SJ, Rapoport A, Sheftell F.
The pathophysiology of migraine.
"BACKGROUND: Migraine results from episodic changes
in central nervous system physiologic function in hyperexcitable brain manifested
by abnormal energy metabolism, lowered threshold for phosphene generation, and
increased contingent negative variation. Human functional magnetic resonance imaging
and magnetoencepholography data strongly suggest that aura is caused by cortical
spreading depression. REVIEW SUMMARY: Brain hyperexcitability may be caused by
low magnesium levels, mitochondrial abnormalities with abnormal phosphorylation
of adenosine 5'-diphosphate, a dysfunction related to nitric oxide, or calcium
channelopathy. Low magnesium can result in opening of calcium channels, increased
intracellular calcium, glutamate release, and increased extracellular potassium,
which may in turn trigger cortical spreading depression. Mitochondrial dysfunction
has been suggested by a low phosphocreatine:Pi ratio and a possible response by
migraine patients to riboflavin prophylaxis. Nitroglycerine administration results
in a delayed migraine-like headache in migraine patients but not in control patients,
and a nonspecific nitric oxide synthase inhibitor aborted migraine at 2 hours
in the majority of tested migraine patients compared to controls. Many patients
with familial hemiplegic migraine have a missense mutation in the P/Q calcium
channel, so that this form of migraine, at least, is associated with a demonstrable
calcium channelopathy. CONCLUSIONS: The generation of migraine occurs centrally
in the brain stem, sometimes preceded by cortical spreading depression and aura.
Activation of the trigeminovascular system stimulates perivascular trigeminal
sensory afferent nerves with release of vasoactive neuropeptides, resulting in
vasodilation and transduction of central nociceptive information. There is then
a relay of pain impulses to central second- and third-order neurons and activation
of brain stem autonomic nuclei to induce associated symptoms." [Abstract]
Nitric oxide synthase inhibitors
for the treatment of chronic tension-type headache.
Opin Pharmacother. 2002 Apr;3(4):395-9.
"Chronic tension-type headache
may be caused by prolonged painful input from pericranial myofacial tissues, for
example tender points, resulting in central sensitisation (increased excitability
of neurons in the central nervous system). Animal studies have shown that sensitisation
of pain pathways may be caused by or associated with the activation of neuronal
nitric oxide synthase and the generation of nitric oxide. Furthermore, it has
been shown that nitric oxide synthase inhibitors reduce central sensitisation
in animal models of persistent pain. On the basis of this information, the analgesic
effect of the nitric oxide synthase inhibitor L-N(G) methyl arginine hydrochloride
was investigated. This drug significantly reduced headache and myofacial factors
in patients with chronic tension-type headache. These studies show that nitric
oxide plays a crucial role in the pathophysiology of tension-type headache. The
analgesic effect of nitric oxide synthase inhibition in patients with chronic
tension-type headache is probably due to a reduction in central sensitisation
at the level of the spinal dorsal horn, trigeminal nucleus or both. Furthermore,
inhibition of nitric oxide synthase may become a novel principle in the future
treatment of chronic headache." [Abstract]
LL, Olesen J.
Nitric oxide in primary headaches.
Opin Neurol. 2001 Jun;14(3):315-21.
"The molecular mechanisms that underlie
the primary headaches-migraine, cluster headache and tension-type headache-have
not yet been clarified. On the basis of studies in headache induced by intravenous
infusions of glyceryl trinitrate (an exogenous nitric oxide donor) and histamine
(which liberates nitric oxide from vascular endothelium), it has been suggested
that nitric oxide is a likely candidate responsible molecule. The present review
deals with the biology of this small messenger molecule, and the updated scientific
evidence that suggests a key role for this molecule in primary headaches. This
evidence suggests that the release of nitric oxide from blood vessels, perivascular
nerve endings or from brain tissue is an important molecular trigger mechanism
in spontaneous headache pain. Pilot trials have shown efficacy of a nitric oxide
synthase inhibitor in both migraine attacks and chronic tension-type headache.
These observations suggest new approaches to the pharmacological treatment of
SJ, Smith MI, Hunter AJ, Parsons AA.
Enhanced nitric oxide release
during cortical spreading depression following infusion of glyceryl trinitrate
in the anaesthetized cat.
Cephalalgia. 1997 May;17(3):159-65.
infusion of glyceryl trinitrate (GTN) into migraineurs induces an immediate headache
followed by migraine. We studied the effect of GTN (0.25 microgram kg-1 min-1)
on local cerebrovascular laser Doppler flux (rCBFLDF), artery diameter and NO
concentration (selective NO microelectrode) in the pial middle cerebral artery
perfusion territory of the anaesthetized cat, at rest and during cortical spreading
depression (SD). GTN infusion induced a significant increase in pial artery diameter,
rCBFLDF, and NO concentration. Following termination of infusion, NO concentrations
remained significantly elevated above controls for 60 min, other parameters returned
to baseline within 10 min (p < 0.05, ANOVA, post hoc Dunnett's multiple comparison
procedure). Two hours after termination of infusion KCl-evoked SD was initiated.
GTN-treated animals exhibited significantly (p < 0.05, Kruskal-Wallis) elevated
SD-induced NO release compared to controls. All other parameters remained unaffected.
Our results demonstrate that GTN induces a prolonged increase in local NO concentrations
and enhances SD-induced NO release." [Abstract]
M, Schilling L, Parsons AA, Kaumann A.
Involvement of calcitonin
gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation
elicited by cortical spreading depression.
Brain Res. 1994
"The aim of the present study was to examine whether
the initial transient arterial dilatation during cortical spreading depression
(CSD) was mediated by the release of calcitonin gene-related peptide (CGRP) and/or
nitric oxide (NO). This question is of interest as the initial phase of CSD appears
to be a model of events occurring during functional hyperemia and during the first
period of classic migraine. Using an open cranial window technique, pial arterial
diameter in the parietal cortex of cats was recorded with an image splitting method.
Employing micropuncture technique, perivascularly applied CGRP8-37 did not alter
the resting diameter of pial arteries but antagonized concentration dependently
(5 x 10(-9)-10(-6) M) the dilatation (35%) due to 5 x 10(-8) M CGRP. NG-Nitro-L-Arginine
(NOLAG, 10(-4) M) also had no effect on resting diameter of pial arteries, indicating
that their resting tone is neither mediated by a continuous release of CGRP nor
of NO. CSD was triggered by a remote intracortical injection of KCl (150 mM) and
recorded by a microelectrode placed adjacent to the artery under investigation.
CSD elicited a transient negative DC shift which was accompanied by a peak dilatation
of 44 +/- 5.2% (S.E.M.). This dilatation was reduced by approximately 50% during
topical application of 10(-7) M CGRP8-37 and 10(-4) M NOLAG each. A 75% inhibition
of the CSD-induced dilatation was found during simultaneous application of both
compounds. These data indicate that the initial dilatation during CSD is mediated,
at least in part, by a release of CGRP and NO." [Abstract]
TP, Urenjak J, Wang M.
Nitric oxide formation during cortical spreading
depression is critical for rapid subsequent recovery of ionic homeostasis.
Cereb Blood Flow Metab. 2002 Jun;22(6):680-8.
"Cortical spreading depression
(CSD) is a temporary disruption of local ionic homeostasis that propagates slowly
across the cerebral cortex. Cortical spreading depression promotes lesion progression
in experimental stroke, and may contribute to the initiation of migraine attacks.
The purpose of this study was to investigate the roles of the marked increase
of nitric oxide (NO) formation that occurs with CSD. Microdialysis electrodes
were implanted in the cortex of anesthetized rats to perform the following operations
within the same region: (1) elicitation of CSD by perfusion of high K+ medium;
(2) recording of CSD elicitation; (3) application of the NO synthase inhibitor,
NG-nitro-l-arginine methyl ester (l-NAME); and (4) recording of dialysate pH changes.
The primary effect of l-NAME (0.3 to 3.0 mmol/L in the perfusion medium) was a
marked widening of individual CSD wave, resulting essentially from a delayed initiation
of the repolarization phase. This change was due to NO synthase inhibition because
it was not observed with the inactive isomer d-NAME, and was reversed by l-arginine.
This effect did not appear to be linked to the suppression of a sustained, NO-mediated
vascular change associated with the superposition of NO synthase inhibition on
high levels of extracellular K+. The delayed initiation of repolarization with
local NO synthase inhibition may reflect the suppression of NO-mediated negative
feedback mechanisms acting on neuronal or glial processes involved in CSD genesis.
However, the possible abrogation of a very brief, NO-mediated vascular change
associated with the early phase of CSD cannot be ruled out." [Abstract]
M, Obrenovitch TP, Urenjak J.
Effects of the nitric oxide donor,
DEA/NO on cortical spreading depression.
"Cortical spreading depression (CSD) is a transient
disruption of local ionic homeostasis that may promote migraine attacks and the
progression of stroke lesions. We reported previously that the local inhibition
of nitric oxide (NO) synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME)
delayed markedly the initiation of the recovery of ionic homeostasis from CSD.
Here we describe a novel method for selective, controlled generation of exogenous
NO in a functioning brain region. It is based on microdialysis perfusion of the
NO donor, 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO). As DEA/NO does not
generate NO at alkaline pH, and as the brain has a strong acid-base buffering
capacity, DEA/NO was perfused in a medium adjusted at alkaline (but unbuffered)
pH. Without DEA/NO, such a microdialysis perfusion medium did not alter CSD. DEA/NO
(1, 10 and 100 microM) had little effect on CSD by itself, but it reversed in
a concentration-dependent manner the effects of NOS inhibition by 1 mM L-NAME.
