenesis of migraine in children." [Abstract]

Gallai V, Alberti A, Gallai B, Coppola F, Floridi A, Sarchielli P.
Glutamate and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal fluid.
Cephalalgia. 2003 Apr;23(3):166-74.
"A central sensitization has been advocated to explain chronic daily headache (CDH) due to sustained peripheral sensitization of allogenic structures responsible for sustained trigeminovascular system activation. Several mechanisms have been suggested to underlie central sensitization, but have been poorly investigated in CDH. They involve N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) production and supersensitivity and increased and maintained production of sensory neuropeptides. The present study supports the above pathogenic mechanisms demonstrating a significant increase in glutamate and nitrite levels in the CSF of CDH patients, without a significant difference between patients without and those with analgesic overuse headache (P < 0.0001 and P < 0.002). The increase in CSF nitrites was accompanied by a significant rise in the CSF values of cyclic guanosine monophosphate (cGMP) in patients in comparison with controls (P < 0.0001). A statistically significant correlation emerged between visual analogic scale (VAS) values and glutamate, nitrites and cGMP. Although substance P (SP) and calcitonin gene-related peptide (CGRP), and to a lesser extent neurokinin A, were significantly increased in CSF compared with control subjects, their values did not correlate with glutamate, nitrites and cGMP levels in CSF in the patient group. The present study confirms the involvement of glutamate-NO-cGMP-mediated events underlying chronic head pain that could be the target of a new therapeutic approach which should be investigated." [Abstract]

Sarchielli P, Alberti A, Floridi A, Gallai V.
L-Arginine/nitric oxide pathway in chronic tension-type headache: relation with serotonin content and secretion and glutamate content.
J Neurol Sci. 2002 Jun 15;198(1-2):9-15.
"Previous research of our group demonstrated an increase in L-arginine/nitric oxide (NO) pathway activity in patients with chronic daily headache (CDH) with a previous history of migraine, which was associated with a reduced platelet serotonin content and increased Ca(2+) levels. In the present work, we assessed the variations in L-arginine/NO pathway activity and platelet cyclic guanosine 3',5'-monophosphate (cGMP) levels in 25 patients affected by chronic tension-type headache (CTTH) (8 M, 17 F; age range: 34-54 years). The NO production, shown spectrophotometrically by stoichiometric transformation of oxyhemoglobin to methemoglobin due to NO synthase (NOS) activity, and inter platelet cGMP concentration, assessed with a RIA method, were determined in parallel to variations of aggregation response to 0.3 microg/ml collagen. The intracellular platelet calcium concentrations were also determined using fluorescence polarisation spectrometry. Platelet serotonin content and collagen-induced secretion as well as glutamate content were also determined with high-performance liquid chromatography (HPLC). The above parameters were compared with those of an age-matched control group. A reduction in aggregation platelet response was found. The reduction in platelet aggregation was coupled with an increased NO and cGMP production (p<0.0002 and p<0.001, respectively). A significant increase in cytosolic Ca(2+) concentration was also detected compared to control individuals (p<0.001). This was accompanied by a reduced platelet content and collagen-induced secretion of serotonin and increased content of glutamate (p<0.0001, p<0.0001 and p<0.001, respectively). The above findings were more evident in patients with analgesic abuse. It can be hypothesized that the increased NOS activity shown in platelets of CTTH patients reflects an analogous central up-regulation of NOS activity in the spinal horn/trigeminal nucleus and supraspinal structures involved in the modulation of nociceptive input from myofascial cranial structures contributing to central sensitization. The increase in NOS activity seems to be associated with a hyposerotonergic status, particularly in patients with analgesic abuse, and this can contribute to central sensitization in CTTH patients. The increase in platelet glutamate content in the same patients suggests the implication of the above excitatory amino acid in spinal and supraspinal structures involved in head pain induction and maintenance." [Abstract]

