The link between glutamate and migraine.
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]
Z, Coombes N, Waring RH, Williams AC, Steventon GB.
of neuroexcitatory amino acids in patients with migraine or tension headache.
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
Platelet and plasma levels of glutamate and glutamine in migraine
with and without aura.
Cephalalgia. 1995 Apr;15(2):132-5.
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."
MD, Odink J, Bos KD, Malessy MJ, Bruyn GW.
amino acids are elevated in migraine.
Neurology. 1990 Oct;40(10):1582-6.
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]
J, Martinez F, Leira R, Prieto JM, Lema M, Noya M.
[Changes in neuroexcitatory
amino acids during and between migraine attacks]
"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]
JF, Mar KR, Yaksh TL, Golbeck A, Moore AC.
Cerebrospinal fluid analyses
in migraine patients and controls.
Cephalalgia. 1995 Dec;15(6):489-93.
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]
F, Castillo J, Rodriguez JR, Leira R, Noya M.
acid levels in plasma and cerebrospinal fluid during migraine attacks.
"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]
G, Cananzi AR, Joseph R, Morra M, Zamberlan F, Ferro Milone F, Grunfeld S, Welch
Platelet glycine, glutamate and aspartate in primary headache.
"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]
P, Finocchiaro R, Lendvai D, Celli M, Viozzi L, Troiani P, Turri E, Giardini O.
and plasma levels of glutamate and aspartate in children affected by migraine.
"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]
V, Alberti A, Gallai B, Coppola F, Floridi A, Sarchielli P.
and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal
Cephalalgia. 2003 Apr;23(3):166-74.
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."
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.
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]
Acute treatments: future developments.
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]
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.
bonylimidazol-1-ylmethyl)decahydroiso-quinoline-3-carboxylic ester: a prodrug
of a GluR5 kainate receptor antagonist active in two animal models of acute migraine.
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]
PJ, Akerman S, Storer RJ.
Evidence for postjunctional serotonin (5-HT1)
receptors in the trigeminocervical complex.
"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]
Co-localization of 5-HT(1B/1D/1F) receptors and glutamate in
trigeminal ganglia in rats.
Neuroreport. 2001 Jun 13;12(8):1589-91.
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]
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.
"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]
Pathophysiology of the
migraine aura. The spreading depression theory.
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]
A, Scheller D, Straub H, Tegtmeier F, Kohling R, Hohling JM, Tuxhorn I, Ebner
A, Wolf P, Werner Panneck H, Oppel F, Speckmann EJ.
in human neocortical slices.
Brain Res. 2001 Jul 6;906(1-2):74-83.
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."
LC, Mody I.
Protective Effect of Ifenprodil against Spreading Depression
in the Mouse Entorhinal Cortex.
J Neurophysiol. 2004 Jun
"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."
RJ, Goadsby PJ.
Trigeminovascular nociceptive transmission involves
N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptors.
"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.
NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical
complex following superior sagittal sinus stimulation in the cat.
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."
DD, Sanchez del Rio M.
Receptor systems mediating c-fos expression
within trigeminal nucleus caudalis in animal models of migraine.
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]
PJ, Classey JD.
Glutamatergic transmission in the trigeminal nucleus
assessed with local blood flow.
Brain Res. 2000 Sep 1;875(1-2):119-24.
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]
TR, Andrew RD.
Spreading depression: imaging and blockade in the
rat neocortical brain slice.
J Neurophysiol. 2002 Nov;88(5):2713-25.
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]
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.
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."
RJ, Akerman S, Goadsby PJ.
Characterization of opioid receptors that
modulate nociceptive neurotransmission in the trigeminocervical complex.
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]