These data demonstrate that increased formation of endogenous NO associated with
CSD is critical for subsequent, rapid recovery of cellular ionic homeostasis.
In this case, the molecular targets for NO may be located either on brain cells
to suppress mechanisms directly involved in CSD genesis, or on local blood vessels
to couple flow to the increased energy demand associated with CSD." [Abstract]
Fabricius M, Akgoren N, Lauritzen
Arginine-nitric oxide pathway and cerebrovascular regulation in
cortical spreading depression.
Am J Physiol. 1995 Jul;269(1
"Nerve cells release nitric oxide (NO) in response to activation
of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype. We explored
the hypothesis that NO influences the changes of cerebral blood flow (CBF) during
cortical spreading depression (CSD), which is known to be associated with NMDA
receptor activation. CBF was monitored in parietal cortex by laser-Doppler flowmetry
in halothane-anesthetized rats. Under control conditions, CSD induced regular
changes of CBF, which consisted of four phases: a brief hypoperfusion before the
direct current (DC) shift; a marked CBF rise during the DC shift; followed by
a smaller, but protracted increase of CBF; and a prolonged CBF reduction (the
oligemia). NO synthase inhibition by intravenous and/or topical application of
NG-nitro-L-arginine enhanced the brief initial hypoperfusion, but the CBF increases
and the oligemia were unchanged. L-Arginine prevented the development of the prolonged
oligemia after CSD but had no influence on the marked rise of CBF during CSD.
Animals treated with L-arginine recovered the reduced vascular reactivity to hypercapnia
after CSD much faster than control rats. Functional denervation of cortical and
pial arterioles by tetrodotoxin accentuated the pre-CSD hypoperfusion and the
oligemia but did not affect the CBF increases. The results suggest that NO is
important for the changes of cerebrovascular regulation following CSD. The observations
may have clinical importance, since CBF changes during migraine may be triggered
by CSD." [Abstract]
SJ, Hirst WD, Upton N, Parsons AA.
Cortical spreading depression
produces increased cGMP levels in cortex and brain stem that is inhibited by tonabersat
(SB-220453) but not sumatriptan.
Brain Res. 2001 Feb 9;891(1-2):69-77.
headache is proposed to be mediated by nitric oxide (NO). Suitable mechanisms
for eliciting increases in brain NO concentration in migraineurs have not yet
been identified, although, animal models highlight cortical spreading depression
(CSD) as a potential candidate. These studies have focused on CSD-associated NO
release at highly acute time points (min-hours) and have not employed markers
of NO metabolism with direct clinical application e.g. cGMP. The current study
evaluated changes in plasma cGMP concentrations 3 h, 24 h and 3 days post-CSD
and compared these to cortical and brainstem cGMP concentrations at 3 days. Moreover,
this study also examined the effect of sumatriptan, a clinically effective antimigraine
agent, and tonabersat (SB-220453) a potential novel antimigraine agent, on any
observed changes in cGMP. Following pre-treatment with vehicle (n=3), sumatriptan
(300 microg kg(-1) i.v, n=3) or tonabersat (SB-220453 10 mg kg(-1) i.p., n=3),
CSD was evoked in anaesthetised rats by a 6-min KCl application to the parietal
cortex. In the vehicle-treated group a median of eight depolarisations, were observed.
Sumatriptan had no effect on the number of depolarisations, whereas tonabersat
significantly reduced the number of events (median=2). No depolarisation events
were observed throughout the recording period in the sham group. Following KCl
application plasma cGMP concentrations were reduced up to 24 h post-CSD, but not
significantly different from sham animals at 3 days. CSD in vehicle-treated animals
produced a highly significant elevation in cGMP concentration in the brain stem
3 days after application of KCl. cGMP concentration increased 2.3-fold from 68+/-8
fmol/mg in sham animals (n=3) to 158+/-28 fmol/mg in the vehicle group. This increase
in brain stem cGMP was abolished by tonabersat pre-treatment but not by sumatriptan."
MI, Read SJ, Chan WN, Thompson M, Hunter AJ, Upton N, Parsons AA.
cortical spreading depression in a gyrencephalic feline brain: inhibition by the
novel benzoylamino-benzopyran SB-220453.
"Transient cortical depolarization is implicated in
the pathology of migraine. SB-220453 is a potent anti-convulsant which inhibits
neurogenic inflammation and cortical spreading depression (SD)-evoked nitric oxide
release via a novel but unknown mechanism. This study further investigates the
effects of SB-220453 on generation and propagation of repetitive SD in the anaesthetized
cat. Vehicle or SB-220453 1, 3 or 10 mg/kg was administered intraperitoneally
90 min prior to induction of SD in the suprasylvian gyrus (SG). Changes in d.c.
potential were recorded in the SG and the adjacent marginal gyrus (MG). In vehicle-treated
animals (n = 7), a brief exposure (6 min) to KCl induced a median (25-75% range)
number of five (four to six) and three (two to four) depolarizations over a duration
of 55 min (32-59 min) and 51 min (34-58 min) in the SG and MG, respectively. SB-220453
produced dose-related inhibition of the number of events and period of repetitive
SD activity. SB-220453 also reduced SD-induced repetitive pial vasodilatation
but had no effect on resting haemodynamics. However, when SD events were observed
in the presence of SB-220453, it had no effect on metabolic coupling. These results
show that SB-220453 produces marked inhibition of repetitive SD in the anaesthetized
cat. SB-220453 may therefore have therapeutic potential in treatment of SD-like
activity in migraine." [Abstract]
Knyihar-Csillik E, Tajti J, Chadaide Z, Csillik B,
Functional immunohistochemistry of neuropeptides and nitric
oxide synthase in the nerve fibers of the supratentorial dura mater in an experimental
Microsc Res Tech. 2001 May 1;53(3):193-211.
supratentorial cerebral dura of the albino rat is equipped with a rich sensory
innervation both in the connective tissue and around blood vessels, which includes
nociceptive axons and their terminals; these display intense calcitonin gene-related
peptide (CGRP) immunoreactivity. Stereotactic electrical stimulation of the trigeminal
(Gasserian) ganglion, regarded as an experimental migraine model, caused marked
increase and disintegration of club-like perivascular CGRP-immunopositive nerve
endings in the dura mater and induced an apparent increase in the lengths of CGRP-immunoreactive
axons. Intravenous administration of sumatriptan or eletriptan, prior to electrical
stimulation, prevented disintegration of perivascular terminals and induced accumulation
of CGRP in terminal and preterminal portions of peripheral sensory axons. Consequently,
immunopositive terminals and varicosities increased in size; accumulation of axoplasmic
organelles resulted in the "hollow" appearence of numerous varicosities.
Since triptans exert their anti-migraine effect by virtue of agonist action on
5-HT(1D/B) receptors, we suggest that these drugs prevent the release of CGRP
from perivascular nerve terminals in the dura mater by an action at 5-HT(1D/B)
receptors. Nitroglycerine (NitroPOHL), given subcutaneously to rats, induces increased
beading of nitric oxide synthase (NOS)-immunoreactive nerve fibers in the supratentorial
cerebral dura mater, and an apparent increase in the number of NOS-immunoreactive
nerve fibers in the dural areas supplied by the anterior and middle meningeal
arteries, and the sinus sagittalis superior. Structural alterations of nitroxidergic
axons innervating blood vessels of the dura mater support the idea that nitric
oxide (NO) is involved in the induction of headache, a well-known side effect
of coronary dilator agents." [Abstract]
T, Messlinger K.
[Neuropeptide release in the dura mater encephali
in response to nitric oxide--relevance for the development of vascular headaches?]
"Nitric oxide (NO) and calcitonin gene-related
peptide (CGRP), potent vasodilators in the meninges,may be involved in the pathophysiology
of vascular headaches such as migraine pain. NO donators can provoke headache
attacks in migraineurs and increased levels of CGRP have been found in the venous
outflow from the head during migraine attacks. We therefore examined the effect
of both NO and CGRP on dural blood, a process which may parallel nociceptive processes
in the meninges. 1.Arterial blood flow was measured in the exposed dura mater
encephali of the rat using laser Doppler flowmetry. Local application of different
NO donors (SNAP,NONOate, and NOC-12) caused dose-dependent increases in meningeal
blood flow. CGRP(8-37) at 10(-4) M did not significantly change the basal flow
but attenuated increases in blood flow caused by the NO donors at concentrations
of 10(-5)-10(-3) M.2. In another series of experiments, the hemisected skulls
of adult Wistar rats, complete with intact dura mater, were filled with oxygenated
synthetic interstitial fluid (SIF) and the CGRP content of this fluid was assessed
every 5 min. When the NO donator NONOate, at concentrations of 10(-5)-10(-3) M,
was added to the SIF, or when the SIF was bubbled with NO gas (1000 ppm in N(2)
atmosphere) instead of carbogen, CGRP release increased in a concentration-dependent
manner. We conclude that the vasodilatory effect of NO that causes increased meningeal
blood flow is in part the result of both stimulating the release of CGRP and promoting
the vasodilatory action of CGRP. Since NO donors such as nitroglycerin are known
to provoke headache and CGRP is released during migraine pain, the NO-stimulated
CGRP release may be relevant for the development of vascular headaches that are
accompanied by meningeal hyperaemia." [Abstract]
T, Dux M, Messlinger K.