Ramadan NM.
Acute treatments: future developments.
Curr Med Res Opin. 2001;17 Suppl 1:s81-6.
"In Chapter 14, blind alleys in acute anti-migraine drug development were discussed. In this chapter, future therapies are covered. There is growing interest and support for the use of CGRP antagonists, nitric oxide synthase inhibitors, and ionotropic glutamate receptor antagonists. The hope is to strike the balance of high efficacy with minimal to no safety concern and good tolerability. Some of the targets discussed in this chapter have been in early efficacy trials and others are in first human dose stages. Large-scale efficacy and safety trials are eagerly awaited." [Abstract]

Filla SA, Winter MA, Johnson KW, Bleakman D, Bell MG, Bleisch TJ, Castano AM, Clemens-Smith A, del Prado M, Dieckman DK, Dominguez E, Escribano A, Ho KH, Hudziak KJ, Katofiasc MA, Martinez-Perez JA, Mateo A, Mathes BM, Mattiuz EL, Ogden AM, Phebus LA, Stack DR, Stratford RE, Ornstein PL.
Ethyl (3S,4aR,6S,8aR)-6-(4-ethoxycar- bonylimidazol-1-ylmethyl)decahydroiso-quinoline-3-carboxylic ester: a prodrug of a GluR5 kainate receptor antagonist active in two animal models of acute migraine.
J Med Chem. 2002 Sep 26;45(20):4383-6.
"Amino diacid 3, a highly selective competitive GluR5 kainate receptor antagonist, exhibited high GluR5 receptor affinity and selectivity over other glutamate receptors. Its diethyl ester prodrug 4 was orally active in two models of migraine: the neurogenic dural plasma protein extravasation model and the nucleus caudalis c-fos expression model. These data suggest that a GluR5 kainate receptor antagonist might be an efficacious antimigraine therapy with a novel mechanism of action." [Abstract]

Goadsby PJ, Akerman S, Storer RJ.
Evidence for postjunctional serotonin (5-HT1) receptors in the trigeminocervical complex.
Ann Neurol. 2001 Dec;50(6):804-7.
"Units linked to stimulation of the superior sagittal sinus were identified and recorded from in the trigeminocervical complex of the anesthetized cat. Iontophoresis of glutamate NMDA receptor agonists increased the baseline-firing rate of these neurons. Coejection of sumatriptan, 4991W93, or ergometrine resulted in a significant reduction in NMDA agonist-induced increases in firing. These data establish the existence of triptan-sensitive (5-HT1) receptors on postsynaptic central trigeminal neurones." [Abstract]

Ma QP.
Co-localization of 5-HT(1B/1D/1F) receptors and glutamate in trigeminal ganglia in rats.
Neuroreport. 2001 Jun 13;12(8):1589-91.
"Anti-migraine triptan drugs are 5-HT(1B/1D) receptor agonists which are thought to block the neurotransmitter/neuropeptide release from sensory nerve terminals and directly constrict blood vessel smooth muscles. In the present study, we have investigated the anatomical basis for a possible modulation of glutamate release from trigeminal ganglion neurons by 5-HT(1B/1D) receptor agonists and by 5-HT1F receptor agonists, using double immunohistochemical staining technique in the rat. The majority of 5-HT1B, 5-HT1D or 5-HT1F receptor positive neurons were also glutamate positive, but both 5-HT1B, 5-HT1D or 5-HT1F receptor single-labeled and glutamate single-labeled neurons were observed. These results suggest that 5-HT(1B/1D/1F) receptor agonists may modulate glutamate release, and that one mechanism of their anti-migraine action could be the blockade of glutamate release." [Abstract]

Stepien A, Chalimoniuk M, Strosznajder J.
Serotonin 5HT1B/1D receptor agonists abolish NMDA receptor-evoked enhancement of nitric oxide synthase activity and cGMP concentration in brain cortex slices.
Cephalalgia. 1999 Dec;19(10):859-65.
"Our previous studies indicating that the function of excitatory amino acids, NMDA type receptor, is modulated by serotonin focused on the interaction between serotonin 5HT1B/1D and glutamate, NMDA receptor in brain cortex. The effect of agonists of 5HT1B/1D receptor, sumatriptan, and zolmitriptan on NMDA receptor-evoked activation of nitric oxide (NO) and cGMP synthesis in adult rat brain cortex slices was investigated. Two kinds of experiment were carried out using adult rats. In one of them, sumatriptan or zolmitriptan was administered in vivo subcutaneously (s.c.) in a dose of 0.1 mg per kg body weight. Brain slices were then prepared and used in the experiments or, in the other exclusively in vitro studies, both agonists at 10 microM concentration were added directly to the incubation medium containing adult rat brain cortex slices. The data obtained from these studies indicated that stimulation of NMDA receptor in brain cortex slices leads to a large increase in calcium, calmodulin-dependent NO synthase (NOS) activity and to significant enhancement of the cGMP level. This NMDA receptor-dependent NO and cGMP release was completely blocked by competitive and noncompetitive NMDA receptor antagonists APV (10 microM) or MK-801 (10 microM.), respectively. The specific inhibitor of Ca(2+)-dependent isoforms of NOS (N-nitro-1-arginine NNLA and 7-nitroindozole (7-N1)) eliminated the NMDA receptor-mediated enhancement of NO and cGMP release. Moreover, the serotonin 5HT1B/1D receptor agonists sumatriptan and zolmitriptan administrated in vivo (s.c.) or in vitro abolished NMDA receptor-evoked NO signalling in brain cortex. The potency of both agonists investigated directly in vitro was similar to their effect after in vivo administration. These results suggest that both serotonin 5HT1B/1D receptor agonists may play an important role in modulating the NO and cGMP-dependent signal transduction pathway in the brain. This effect of sumatriptan and zolmitriptan on NO signaling in the brain system should be taken into consideration when investigating their mechanism of action in the migraine attack." [Abstract]

Lauritzen M.
Pathophysiology of the migraine aura. The spreading depression theory.
Brain. 1994 Feb;117 ( Pt 1):199-210.
"The characteristic form and development of sensory disturbances during migraine auras suggests that the underlying mechanism is a disturbance of the cerebral cortex, probably the cortical spreading depression (CSD) of Leao. The demonstration of unique changes of brain blood flow during attacks of migraine with aura, which have been replicated in animal experiments during CSD, constitutes another important line of support for the 'spreading depression' theory, which may be a key to an understanding of the migraine attack. Cortical spreading depression is a short-lasting depolarization wave that moves across the cortex at a rate of 3-5 mm/min. A brief phase of excitation heralds the reaction which is immediately followed by prolonged nerve cell depression synchronously with a dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells and enhanced energy metabolism. Recent experimental work has shown that CSD in the neocortex of a variety of species including man is dependent on activation of a single receptor, the N-methyl-D-aspartate receptor, one of the three subtypes of glutamate receptors. The combined experimental and clinical studies point to fruitful areas in which to look for migraine treatments of the future and provide a framework within which important aspects of the migraine attack can be modelled." [Abstract]

Gorji A, Scheller D, Straub H, Tegtmeier F, Kohling R, Hohling JM, Tuxhorn I, Ebner A, Wolf P, Werner Panneck H, Oppel F, Speckmann EJ.
Spreading depression in human neocortical slices.
Brain Res. 2001 Jul 6;906(1-2):74-83.
"Cortical spreading depression (CSD) occurrence has been suggested to be associated with seizures, migraine aura, head injury and brain ischemia-infarction. Only few studies identified CSD in human neocortical slices and no comprehensive study so far evaluated this phenomenon in human. Using the neocortical tissue excised for treatment of intractable epilepsy, we aimed to investigate CSD in human. CSD was induced by KCl injection and by modulating T-type Ca(2+) currents in incubated human neocortical tissues in an interphase mode. The DC-fluctuations were recorded by inserting microelectrodes into different cortical layers. Local injection of KCl triggered single CSD that propagated at 3.1+/-0.1 mm/min. Repetitive CSD also occurred spontaneously during long lasting application (5 h) of the T-type Ca(2+) channel blockers amiloride (50 microM) or NiCl(2) (10 microM) which was concomitant with a reversible extracellular potassium increase up to 50 mM. CSD could be blocked by the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovaleric acid in all cases. The results demonstrate that modulation of the Ca(2+) dynamics conditioned human neocortical slices and increased their susceptibility to generate CSD. Furthermore, these data indicate that glutamatergic pathway plays a role in CSD phenomenon in human." [Abstract]