Nitric oxide releases calcitonin-gene-related
peptide from rat dura mater encephali promoting increases in meningeal blood flow.
Vasc Res. 2002 Nov-Dec;39(6):489-96.
"Nitric oxide (NO) and calcitonin-gene-related
peptide (CGRP) are implicated in the pathophysiology of vascular headaches. We
studied the interaction of these two vasodilatory mediators in an animal model
and suggest that NO may increase meningeal blood flow not only by its direct vasodilatory
action but also by stimulating CGRP release. First, CGRP release from the rat
cranial dura mater was measured in vitro using an enzyme immunoassay. Hemisected
skulls with adhering dura mater were filled with synthetic interstitial fluid
and stimulated with the NO donor diethylamine-NONOate (10(-5)-10(-3) M) or with
NO gas (1,000 ppm), which caused concentration-dependent increases in CGRP release
up to 166.8%. Second, meningeal blood flow was recorded in vivo in the exposed
dura mater using laser Doppler flowmetry. Topical application of the NO donors
NONOate, S-nitroso-N-acetylpenicillamine and N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethenamine
(10(-5)-10(-3) M) caused concentration-dependent increases in blood flow. These
increases were significantly reduced by local preliminary application of the CGRP
receptor antagonist CGRP(8-37) (10(-4) M). We conclude that NO stimulates the
release of CGRP from dural afferents. The blood-flow-increasing effect of NO seems
to be partly mediated by CGRP. The interaction of NO and CGRP may be relevant
for the development of vascular headaches." [Abstract]
T, Dux M, Messlinger K.
Increase in meningeal blood flow by nitric
oxide--interaction with calcitonin gene-related peptide receptor and prostaglandin
Cephalalgia. 2002 Apr;22(3):233-41.
study addresses possible interactions of the vasodilators nitric oxide (NO), calcitonin
gene-related peptide (CGRP) and prostaglandins, which may be implicated in the
generation of vascular headaches. Local application of the NO donator diethylamine-NONOate
(NONOate) to the exposed dura mater encephali of the rat caused dose-dependent
increases in meningeal blood flow recorded by laser Doppler flowmetry. Pre-application
of the CGRP receptor antagonist CGRP8-37 significantly attenuated the evoked blood
flow increases, while the cyclooxygenase inhibitors acetylsalicylic acid and metamizol
were only marginally effective. Stimulation of rat dura mater with NONOate in
vitro caused increases in CGRP release. NADPH-diaphorase activity indicating NO
production was restricted to the endothelium of dural arterial vessels. We conclude
that increases in meningeal blood flow caused by NO depend partly on the release
and vasodilatory action of CGRP from dural afferents, while prostaglandins are
not significantly involved." [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."
CT, Jansen-Olesen I, Hansen AJ.
Release of calcitonin gene-related
peptide (CGRP) from guinea pig dura mater in vitro is inhibited by sumatriptan
but unaffected by nitric oxide.
Cephalalgia. 2000 Nov;20(9):838-44.
attacks can be provoked by administration of nitroglycerin, suggesting a role
for nitric oxide (NO). The fact that release of the neuropeptide CGRP from trigeminal
sensory nerves occurs during the pain phase of migraine and that NO can augment
transmitter release prompted us to study CGRP release from the in situ dura mater
in guinea pig skulls. Release of CGRP by capsaicin or by high potassium concentration
was concentration-dependent and counteracted in calcium-free medium. The anti-migraine
compound, sumatriptan, inhibited CGRP release via the 5-HT1-receptor. The NO donors,
nitroglycerin, sodium nitroprusside and S-nitroso-N-acetylpenicillamine did not
influence CGRP release, alone or together with the stimulants. We concluded that
the skull preparation is well suited for scrutinizing CGRP release from dura mater.
The fact that sumatriptan inhibits CGRP release as in migraine patients suggests
a use for the present preparation in headache research." [Abstract]
M, Bendtsen L, Jensen R, Schifter S, Olesen J.
peptide levels during nitric oxide-induced headache in patients with chronic tension-type
Eur J Neurol. 2001 Mar;8(2):173-8.
has been proposed that nitric oxide (NO) induced headache in primary headaches
may be associated with release of calcitonin gene-related peptide (CGRP). In the
present study we aimed to investigate plasma levels of CGRP during headache induced
by the NO donor glyceryl trinitrate (GTN) in 16 patients with chronic tension-type
headache and 16 healthy controls. The subjects were randomly allocated to receive
0.5 microg/kg/min GTN or placebo over 20 min on two headache-free days. Blood
samples were collected at baseline, 10, 20 and 60 min after start of infusion.
Both patients and controls developed significantly stronger immediate headache
on the GTN day than on the placebo day and the headache was significantly more
pronounced in patients than in controls. There was no difference between the area
under the CGRP curve (AUCCGRP) on GTN vs. placebo day in either patients (P=0.65)
or controls (P=0.48). The AUCCGRP recorded on the GTN day did not differ between
patients and controls (P=0.36). Both in patients and controls, CGRP levels changed
significantly over time, on both the GTN and placebo days (P < 0.05). The present
study indicates that NO-induced immediate headache is not associated with release
of CGRP." [Abstract]
K, Suzuki A, Pawlak M, Zehnter A, Schmidt RF.
Involvement of nitric
oxide in the modulation of dural arterial blood flow in the rat.
J Pharmacol. 2000 Apr;129(7):1397-404.
"1. Nitric oxide (NO) has been
proposed to be a key molecule in the pathogenesis of migraine pain and other headaches
that are linked to vascular disorders. Several lines of evidence indicate that
the meningeal vascularization is crucially involved in the generation of these
headaches. In an experimental model in the rat a dominating role of calcitonin
gene-related peptide (CGRP) in causing neurogenic vasodilatation and increased
blood flow has been shown. The aim of the present study was to clarify the role
of NO in this model with regard to the meningeal blood flow. 2. The blood flow
in and around the medial meningeal artery (dural arterial flow) was recorded in
the exposed parietal dura mater encephali of barbiturate anaesthetized rats using
laser Doppler flowmetry. Local electrical stimulation of the dura mater (pulses
of 0.5 ms delivered at 7.5 - 17.5 V and 5 or 10 Hz for 30 s) caused temporary
increases in dural arterial flow for about 1 min that reached peaks of 1.6 - 2.6
times the basal flow. The effects of NO synthase (NOS) inhibitors on the basal
flow and the electrically evoked increases in flow were examined. 3. Systemic
(i. v.) administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) at cumulative
doses of 10 and 50 mg kg(-1) lowered the basal flow to 87 and 72%, respectively,
of the control and reduced the evoked increases in blood flow to 82 and 44% on
an average. Both these effects could partly be reversed by 300 mg kg(-1) L-arginine.
The systemic arterial pressure was increased by L-NAME at both doses. Injection
of the stereoisomer D-NAME at same doses did not change basal flow and evoked
increases in flow. 4. 4. Topical application of L-NAME (10(-4) - 10(-2) M) was
effective only at the highest concentration, which caused lowering of the basal
blood flow to 78% of the control; the evoked increases in flow were not changed.
Topical application of 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a specific
inhibitor of the inducible NOS, at concentrations of 10(-4) - 10(-2) M lowered
the basal flow to 89, 87.5 and 85%, respectively, but did not significantly change
the evoked flow increases. Same concentrations of 7-nitroindazole monosodium salt
(7-NINA), a specific inhibitor of the neuronal NOS, had no significant effects
on basal flow and evoked increases in flow. 5. It is concluded that NO is involved
in the maintenance of the basal level of dural arterial blood flow as well as
in the electrically evoked flow increases, which have been shown to be mainly
mediated by CGRP released from dural afferent fibres. The most important source
of NO is probably the endothelium of dural arterial vessels. The synergistic effect
of NO and CGRP on the stimulated blood flow may be in part due to a NO mediated
facilitation of the CGRP release." [Abstract]
S, Williamson DJ, Kaube H, Goadsby PJ.
Nitric oxide synthase inhibitors
can antagonize neurogenic and calcitonin gene-related peptide induced dilation
of dural meningeal vessels.
Br J Pharmacol. 2002 Sep;137(1):62-8.
The detailed pathophysiology of migraine is beginning to be understood and is
likely to involve activation of trigeminovascular afferents. 2. Clinically effective
anti-migraine compounds are believed to have actions that include peripheral inhibition
of calcitonin gene-related peptide (CGRP) release from trigeminal neurones, or
preventing dural vessel dilation, or both. CGRP antagonists can block both neurogenic
and CGRP-induced dural vessel dilation. 3. Nitric oxide (NO) can induce headache
in migraine patients and often triggers a delayed migraine. The initial headache
is thought to be caused via a direct action of the NO-cGMP pathway that causes
vasodilation by vascular smooth muscle relaxation, while the delayed headache
is likely to be a result of triggering trigeminovascular activation. Nitric oxide
synthase (NOS) inhibitors are effective in the treatment of acute migraine. 4.
The present studies used intravital microscopy to examine the effects of specific
NOS inhibitors on neurogenic dural vasodilation (NDV) and CGRP-induced dilation.
5. The non-specific and neuronal NOS (nNOS) inhibitors were able to partially
inhibit NDV, while the non-specific and endothelial NOS (eNOS) inhibitors were
able to partially inhibit the CGRP induced dilation. 6. There was no effect of
the inducible NOS (iNOS) inhibitor. 7. The data suggest that the delayed headache
response triggered by NO donors in humans may be due, in part, to increased nNOS
activity in the trigeminal system that causes CGRP release and dural vessel dilation.