Faria LC, Mody I.
Protective Effect of Ifenprodil against Spreading Depression in the Mouse Entorhinal Cortex.
J Neurophysiol. 2004 Jun 16
"In the brain, spreading depression (SD) is characterized by a large extracellular DC shift, a massive failure of ion homeostasis and a transient cessation of neuronal function. Clinically, SD is believed to be involved in various neurological disorders including migraine and cerebrovascular diseases. The propagation of cortical SD requires the release of glutamate, and NMDA receptors play a crucial role in this process. Here, we have isolated the NMDA-receptor-mediated component of extracellularly recorded field EPSPs (fEPSPs) in layers 2-3 of the entorhinal cortex of murine brain slices. In the absence of GABAA and AMPA receptor mediated synaptic transmission, stimulation of layer 6 afferents every 15 - 90 s elicited spontaneous SD on average within 18.5 min after the start of the stimulation. In the presence of ifenprodil, an NR2B receptor subunit-selective NMDA receptor antagonist, the occurrence of SD was nearly abolished. Our results are consistent with an important role of NR2B subunits in triggering SD in the entorhinal cortex." [Abstract]

Storer RJ, Goadsby PJ.
Trigeminovascular nociceptive transmission involves N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors.
Neuroscience. 1999;90(4):1371-6.
"Interest in the fundamental mechanisms underlying headache, particularly the pathophysiology of migraine and cluster headache, has lead to the study of the physiology and pharmacology of the trigeminovascular system and its central ramifications. Cats were anaesthetized (60 mg/kg alpha-chloralose, i.p., along with halothane for all surgical procedures) and prepared for physiological monitoring. The animals were placed in a stereotaxic frame and ventilated. A midline craniotomy and C2 laminectomy were performed for access to the superior sagittal sinus and C2 dorsal horn, respectively. The sinus was isolated from the underlying cortex and stimulated electrically after the animals had been paralysed with gallamine (6 mg/kg, i.v.). Units linked to stimulation were recorded with a tungsten-in-glass microelectrode placed in the most caudal part of the trigeminal nucleus, the trigeminocervical complex. Signals from the neurons were amplified, filtered and passed to a microcomputer, where post-stimulus histograms were constructed on-line to analyse the responses to stimulation. Units responded to sagittal sinus stimulation with a typical latency of 8-10 ms. All units studied had a probability of firing of 0.6 or greater. Intravenous injection of the non-competitive N-methyl-D-aspartate receptor antagonist, dizocilpine maleate (4 mg/kg, i.v.), resulted in a substantial and prolonged blockade of firing of units in the trigeminocervical complex. Similarly, administration of the non-N-methyl-D-aspartate excitatory amino acid receptor blocker, GYKI 52466, lead to a dose-dependent inhibition of trigeminovascular-evoked responses in the trigeminocervical complex. These data demonstrate the participation of both N-methyl-D-aspartate- and non-N-methyl-D-aspartate-mediated mechanisms in transmission within the trigeminocervical complex, and suggest a clear preclinical role of glutamatergic mechanisms in primary headache syndromes, such as migraine and cluster headache." [Abstract]

Classey JD, Knight YE, 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 Jul 13;907(1-2):117-24.
"Expression of Fos protein is an indicator of neuronal perturbation and is readily observed in the caudal medulla and the spinal cord following trigeminovascular nociceptive activation by electrical stimulation of the superior sagittal sinus (SSS) in the cat. It has been shown in the rat that N-methyl-D-aspartate (NMDA) receptor blockade causes a reduction in Fos protein expression after generalised meningeal irritation. We wished to examine if the same relationship was true in the cat, using the same non-competitive NMDA receptor antagonist MK-801, and a trigeminovascular-specific stimulus. A group of experimental animals underwent stimulation following blinded administration of MK-801 (4 mg/kg i.v.); control animals underwent stimulation minus MK-801, and a non-stimulated control animal underwent surgery alone. The regions examined for Fos-like immunoreactivity were the trigeminal nucleus caudalis (TNC) and its caudal extension into the C(1) and C(2) levels of the upper cervical spinal cord. The Fos-positive cell counts for the three regions (TNC, C(1) and C(2)) were grouped together for analysis. In the control stimulated group a median of 78 (56-99, quartile range, n=4) cells were Fos-positive. In the group treated with MK-801 the median number of Fos-positive cells was reduced to 40 (30-48; P<0.03, n=7). The large reduction that was observed in SSS stimulation-evoked Fos protein expression following the administration of MK-801, taken together with electrophysiological data, indicates a role for glutamate in neurotransmission within the trigeminocervical complex. Understanding glutamatergic mechanisms in the trigeminocervical complex offers mechanistic insight and therapeutic possibilities for primary neurovascular headaches, such as migraine." [Abstract]

Mitsikostas DD, Sanchez del Rio M.
Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine.
Brain Res Brain Res Rev. 2001 Mar;35(1):20-35.
"In intracranial structures unmyelinated C- and Adelta-fibers of the trigeminal nerve transmit pain stimuli from meninges to the trigeminal nucleus caudalis (Sp5C). Peripheral nerve endings surround meningeal vessels (the so-called trigeminovascular system) and contain vasoactive neuropeptides (calcitonin gene-related peptide, substance P and neurokinin A). Activation of the trigeminovascular system promotes a meningeal sterile inflammatory response through the release of neuropeptides by peripheral endings. Orthodromic conduction along trigeminovascular fibers transmits information centrally with induction of immediate early c-fos gene within post-synaptic Sp5C neurons, as a marker of neuronal activity within central nociceptive pathways. In laboratory animals the system is activated by either electrical stimulation of the TG, chemical stimulation of the meninges, electrical or mechanical stimulation of the superior sagittal sinus or by induction of cortical spreading depression. All these techniques induce c-fos within Sp5C and are used as a rodent/feline model of vascular headache in humans. Up-to-date there is evidence that at least ten receptors (5-HT(1B), 5-HT(1D), 5-HT(lF), 5-HT(2B), NK-1, GABA(A), NMDA, AMPA, class III metabotropic glutamate receptors, and opioids mu receptors) modulate c-fos expression within Sp5C. These receptors represent potential targets for anti-migraine drugs as shown by triptans (5-HT(1B/1D/1F)) and ergot alkaloids (5-HT(1A1B/1D/1F)). This review discusses the importance of c-fos expression within Sp5C as a marker of cephalic nociception, the different cephalic pain models that induce c-fos within Sp5C, the receptors involved and their potential role as targets for anti-migraine drugs." [Abstract]

Goadsby PJ, Classey JD.
Glutamatergic transmission in the trigeminal nucleus assessed with local blood flow.
Brain Res. 2000 Sep 1;875(1-2):119-24.
"Stimulation of the superior sagittal sinus in humans is pain-producing and in experimental animals leads to excitation of neurons in the caudal trigeminal nucleus and dorsal horns of the C(1/)C(2) cervical spinal cord: the trigeminocervical complex. Neuronal excitation is generally associated with an increase in local blood flow due to flow/metabolism coupling and we have used local blood flow in the trigeminocervical complex to examine the role of N-methyl-D-aspartate (NMDA)-mediated transmission in these neurons. Cats were anaesthetised with alpha-chloralose (60 mg/kg, ip; supplements 20 mg/kg iv) after surgical preparation under halothane (0.5-3%). Animals were paralysed with gallamine triethiodide to prevent possible movement artefact distorting the laser Doppler signals. The superior sagittal sinus was isolated for electrical stimulation (150 V; 250 microsec duration; 0.5, 1, 2, 5, 10 and 20 Hz) and the dorsal surface of the spinal cord exposed at the C(2) level. Blood flow was recorded from the region over the trigeminocervical complex by careful placement of a laser Doppler flow probe. Flow was recorded continuously by an online collection programme and NMDA-mediated transmission modulated by intravenous administration of MK-801 (0.4, 1 and 4 mg/kg, iv) at the stimulation frequency of 5 Hz. Stimulation of the superior sagittal sinus produced a stimulus-locked, frequency-dependent increase in blood flow in the region of the trigeminocervical complex. The mean maximum response was 39+/-4% at 20 Hz. MK-801 had no effect on the resting flow signal but markedly attenuated the SSS-evoked response in a dose-dependent manner. The mean maximum response after 4 mg/kg MK-801 was 13+/-2%. NMDA-mediated transmission is likely to be involved in nociceptive trigeminovascular transmission within the trigeminocervical complex and offers a possible target for both acute and preventative treatment of migraine." [Abstract]