8. Further, eNOS activity in the endothelium causes NO production and smooth muscle
relaxation by direct activation of the NO-cGMP pathway, and may be involved in
the initial headache response." [Abstract]
M, Lassen LH, Bendtsen L, Jensen R, Olesen J.
Effect of inhibition
of nitric oxide synthase on chronic tension-type headache: a randomised crossover
Lancet. 1999 Jan 23;353(9149):287-9.
Studies in animals have shown that nitric oxide plays an important part in central
sensitisation and that inhibitors of nitric oxide synthase (NOS) decrease sensitisation
in models of persistent pain. The efficacy of inhibitors of NOS has not been tested
in patients with tension-type chronic headache. We aimed to show whether N(G)-monomethyl-L-arginine
hydrochloride (L-NMMA), an inhibitor of NOS, is effective in relieving pain in
such patients. METHODS: We undertook a randomised double-blind, crossover trial
of 16 patients with chronic-tension-type headache. Patients were assigned intravenous
infusion of 6 mg/kg L-NMMA or placebo on 2 days separated by at least 1 week in
a randomised order. Headache intensity was measured on a 100 mm visual analogue
scale, and on a verbal rating scale at baseline and at 30 min, 60 min, and 120
min after start of treatment. The primary endpoint was reduction of pain intensity
on the visual analogue scale by the active treatment compared with placebo. FINDINGS:
L-NMMA reduced pain intensity on the visual analogue scale significantly more
than placebo: 120 min after start of treatment, the mean pain score was decreased
from 49 to 33 with L-NMMA and from 44 to 40 with placebo (p=0.01). Pain intensity
on the verbal rating scale was also significantly lower for treatment with L-NMMA
than for treatment with placebo (p=0.02). INTERPRETATION: Inhibition of NOS had
an analgesic effect in chronic tension-type headache. Further tests are required
before clinical application." [Abstract]
LH, Ashina M, Christiansen I, Ulrich V, Grover R, Donaldson J, Olesen J.
oxide synthase inhibition: a new principle in the treatment of migraine attacks.
"Glyceryl trinitrate, an exogenous nitric oxide
(NO) donor, and histamine, which causes NO formation in vascular endothelium,
have been shown to trigger migraine attacks. However, it remains uncertain whether
NO is involved in the subsequent phase of migraine attacks. To answer this question
we studied the effect of L-NGmethylarginine hydrochloride (546C88), a NO-synthase
inhibitor, on spontaneous migraine attacks. In a double-blind study design, 18
patients with migraine without aura randomly received 546C88 (6 mg/kg) or placebo
(5% dextrose) i.v. given over 15 min for a single migraine attack (546C88:placebo,
15:3). Furthermore, 11 placebo-treated patients from previous double-blind trials
with almost identical design were added to the placebo group in the statistical
evaluation. Two hours after the infusion, 10 of 15 L-NGmethylarginine hydrochloride-treated
patients experienced headache relief compared to 2 of 14 placebo-treated patients
(p = 0.01). Symptoms such as phono- and photophobia were also significantly improved.
A similar trend for nausea was not significant. We conclude that NO may be involved
in the pain mechanisms throughout the course of spontaneous migraine attacks."
der Kuy PH, Merkus FW, Lohman JJ, ter Berg JW, Hooymans PM.
a nitric oxide scavenger, in the prophylaxis of migraine: an open, pilot study.
"Drugs which directly counteract nitric oxide (NO),
such as endothelial receptor blockers, NO-synthase inhibitors, and NO-scavengers,
may be effective in the acute treatment of migraine, but are also likely to be
effective in migraine prophylaxis. In the underlying pilot study the prophylactic
effect of the NO scavenger hydroxocobalamin after intranasal administration in
migraine was evaluated. Twenty patients, with a history of migraine of > 1
year and with two to eight migraine attacks per month, were included in an open
trial. A baseline period was followed by an active treatment period of 3 months
with 1 mg intranasal hydroxocobalamin daily. Patients were instructed to complete
a diary in which details of each attack were described. A reduction in migraine
attack frequency of >/ or = 50% was seen in 10 of 19 patients, which corresponds
to 53% of the patients (responders). A reduction of > or = 30% was noted in
63% of the patients. The mean attack frequency in the total study population showed
a reduction from 4.7 +/- 1.7 attacks per month to 2.7 +/- 1.6 (P < 0.001).
For the responders the migraine attack frequency was reduced from 5.2 +/- 1.9
(baseline) to 1.9 +/- 1.3 attacks per month (P < 0.005), while for those who
did not respond a non-significant reduction was found: 4.1 +/- 1.4 to 3.7 +/-
1.5 (P > 0.1). A reduction was also observed for the total duration of the
migraine attacks per month, the total number of migraine days per month and the
number of medication doses for acute treatment used per month. This is the first
prospective, open study indicating that intranasal hydroxocobalamin may have a
prophylactic effect in migraine. As a percentage of responders in prophylactic
trials of > 35-40% is unlikely to be a placebo effect, a double-blind study
is warranted." [Abstract]
SJ, Parsons AA.
Sumatriptan modifies cortical free radical release
during cortical spreading depression. A novel antimigraine action for sumatriptan?
Res. 2000 Jul 7;870(1-2):44-53.
"Increases in concentration of brain NO
are proposed to initiate and mediate migraine headache. Triggered by focal depolarisation,
spreading depression (SD) represents a suitable mechanism for eliciting widespread
release of nitric oxide. The current study examines the effect of sumatriptan,
a 5-HT(1B/1D) agonist and effective antimigraine therapy, on free radical release
(nitric oxide and superoxide) in SD in the simple and complex cortices of the
rat and cat. Following initiation of SD, sumatriptan pretreatment (300 microg
kg(-1) i.v., 15 min prior to SD) modulated all phases of nitric oxide release
associated with each SD in both cats and rats. As a result, superoxide levels
were observed to significantly (ANOVA, post hoc LSD) increase versus vehicle treated
animals (saline 1 ml kg(-1) i.v. 15 min prior to SD) during specific phases of
each SD depolarisation. Averaged over all SD depolarisations, mean peak SD nitric
oxide levels per depolarisation were 0.73+/-0.23 microM (n=29) in cats, and 0.42+/-0.09
microM (n=34) in rats. Sumatriptan significantly (Students t-test, P<0.05,
two tailed hypothesis, P<0.05) modulated this increase in cortical nitric oxide
concentrations to 0.32+/-0.06 microM (n=25) and 0. 22+/-0.07 microM (n=37) in
cats and rats. Sumatriptan appears to decrease the amplitude of nitric oxide release
but enhances extracellular superoxide concentrations in both lissencephalic and
gyrencephalic cortices during SD." [Abstract]
Y, Jimbo H, Shimazu M, Satoh K.
Sumatriptan scavenges superoxide,
hydroxyl, and nitric oxide radicals: in vitro electron spin resonance study.
"BACKGROUND: The molecular mechanisms of migraine
have not yet been clarified. Oxygen free radicals have been implicated in the
genesis of many pathological processes, including migraine. Sumatriptan succinate
is known to be a very effective drug for acute relief of migraine attack. OBJECTIVE:
To investigate the direct scavenging activities of sumatriptan for superoxide,
hydroxyl, and nitric oxide (NO) radicals using electron spin resonance (ESR) spectroscopy.
METHODS: Measurement of superoxide and hydroxyl radical scavenging activities
was performed by ESR using 5,5-dimethyl-1-pyrroline-N-oxide as a spin trap. NO
was generated from 1-hydroxy-2-oxo-3-(N-3-methyl-3-aminopropyl)-3-methyl-1-triazene
and analyzed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl produced
from the reaction between 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide
and NO. RESULTS: The ESR study demonstrated that sumatriptan scavenged superoxide,
hydroxyl, and NO in a dose-dependent manner. CONCLUSIONS: Sumatriptan has direct
scavenging activity on free radicals and NO. Acute migraine drugs with antioxidant
properties may provide heretofore unheralded benefits via this mechanism."
SJ, Manning P, McNeil CJ, Hunter AJ, Parsons AA.
Effects of sumatriptan
on nitric oxide and superoxide balance during glyceryl trinitrate infusion in
the rat. Implications for antimigraine mechanisms.
Res. 1999 Nov 13;847(1):1-8.
"Infusion of glyceryl trinitrate (GTN) into
patients with migraine precipitates the onset of a migraine attack several hours
after completion of the infusion. Using an infusion of GTN into anaesthetised
rats, this study investigates the relationship of regional cerebral blood flux
rCBF(ldf), cortical nitric oxide (NO) and cortical superoxide concentrations and
the effect of sumatriptan on each variable. In saline treated animals, a 30 min
infusion of GTN (2 microgram kg(-1) min(-1), i.v.) was found to markedly increase
cortical rCBF(ldf) (133+/-3% of baseline) and NO concentrations (141+/-13% of
baseline). Superoxide levels exhibited an inverse relationship to NO levels, decreasing
below basal to 48+/-14% of baseline. It is hypothesised that high NO levels during
GTN infusion may decrease the detectable superoxide due to "leeching"
of the superoxide into low level peroxynitrite formation. In the presence of sumatriptan,
a decrease below baseline in cortical rCBF(ldf) (82+/-5% of baseline) and NO concentration
(64+/-13% of baseline) was observed throughout GTN infusion, although superoxide
levels significantly increased above baseline by 105+/-14 nM (p<0.05, ANOVA
post hoc LSD test). The mechanism for this action of sumatriptan is unknown but
may include; modulation of cell redox state, NO scavenging or direct manipulation
of superoxide release." [Abstract]
Iversen HK, Olesen J.
by a nitric oxide donor (nitroglycerin) responds to sumatriptan. A human model
for development of migraine drugs.
Cephalalgia. 1996 Oct;16(6):412-8.
"vascular" headache in humans may be used in characterizing new migraine
drugs. The effects of sumatriptan on nitroglycerin-(NTG)-induced headache and
arterial responses were therefore studied. Following a double-blind randomized
crossover design, 10 healthy volunteers received sumatriptan 6 mg s.c. or placebo
succeeded by 20 min NTG (0.12 microgram/kg/min) infusion. Headache was rated on
a 10 points scale. Temporal and radial artery diameters and velocity in the middle
cerebral artery (MCA) were measured with ultrasound. Sumatriptan reduced the NTG-induced
headache, median score 1.5 versus 4 after placebo (p < 0.01) and decreased
temporal and radial artery diameters 75 +/- 3 and 86 +/- 3% of baseline respectively
(p < 0.05). Blood velocity in the MCA was unaffected. The NTG model may prove
to be a valuable tool in the development of future migraine drugs. The results
suggest that NTG headache in non-migraineurs may share mechanisms with migraine
S, Williamson DJ, Kaube H, Goadsby PJ.
The effect of anti-migraine
compounds on nitric oxide-induced dilation of dural meningeal vessels.
J Pharmacol. 2002 Oct 4;452(2):223-8.
"Migraine is characteristically
accompanied by a throbbing quality of head pain thought to involve trigeminovascular
afferents. Administration of nitric oxide (NO) donors provides the most reliable
model of migraine induction in humans. The present studies used intravital microscopy
to monitor the effect of local meningeal nerve stimulation and NO on dural blood
vessels and any modulation of that effect by anti-migraine compounds. NO caused
an immediate and reproducible dilation of meningeal blood vessels that was partially
blocked by sumatriptan and indomethacin, while flunarizine and histamine H(1)
and H(2) receptor antagonists were unable to block the dilation. Indomethacin
also inhibited the neurogenic dilation while flunarizine did not. The present
studies demonstrate that NO is unlikely to interact with histamine to produce
its dilatory response. Sumatriptan and indomethacin inhibit the NO response by
inhibiting trigeminal activation and calcitonin gene-related peptide (CGRP) release.
Flunarizine does not modify either the neurogenic vasodilator response or the
NO meningeal dilator response at least acutely." [Abstract]
K, Okamura T, Toda N.
Flunarizine, an anti-migraine agent, impairs
nitroxidergic nerve function in cerebral arteries.
Pharmacol. 1997 Jun 18;329(1):49-53.
"Flunarizine is an anti-migraine
agent that blocks the Ca2+ entry across cell membrane. In order to obtain a clue
of mechanisms underlying the migraine headache, modifications by flunarizine of
the response to nitric oxide (NO), a cerebral vasodilator and algogenic agent,
derived from perivascular nerves were evaluated. Relaxations due to nerve stimulation
by electrical pulses (5 Hz) and nicotine (10(-4) M) in canine cerebral arterial
strips were attenuated by treatment with flunarizine dose-dependently, whereas
the responses to exogenous NO (10(-7)-10(-6) M) and nitroprusside (10(-8)-10(-6)
M) were unaffected. The inhibition by the Ca2+ entry blocker of the response to
electrical nerve stimulation and nicotine was obtained in a concentration (10(-6)
M) that did not significantly relax the arterial strips. NO derived from perivascular
nerve may be one of the factors involved in the genesis of migraine attack, which
is expected to be relieved by a reduction of neural NO synthase activity associated
with a decreased Ca2+ influx by flunarizine during nerve activation." [Abstract]
G, Mengozzi G, Inconis T, Paradisi L.
Nitric oxide, endothelin-1,
and transcranial Doppler in migraine. Findings in interictal conditions and during
Headache. 1996 May;36(5):307-11.
role of vascular phenomena taking place during an attack of migraine are poorly
understood. The aim of this study was to measure systemic levels of nitric oxide
and endothelin-1, two of the most potent vasoactive mediators known, and to assess
vasomotor responses through transcranial Doppler ultrasound monitoring in patients
suffering from migraine without aura, both during the headache event and in headache-free
periods as well as after pharmacologically induced pain relief. Seven patients
(mean age 31.3 years, range 24 to 49 years), five women and two men, were enrolled
in the pilot study. Transcranial Doppler recordings were performed according to
conventional procedure. Endothelin-1 concentrations were measured by means of
radioimmunoassay, whereas nitric oxide levels were estimated using electron paramagnetic
resonance spectroscopy. Ultrasound evaluation did not show significant changes
during migraine attacks compared to the interictal condition. Nitric oxide levels
showed only slight differences between basal and attack conditions (0.85 +/- 0.46
versus 1.56 +/- 0.88, expressed as arbitrary units), and were raised after pharmacological
intervention (2.91 +/- 1.93, P < 0.05). Plasma endothelin-1 concentrations
decreased during migraine attacks with respect to interictal conditions (3.99
+/- 1.21 pg/mL versus 4.23 +/- 1.19), and returned to basal values (4.44 +/- 1.08
pg/mL) after relief of pain. Coupling the measurements of systemic levels of nitric
oxide and endothelin-1 with transcranial Doppler velocity results will provide
useful information on the hemodynamic changes of cerebral blood flow regulation
in migraineurs, thereby adding new insights into the mechanisms of the migraine
A, Krizbai I, Multon S, Vecsei L, Schoenen J.
increases nNOS levels in rat trigeminal nucleus caudalis.
2000 Sep 28;11(14):3071-5.
"Systemic administration of nitroglycerin,
a nitric oxide donor, triggers in migraineurs a delayed attack of unknown mechanisms.
Subcutaneous nitroglycerin (10 mg/kg) produced a significant increase of nitric
oxide synthase (NOS)- and c-fos-immunoreactive neurons in the cervical part of
trigeminal nucleus caudalis in rats after 4 h. This effect was not observed in
the thoracic dorsal horn. Similar increase of NOS and c-fos was obtained in the
brain stem after a somatic nociceptive stimulus, i.e. on the side of the formalin
injection in the lip. Nitric oxide is thus able to increase NOS availability in
second order nociceptive trigeminal neurons, which may be relevant for central
sensitization and the understanding of its effect in migraine." [Abstract]
Knyihar-Csillik E, Vecsei L.
of a nitric oxide donor on nitroxergic nerve fibers in the rat dura mater.
Lett. 1999 Jan 29;260(2):97-100.
"Nitroglycerine, given subcutaneously
to rats (10 mg/kg body weight) induces increased beading of nitric oxide synthase
immunoreactive (NOS-IR) nerve fibers in the supratentorial cerebral dura mater,
and an apparent increase in the number of NOS-IR nerve fibers in the dural areas
supplied by the anterior and middle meningeal arteries, and the sinus sagittalis
superior. Structural alterations of nitroxergic axons innervating blood vessels
of the dura mater support the idea that nitric oxide is involved in the induction
of headache also by a primary peripheral action, a well-known side effect of coronary
dilator agents." [Abstract]
KL, Bulmer DC, Goadsby PJ.
Fos expression in the trigeminocervical
complex of the cat after stimulation of the superior sagittal sinus is reduced
Neurosci Lett. 1999 May 14;266(3):173-6.
neurovascular headaches, such as migraine and cluster headache probably involve
activation of trigeminovascular pain structures projecting to the trigeminocervical
complex of neurons in the caudal brain stem and upper cervical spinal cord. It
has recently been demonstrated that blockade of the synthesis of nitric oxide
(NO) by an NO synthesis inhibitor can abort acute migraine attacks and thus it
is of interest to determine whether there is an influence of NO generation on
trigeminocervical neurons. Cats were anaesthetised with alpha-chloralose (60 mg/kg,
i.t.). supplemental 20 mg/kg, intravenously (i.v.)) and halothane for surgery
(0.5-3% by inhalation). A circular midline craniotomy was performed to isolate
the superior sagittal sinus (SSS) for electrical stimulation (0.3 Hz, 150 V, 250
micros duration for 2 h). Two groups were compared, one stimulated after administration
of vehicle and the other stimulated after administration of N(G)-nitro-L-arginine
methylester (L-NAME: 100 mg/kg, i.v.). After stimulation of the SSS Fos immunoreactivity
was observed in lamina I/IIo of the trigeminal nucleus caudalis and dorsal horns
of C1 and C2 to a median total of 136 cells (range 122-146). After L-NAME treatment
Fos expression was significantly reduced to 40 cells (24-54; P < 0.02). In
conclusion, inhibition of NO synthesis L-NAME markedly reduces Fos expression
in the trigeminocervical complex of the cat. These data taken together with the
clinical observations of the effect of NO synthesis blockade in migraine suggest
a role for NO generation in mediating nociceptive transmission in acute migraine."
Col R, Koulchitsky SV, Messlinger KB.
Nitric oxide synthase inhibition
lowers activity of neurons with meningeal input in the rat spinal trigeminal nucleus.
2003 Feb 10;14(2):229-32.
"Nitric oxide is thought to control transmitter
release and neuronal activity in the spinal dorsal horn and the spinal trigeminal
nucleus, where nociceptive information from extra- and intracranial tissues is
processed. Extracellular impulse activity was recorded from neurons in the rat
spinal trigeminal nucleus with afferent input from the cranial dura mater. In
contrast to the inactive isomer D-NAME, infusion of the nitric oxide synthase
inhibitor L-NAME (20 mg/kg) significantly reduced neuronal activity and increased
systemic blood pressure. It is concluded that nitric oxide production contributes
to the ongoing activity of sensitized neurons in the spinal trigeminal nucleus.