Anderson TR, Andrew RD.
Spreading depression: imaging and blockade in the rat neocortical brain slice.
J Neurophysiol. 2002 Nov;88(5):2713-25.
"Spreading depression (SD) is a profound but transient depolarization of neurons and glia that migrates across the cortical and subcortical gray at 2-5 mm/min. Under normoxic conditions, SD occurs during migraine aura where it precedes migraine pain but does not damage tissue. During stroke and head trauma, however, SD can arise repeatedly near the site of injury and may promote neuronal damage. We developed a superfused brain slice preparation that can repeatedly support robust SD during imaging and electrophysiological recording to test drugs that may block SD. Submerged rat neocortical slices were briefly exposed to artificial cerebrospinal fluid (ACSF) with KCl elevated to 26 mM. SD was evoked within 2 min, recorded in layers II/III both as a negative DC shift and as a propagating front of elevated light transmittance (LT) representing transient cell swelling in all cortical layers. An SD episode was initiated focally and could be repeatedly evoked and imaged with no damage to slices. As reported in vivo, pretreatment with one of several N-methyl-D-aspartate (NMDA) receptor antagonists blocked SD, but a non-NMDA glutamate receptor antagonist (CNQX) had no effect. NMDA receptor (NMDAR) activation does not initiate SD nor are NMDAR antagonists tolerated therapeutically so we searched for more efficacious drugs to block SD generation. Pretreatment with the sigma-one receptor (sigma(1)R) agonists dextromethorphan (10-100 microM), carbetapentane (100 microM), or 4-IBP (30 microM) blocked SD, even when KCl exposure was extended beyond 5 min. The block was independent of NMDA receptor antagonism. Two sigma(1)R antagonists [(+)-3PPP and BD-1063] removed this block but had no effect upon SD alone. Remarkably, the sigma(1)R agonists also substantially reduced general cell swelling evoked by bath application of 26 mM KCl. More potent sigma(1)R ligands that are therapeutically tolerated could prove useful in reducing SD associated with migraine and be of potential use in stroke or head trauma." [Abstract]

Obrenovitch TP, Zilkha E.
Inhibition of cortical spreading depression by L-701,324, a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor complex.
Br J Pharmacol. 1996 Mar;117(5):931-7.
"1. Spreading depression (SD) is a propagating transient suppression of electrical activity, associated with cellular depolarization, which probably underlies the migraine aura and may contribute to neuronal damage in focal ischaemia. The purpose of this study was to examine whether L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2-(1H)-quinolone), a high affinity antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex, inhibits the initiation and propagation of K(+)-induced SD in the rat cerebral cortex in vivo. 2. Microdialysis probes incorporating a recording electrode were implanted in the cerebral cortex of anaesthetized rats and perfused with artificial cerebrospinal fluid (ACSF). Five episodes of repetitive SD were elicited by switching to a medium containing 130 mM K+ for 20 min, each separated by 40 min of recovery (i.e. perfusion with normal ACSF). The brief negative shifts of the extracellular direct current (d.c.) potential, characteristic of SD elicitation, were recorded with the microdialysis electrode and a reference electrode placed under the scalp. Propagation of SD was examined using glass capillary electrodes inserted about 3 mm posterior to the microdialysis electrode. L-701,324 (5 or 10 mg kg-1) or its vehicle were administered i.v. 10 min after the end of the second K(+)-stimulus. The effects of L-701,324 were compared to those of dizocilpine (MK-801; 1 mg kg-1 i.v.), a NMDA-channel blocker known to potently block SD elicitation. 3. Potassium-induced SD initiation was inhibited by 10 mg kg-1 (but not by 5 mg kg-1) of L-701,324. Thirty minutes after administration of 10 mg kg-1 L-701,324, the cumulative area of SD peaks elicited during 20 min was 15.3 +/- 2.1 mV min, versus 23.2 +/- 1.1 mV min in animals which received only the drug vehicle (P < 0.02; n = 6). The delay between application of 130 mM K+ and occurrence of the first SD was also significantly increased. It was approximately doubled in animals treated with 10 mg kg-1 of L-701,324. 4. SD propagation was more sensitive than SD elicitation to L-701,324, as both 5 and 10 mg kg-1 produced an effective inhibition. Even at the lower dose of 5 mg kg-1, L-701,324 completely blocked the propagation of SD elicited 30 min after drug administration. This differential sensitivity of SD elicitation and propagation is not specific to L-701,324 since it was previously observed with other drugs. At doses effective against SD, L-701,324 did not produce any marked alterations of the electroencephalogram. 5. L-701,324 (10 mg kg-1) and MK-801 (1 mg kg-1) had identical effects on the d.c. potential when administered during the recovery which followed the second K+ stimulus. Both drugs produced a positive shift of around 4.5 mV within 10 min of i.v. drug administration, indicating rapid drug penetration into the CNS. Paradoxically, L-701,324 (10 mg kg-1) was markedly less effective than MK-801 (1 mg kg-1) in blocking SD, since this dose of MK-801 was sufficient virtually to abolish SD initiation and completely block its propagation. The higher potency of MK-801 against SD may reflect its use-dependency, i.e. binding of MK-801 and channel blockade are enhanced when the NMDA-receptor ionophore is open. 6. Taken together, these data demonstrate that L-701,324 has an inhibitory effect on both SD initiation and propagation. This action may be beneficial in focal ischaemia, and possibly also against migraine, especially as this drug was shown to be active when administered orally." [Abstract]

Storer RJ, Akerman S, Goadsby PJ.
Characterization of opioid receptors that modulate nociceptive neurotransmission in the trigeminocervical complex.
Br J Pharmacol. 2003 Jan;138(2):317-24.
"1. Opioid agonists have been used for many years to treat all forms of headache, including migraine. We sought to characterize opioid receptors involved in craniovascular nociceptive pathways by in vivo microiontophoresis of micro -receptor agonists and antagonists onto neurons in the trigeminocervical complex of the cat. 2. Cats were anaesthetized with alpha-chloralose 60 mg kg(-1), i.p. and 20 mg kg(-1), i.v. supplements after induction and surgical preparation using halothane. Units were identified in the trigeminocervical complex responding to supramaximal electrical stimulation of the superior sagittal sinus, and extracellular recordings of activity made. 3. Seven- or nine-barrelled glass micropipettes incorporating tungsten recording electrodes in their centre barrels were used for microiontophoresis of test substances onto cell bodies. 4. Superior sagittal sinus (SSS)-linked cells whose firing was evoked by microiontophoretic application of L-glutamate (n=8 cells) were reversibly inhibited by microiontophoresis of H(2)N-Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) (n=12), a selective micro -receptor agonist, in a dose dependent manner, but not by control ejection of sodium or chloride ions from a barrel containing saline. 5. The inhibition by DAMGO of SSS-linked neurons activated with L-glutamate could be antagonized by microiontophoresis of selective micro -receptor antagonists D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), or both, in all cells tested (n=4 and 6, respectively). 6. Local iontophoresis of DAMGO during stimulation of the superior sagittal sinus resulted in a reduction in SSS-evoked activity. This effect was substantially reversed 10 min after cessation of iontophoresis. The effect of DAMGO was markedly inhibited by co-iontophoresis of CTAP. 7. Thus, we found that micro -receptors modulate nociceptive input to the trigeminocervical complex. Characterizing the sub-types of opioid receptors that influence trigeminovascular nociceptive transmission is an important component to understanding the pharmacology of this synapse, which is pivotal in primary neurovascular headache." [Abstract]