The results suggest that nitric oxide may be involved in the generation and maintenance
of primary headaches such as migraine." [Abstract]
MG, Lever I, Bingham S, Read S, McMahon SB, Parsons A.
potentiates response of trigeminal neurones to dural or facial stimulation in
Cephalalgia. 2001 Jul;21(6):643-55.
glyceryl trinitrate as a donor molecule, we have used electrophysiological and
c-fos immunostaining techniques to study the effects of nitric oxide on neurones
in the nucleus trigeminalis caudalis. Following infusion of glyceryl trinitrate,
responses of neurones to electrical stimulation of periorbital cutaneous afferents
were potentiated and threshold for activation of neurones by stimulation of dural
afferents was reduced. Expression of c-fos was unchanged by glyceryl trinitrate
compared to saline controls. Intradermal injection of capsaicin in the periorbital
area increased c-fos expression in nucleus trigeminalis caudalis; this was significantly
potentiated by glyceryl trinitrate. These results suggest that, in the anaesthetized
rat, glyceryl trinitrate alone may not acutely activate the trigeminovascular
system to a significant degree at doses that cause headache and later trigger
migraine headache in migraineurs. Nevertheless, it is susceptible to exogenous
nitric oxide in that activation of trigeminal neurones through cutaneous or dural
pathways is potentiated. This may in some measure underlie the pathogenesis of
migraine headache." [Abstract]
S, Knyihar-Csillik E, Kempfert J, Scholz H, Csillik B, Vecsei L.
trinitrate treatment up-regulates soluble guanylyl cyclase in rat dura mater.
2001 Dec 21;12(18):3993-6.
"Nitric oxide (NO) is a key molecule in vascular
headaches and the dura mater has been implicated as a tissue where vascular headache
develops. Here we demonstrate expression, enzyme activity and cellular distribution
of the intracellular receptor for NO, soluble guanylyl cyclase (sGC), in rat dura
mater. Subcutaneous treatment of rats with the NO-donor glyceryl trinitrate (GTN)
induced an increase of sGC expression and activity in dural blood vessels after
20-30 min. It has previously been shown that GTN induces headache in normal subjects
after 20-30 min. Our findings suggest that an up-regulation of the NO target enzyme
contributes to the pathogenesis of GTN-induced headache explaining the subacute
rather than acute onset of symptoms." [Abstract]
RV, Lewis AI, Zuccarello M, Keller JT.
of endothelial nitric oxide synthase in vessels of the dura mater of the Sprague-Dawley
Neurosci Lett. 1995 Sep 1;197(1):78-80.
oxide (NO) and the dura mater are implicated in the pathogenesis of vascular headache.
Many studies have demonstrated the participation of NO in headache; however, few
studies have identified NO in the dura mater. In this study, nine Sprague-Dawley
rats were examined with immunohistochemistry using two different endothelial nitric
oxide synthase (eNOS) monoclonal antibodies, H32 and ECNOS. eNOS was successfully
localized to the endothelium of the middle meningeal artery. To the best of our
knowledge, this is the first study to report NOS immunopositive endothelial cells
in the blood vessels of the rat dura mater. The authors propose that NO plays
an active role in dural vasodilation, contributing to the pathogenesis of vascular
headache; in the future, NO inhibitors could serve as pharmacological agents to
treat vascular headache." [Abstract]
RF, Donoso MV, Mellado PA, Huidobro-Toro JP.
Migraine, but not subarachnoid
hemorrhage, is associated with differentially increased NPY-like immunoreactivity
in the CSF.
J Neurol Sci. 2000 Feb 15;173(2):140-6.
test whether migraine and subarachnoid hemorrhage (SAH) are associated with increased
sympathetic tone, we compared the neuropeptide Y-like (NPY-LI) and chromogranin
A-like immunoreactivities (LI) of cerebrospinal fluid (CSF) from migraneurs and
SAH patients with those from control subjects. Increased sympathetic tone was
expected to produce higher co-release of these co-stored peptides and concordant
changes in their CSF levels. In addition, we investigated a possible disturbed
nitric oxide homeostasis by measuring CSF nitrites (NO). More than 70% of CSF
NPY-LI corresponded to the chromatographic peak (HPLC) for the intact molecule
in all three groups. Migraneurs had 64% higher CSF NPY-LI, but no significant
difference in CSF chromogranin A-LI, as compared to controls. In contrast, SAH
patients had 74% less CSF chromogranin A-LI and a trend to lower NPY-LI, as compared
to controls. No differences in CSF NO were detected among groups. These results
argue against an increased sympathetic tone in patients with either migraine or
SAH, and suggest that the higher CSF NPY-LI of migraneurs probably originates
from central neurons. Furthermore, our findings in SAH patients argue in favor
of a decreased sympathetic tone; this could be a homeostatic response to counterbalance
vasoconstriction mediated by other mechanisms." [Abstract]
U, Chiarugi A, Bolay H, Moskowitz MA.
Nuclear factor-kappaB as a
molecular target for migraine therapy.
Ann Neurol. 2002
"Nitric oxide (NO) generated from inducible NO synthase
(iNOS) participates in immune and inflammatory responses in many tissues. The
NO donor glyceryl trinitrate (GTN) provokes delayed migraine attacks when infused
into migraineurs and also causes iNOS expression and delayed inflammation within
rodent dura mater. Sodium nitroprusside, an NO donor as well, also increases iNOS
expression. Because inflammation and iNOS are potential therapeutic targets, we
examined transcriptional regulation of iNOS following GTN infusion and the consequences
of its inhibition within dura mater. We show that intravenous GTN increases NO
production within macrophages. L-N(6)-(1-iminoethyl)lysine, a selective iNOS inhibitor,
attenuates the NO signal, emphasizing the importance of enzymatic activity to
delayed NO production. iNOS expression is preceded by significant nuclear factor
kappa B (NF-kappaB) activity, as reflected by a reduction in the inhibitory protein-kappa-Balpha
(IkappaBalpha) and activation of NF-kappaB after GTN infusion. IkappaBalpha degradation,
NF-kappaB activation, and iNOS expression were attenuated by parthenolide (3mg/kg),
the active constituent of feverfew, an anti-inflammatory drug used for migraine
treatment. These findings suggest that GTN promotes NF-kappaB activity and inflammation
with a time course consistent with migraine attacks in susceptible individuals.
We conclude, based on results with this animal model, that blockade of NF-kappaB
activity provides a novel transcriptional target for the development of anti-migraine
RA, Curtain RP, Shepherd AG, Brimage PJ, Griffiths LR.
for involvement of the human inducible nitric oxide synthase (iNOS) gene in susceptibility
to typical migraine.
Am J Med Genet. 2001 Jan 8;105(1):110-3.
I, Iversen HK, Olesen J.
Induction of nitrate tolerance is not a
useful treatment in cluster headache.
Christiansen I, Iversen HK, Olesen J.
characteristics during the development of tolerance to nitrates: pathophysiological
Cephalalgia. 2000 Jun;20(5):437-44.
studies suggest that nitric oxide (NO) plays an important role in nitrate-induced
headache and in spontaneous migraine attacks. Organic nitrates act as prodrugs
for NO and headache is a predominant adverse effect of nitrates but often disappears
during continuous treatment. Insight into tolerance to headache could lead to
insight into vascular headache mechanisms in general. The specific aim of the
present study was therefore to characterize the headache and accompanying symptoms
during continuous nitrate administration until a state of tolerance to headache
had developed. 5-isosorbide-mononitrate (5-ISMN) 30 mg three times daily was administered
orally for 7 days in 11 healthy subjects in a double-blind, randomized placebo
controlled cross-over design. Wash-out between periods was 14 days or more. Haemodynamic
data from the present study were compared to the observed changes of headache
over time. Headache during 5-ISMN was longer lasting and more severe compared
to placebo (P<0.004). In 10 subjects the headache fulfilled the pain sub-criteria
for migraine and in five subjects all diagnostic criteria for migraine without
aura were fulfilled. Conversely, 20 min of intravenous infusion of glyceryl trinitrate
caused a milder headache and no migraine. The present results therefore suggest
that NO may elicit a migraine attack in many healthy subjects if a high enough
dose is given for several hours. A close temporal association between the disappearance
of headache and the attenuation of the 5-ISMN induced dilatation of the superficial
temporal artery was observed. In contrast, tolerance in the middle cerebral artery
already appeared after 24 h, which was earlier than the development of tolerance
to headache. If vasodilatation is the cause of headache the results point to extracerebral
arteries. However, cytotoxic and pain modulating central nervous system effects
of NO, the time courses of which are unknown, may also play a role, involving
both intra- and extracranial arteries." [Abstract]
Stepien A, Chalimoniuk M.
nitric oxide-dependent cGMP in patients with migraine.
"It is believed that nitric oxide (NO) plays a significant
role in migraine attacks. This molecule is formed due to the conversion of L-arginine
into L-citrulline. The target receptor for NO is ferrum in the heme group of cytoplasmic
guanyl cyclase, the enzyme catalyzing cyclic guanosine monophosphate (cGMP) formation.
To confirm this hypothesis, cGMP and nitrite level in the blood serum were measured
in patients with migraine. The group under study included 37 subjects suffering
from migraine with and without aura and 40 normal control subjects. The cGMP was
measured during a migraine attack and 60 min following the administration of sumatriptan
6 mg subcutaneously. A statistically significant increase in cGMP level was observed
in patients during a migraine attack compared to the controls. This level decreased
after the administration of sumatriptan, but it was still higher than in the controls.
No correlation was found between the increased cGMP level and pain intensification
with clinical symptoms of migraine. The results suggest the participation of biochemical
changes in migraine pathogenesis in the L-arginine-NO-cGMP pathway." [Abstract]
Gallai V, Floridi A, Mazzotta G, Codini M, Tognoloni M,
Vulcano MR, Sartori M, Russo S, Alberti A, Michele F, Sarchielli P.
oxide pathway activation in platelets of migraine patients with and without aura.
Neurol Scand. 1996 Aug;94(2):151-60.
"Nitric oxide (NO) in platelets has
been proposed as a promising tool for studying NO variations in migraine. In the
present research the platelet response to collagen and the basal and collagen-induced
production of NO and cGMP in platelet cytosol were assessed in migraine patients
(25 with aura and 35 without aura) both interictally and ictally, and compared
with the same parameters in 30 age-matched control subjects. A reduced responsiveness
to collagen was found in migraine patients, particularly those with aura, and
this was more marked during attacks (ANOVA interictal periods: p < 0.01, attacks:
p < 0.02) The basal and collagen-stimulated production of NO and cGMP in the
platelet cytosol was significantly higher in migraine patients with aura assessed
in interictal periods than in control subjects, and this production was further
increased during attacks (interictal period: NO ANOVA: p < 0.001, ictal period:
p < 0.01; cGMP: interictal period p < 0.01, ictal period: p < 0.02).
The increase in platelet NO and cGMP production was also evident, though to a
lesser extent, in migraine patients without aura. The present research supports
the hypothesis of an activation of the L-arginine/NO pathway in migraine patients,
especially those with aura, and confirms the findings of a previous study of increased
levels of L-arginine in platelets of migraine patients studied in headache free-periods,
and decreased collagen aggregation in whole blood." [Abstract]
Shimomura T, Murakami F, Kotani K, Ikawa S, Kono S.
nitric oxide metabolites in migraine.
"Nitric oxide (NO) is a candidate as a causative molecule
in migraine. We determined nitrite, total nitrate/nitrite, and cyclic guanosine
3',5'-monophosphate (cGMP) concentrations in platelets from 30 migraine without
aura (MwoA) patients and 17 migraine with aura (MwA) patients. All migraine patients
were studied during their migraine attacks. The control group consisted of 28
healthy volunteers. Concentrations of platelet nitrite and total nitrate/nitrite
were determined using simple and sensitive nitrate/nitrite fluorometric assay
techniques. High concentrations of platelet nitrite and total nitrate/nitrite
were found in patients with MwoA and MwA when compared with healthy controls.
High concentrations of platelet cGMP were also found in patients with MwoA and
MwA. The levels of platelet total nitrate/nitrite significantly decreased in headache-free
periods after treatment with oral propranolol. These findings suggest that NO
is produced in platelets during migraine attacks. It may also be related to the
migrainous pain and the changes in cerebral blood flow experienced during migraine
attacks. These data may provide new strategies for the treatment of migraine."
D'Amico D, Ferraris A, Leone M, Catania A, Carlin A, Grazzi
L, Bussone G.
Increased plasma nitrites in migraine and cluster headache
patients in interictal period: basal hyperactivity of L-arginine-NO pathway?
"Nitrite concentrations in plasma were investigated
in a population of migraine and cluster headache patients and a group of healthy
non-headache controls. A hundred migraine patients and 69 cluster headache patients
in the interictal period, and 112 controls, were studied. Significantly higher
nitrite concentrations were found in migraine patients, with and without aura,
and cluster headache patients, in remission and cluster phase, than in controls.
These findings suggest that a basal dysfunction in the L-arginine-NO pathway may
be involved in the peripheral mechanisms predisposing subjects with neurovascular
headaches to individual attacks." [Abstract]
Shukla R, Barthwal MK, Srivastava
N, Nag D, Seth PK, Srimal RC, Dikshit M.
Blood nitrite levels in
patients with migraine during headache-free period.
"OBJECTIVE: To investigate blood nitrite levels
after migraine attacks and to assess whether or not the change in nitric oxide
levels observed during acute migraine persist after the attacks. BACKGROUND: Involvement
of nitric oxide has been suggested in the initiation of acute migraine. Recent
studies have shown alteration in the platelet response and platelet nitrite levels
during migraine attacks. METHODS: Patients with migraine with aura and patients
without aura were included in the study. The study was conducted on 50 patients
with migraine and 90 healthy controls. Blood from the patients was collected at
least 7 +/- 0.8 days after the last attack of migraine. Nitrite levels in the
polymorphonuclear leukocytes, platelets, and plasma were estimated. Platelet aggregation
response in some of these patients was also studied. RESULTS: No significant change
in the polymorphonuclear leukocyte, platelet, and plasma nitrite levels in patients
with migraine compared to controls was observed. Patients with migraine with aura
had significantly lower polymorphonuclear leukocyte nitrite levels compared to
those without aura (P<.05). In addition, no significant difference in the adenosine
diphosphate-induced platelet aggregation was observed in the migraineurs compared
to the healthy controls. CONCLUSIONS: Results obtained indicate that the platelet
aggregation response and the blood nitrite levels were not altered significantly
after an attack in the patients with migraine." [Abstract]
Costa A, Ravaglia S, Sances G, Antonaci F, Pucci E, Nappi
Nitric oxide pathway and response to nitroglycerin in cluster
headache patients: plasma nitrite and citrulline levels.
"Nitric oxide (NO) may participate in the mechanisms
underlying vascular headaches, such as migraine and cluster headache (CH), by
triggering neurogenic inflammation and activation of fibres conveying nociceptive
inputs to the trigeminal ganglion. Similarly to migraine, the administration of
the NO donor glyceryltrinitrate (GTN) to CH patients is a known model of inducing
spontaneous-like attacks. We carried out a GTN test (0.9 mg, sublingually) in
18 patients with episodic CH in active phase and 12 controls. The plasma levels
of NO metabolite nitrites (NO2-), after conversion of nitrates to NO2-, were measured
spectrophotometrically at baseline, at the maximum intensity of the induced response
(or 45 min after GTN in controls), and 120 min after GTN administration. The basal
plasma levels of L-citrulline were also assayed in patients and controls using
high-performance liquid chromatography. Basal NO2- levels, similar in GTN-responsive
patients and controls (48.3 +/- 10.6 and 44.6 +/- 9.5 micromol/l, respectively)
were found to be increased significantly at pain peak in patients (76.1 +/- 10.2
micromol/l) and after 45 min in controls (78.2 +/- 9.6 micromol/l) (P < 0.01
vs. respective baseline values), but not after 120 min, without differences between
groups. L-citrulline levels in basal conditions showed no differences between
groups (patients 64.8 +/- 11.7, controls 67.3 +/- 10.8 micromol/l). These data
do not support the presence of a basal hyperactivity of the L-arginine-NO pathway
in CH patients. Increased NO production may be of importance in the mechanisms
leading to CH attacks, but other factors are likely to render CH patients hyperresponsive
to NO, and ultimately to cause the occurrence of pain and associated features."
Ciancarelli I, Tozzi-Ciancarelli MG, Di Massimo C, Marini
C, Carolei A.
Urinary nitric oxide metabolites and lipid peroxidation
by-products in migraine.
Cephalalgia. 2003 Feb;23(1):39-42.
endothelium nitric oxide (NO) and superoxide anion release may cause migraine
through related cerebral blood flow changes. Thirty subjects suffering from migraine
with and without aura and 20 healthy controls were investigated. Urine samples
collected for 24 h during and after the migraine attack, and during the headache-free
period, were assayed for urinary NO stable metabolites (NOx) and thiobarbituric
acid reactive substances (TBARS). During the headache-free period urinary NOx
and TBARS levels were higher in migraine sufferers than in controls (NOx 0.77
+/- 0.14 vs. 0.28 +/- 0.15 mmol/mmol creatinine, P < 0.05; TBARS 0.40 +/- 0.19
vs. 0.26 +/- 0.13 micro mol/mol creatinine, P < 0.05). Also, NOx excretion
was higher during the headache-free period than during or after the migraine attack
(P < 0.05). Urinary TBARS were increased during the attack with respect to
the headache-free period (P < 0.05). No differences were observed in the same
parameters between sufferers of migraine with and without aura. Urinary NOx and
TBARS might be promising as markers of their systemic levels to evaluate the increased
vulnerability to oxidative stress in migraine sufferers." [Abstract]
G, Cananzi AR, Perini F, Alecci M, Zamberlan F, Hasselmark L, Welch KM.
collagen-induced platelet aggregation and increased platelet arginine levels in
migraine: a possible link with the NO pathway.
"We studied whole blood platelet aggregation induced
by collagen, platelet activating factor (PAF) and measured basal platelet L-arginine
(L-arg) levels, as an indirect index of the nitric oxide (NO) pathway in migraine.
Migraine, both with and without aura groups, showed a reduced aggregation to collagen,
but not to PAF, compared with control subjects. Platelet L-arg levels were significantly
increased in migraine with aura sufferers, whereas the plasma levels were in the
same range in migraineurs and controls. Platelet hyperesponsiveness to collagen
stimulation in migraine may be linked to an increased availability of the amino
acid precursor and an abnormal NO synthesis." [Abstract]
Sarchielli P, Tognoloni M, Russo S, Vulcano MR, Feleppa
M, Mala M, Sartori M, Gallai V.
Variations in the platelet arginine/nitric
oxide pathway during the ovarian cycle in females affected by menstrual migraine.
"Previous studies have reported the existence of
an arginine/nitric oxide (NO) pathway and the involvement of a Ca2+, NADPH-dependent
nitric oxide synthase enzyme (NOS) in the generation of NO in human platelets.
In the present research, we determined the rate of production of NO and cGMP in
the cytosol of platelets stimulated by collagen in 20 females with menstrual migraine
(MM), (age range 24-40 years), assessed in the follicular and luteal phases, interictally
and ictally in the latter period. The same patients were also assessed at mid-cycle.
At the same time, the variations in the collagen response of platelets were evaluated.
Moreover, these parameters were determined in the same periods in 20 age-matched
control females and in 20 females affected by non-menstrually related migraine
(nMM). The collagen-stimulated production of NO in the cytosol of the platelet
cytosol was significantly higher in migraine patients with MM than in the control
subjects. In MM patients, the increase was greater in the luteal phase of the
cycle than during the follicular phase (p < 0.005). A rise in NO production
in platelets was also present, although to a lesser extent, in females affected
by nMM compared to the healthy females, but this rise was most evident at ovulation
(p < 0.001). A slight but significant increase was also observed at mid-cycle
in control women, but this increase did not reach the values determined in the
migraine groups (p < 0.02). NO production in platelets stimulated by collagen
was significantly increased during attacks with respect to the interictal period
in both patient groups. Similar variations were observed in the production of
cGMP in MM and nMM patients. The increase in NO production was accompanied by
a decrease in platelet aggregation in the migraine groups compared with the control
group; this decrease was most evident at mid-cycle in nMM patients and in the
luteal phase in MM patients. These data suggest an activation of the L-arginine/
NO pathway in MM and nMM patients which could explain the modifications in the
platelet response to collagen evidenced in migraine-free periods and during attacks.
The activation of this pathway is more accentuated in the luteal phase in MM patients,
and this could be the cause of the increased susceptibility to migraine attacks
in perimenstrual and menstrual periods in these patients." [Abstract]
A, Multon S, Malgrange B, Parducz A, Vecsei L, Schoenen J.
of systemic nitroglycerin on CGRP and 5-HT afferents to rat caudal spinal trigeminal
nucleus and its modulation by estrogen.
Eur J Neurosci.
"Systemic administration of nitroglycerin, a nitric
oxide donor, triggers in migraine patients a delayed attack of unknown mechanism.
After puberty migraine is more prevalent in women. Attacks can be triggered by
abrupt falls in plasma estrogen levels, which accounts in part for sexual dimorphism,
but lacks an established neurobiological explanation. We studied the effect of
nitroglycerin on the innervated area of calcitonin gene-related peptide (CGRP)
and serotonin-immunoreactive afferents to the superficial laminae of the spinal
portion of trigeminal nucleus caudalis, and its modulation by estrogen. In male
rats, nitroglycerin produced after 4 h a significant decrease of the area innervated
by CGRP-immunoreactive afferents and an increase of that covered by serotonin-immunoreactive
fibres. These effects were not observed in the superficial laminae of thoracic
dorsal horns. The effect of nitroglycerin was similar in ovariectomized females.
In estradiol-treated ovariectomized females the area in the spinal portion of
trigeminal nucleus caudalis laminae I-II covered by CGRP-immunoreactive fibres
was lower and that of serotonin-immunoreactive fibres was higher than in males
and for both transmitters not significantly changed after nitroglycerin. The bouton
size of CGRP profiles was smaller in estradiol-treated ovariectomized females,
whereas after nitroglycerin it decreased significantly but only in males and ovariectomized
females. Nitroglycerin, i.e. nitric oxide, is thus able to differentially influence
afferent fibres in the superficial laminae of rat spinal trigeminal nucleus caudalis.
Estradiol modulates the basal expression of these transmitters and blocks the
nitroglycerin effect. These data may contribute to understanding the mechanisms
by which estrogens influence migraine severity and the triggering of attacks by
nitric oxide." [Abstract]
GG, Krause DN, Duckles SP.
Estrogen reduces myogenic tone through
a nitric oxide-dependent mechanism in rat cerebral arteries.
J Physiol. 1998 Jul;275(1 Pt 2):H292-300.
"Gender differences in the incidence
of stroke and migraine appear to be related to circulating levels of estrogen;
however, the underlying mechanisms are not yet understood. Using resistance-sized
arteries pressurized in vitro, we have found that myogenic tone of rat cerebral
arteries differs between males and females. This difference appears to result
from estrogen enhancement of endothelial nitric oxide (NO) production. Luminal
diameter was measured in middle cerebral artery segments from males and from females
that were either untreated, ovariectomized (Ovx), or ovariectomized with estrogen
replacement (Ovx + Est). The maximal passive diameters (0 Ca2+ + 1 mM EDTA) of
arteries from all four groups were identical. In response to a series of 10-mmHg
step increases in transmural pressure (20-80 mmHg), myogenic tone was greater
and vascular distensibility less in arteries from males and Ovx females compared
with arteries from either untreated or Ovx + Est females. In the presence of NG-nitro-L-arginine
methyl ester (L-NAME; 1 microM), an NO synthase inhibitor, myogenic tone was increased
in all arteries, but the differences among arteries from the various groups were
abolished. Addition of L-arginine (1 mM) in the presence of L-NAME restored the
differences in myogenic tone, suggesting that estrogen works through an NO-dependent
mechanism in cerebral arteries. To determine the target of NO-dependent modulation
of myogenic tone, we used tetraethylammonium (TEA; 1 mM) to inhibit large-conductance,
calcium-activated K+ (BKCa) channels. In the presence of TEA, the myogenic tone
of arteries from all groups increased significantly; however, myogenic tone in
arteries from males and Ovx females remained significantly greater than in arteries
from either untreated or Ovx + Est females. This suggests that activity of BKCa
channels influences myogenic tone but does not directly mediate the effects of
estrogen. Estrogen appears to alter myogenic tone by increasing cerebrovascular
NO production and/or action." [Abstract]
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]
Investigations into the
role of nitric oxide and the large intracranial arteries in migraine headache.
"Previous studies suggest that nitric oxide (NO)
is involved in headaches induced by i.v. infusion of the vasodilator and NO donor
glyceryl trinitrate (GTN) in healthy subjects. Extending these studies to sufferers
of migraine without aura, it was found that migraineurs experienced a stronger
headache than non-migraineurs. In addition, most migraineurs experienced a delayed
migraine attack at variable times (mean 5.5 h) after GTN provocation. This biphasic
headache response in migraineurs may be linked to hypersensitivity in the NO-cGMP
pathway. Thus, compared to controls, migraineurs were found to be more sensitive
to GTN-induced intracranial arterial dilatation, which is known to be mediated
via liberation of NO and subsequent synthesis of cGMP Furthermore, histamine infusions
in migraineurs induced headache responses and intracranial arterial responses
resembling those induced by GTN in migraineurs. Histamine is known to liberate
NO from the endothelium via stimulation of the H1 receptor, which is present in
the large intracranial arteries in man. Because both immediate histamine-induced
headache and intracranial arterial dilatation and delayed histamine-induced migraine
are blocked by H1-receptor blockade, a likely common pathway for GTN and histamine-induced
headaches/migraines and intracranial arterial responses may be via activation
of the NO-cGMP pathway. The delay in the development of these experimental migraines
may reflect activation of multiple physiological processes. The intracranial arteries
of migraineurs were found supersensitive to the vasodilating effect of GTN (exogenous
NO). This relates to clinical findings suggesting dilatation of the large intracranial
arteries on the headache side during spontaneous migraine attacks. The function
of arterial regulatory mechanisms involving NO in migraine was therefore studied.
In peripheral arteries, no endothelial dysfunction of NO was found and cardiovascular
and intracranial arterial sympathetic function was normal. A mild parasympathetic
dysfunction may be involved and may, via denervation supersensitivity, be responsible
for the observed supersensitivity to NO. Another possibility is that NO initiates
a perivascular neurogenic inflammation with liberation of vasoactive peptides.
NO also mediates a variety of other physiological phenomena. One of these, the
pain-modulating effect observed in animals, was evaluated in a human study using
GTN infusion and measurements of pain thresholds. No definite effects of GTN were
demonstrated. The precise mechanisms involved in NO-triggered migraines and which
part of the NO-activated cascade that is involved remain to be determined. The
possibilities for pharmacological stimulation and/or inhibition of several steps
of the NO-activated cascade increase rapidly and soon may be available for human
I, Daugaard D, Lykke Thomsen L, Olesen J.
Glyceryl trinitrate induced
headache in migraineurs - relation to attack frequency.
J Neurol. 2000 Jul;7(4):405-11.
"Glyceryl trinitrate, a prodrug of nitric
oxide, induces a mild to moderate headache in healthy subjects, whilst migraineurs
develop a more severe headache, resembling spontaneous migraine attacks. In order
to investigate whether this increased nitric oxide sensitivity depends upon the
frequency of spontaneously occurring migraine attacks, intravenous infusion of
glyceryl trinitrate (0.5 microg/kg/min) was given to 15 migraine patients with
rare attacks (</=4 attacks/year) of migraine without aura. Fourteen age-matched
migraine patients with frequent attacks of migraine without aura (>/=12 attacks/year)
and 14 healthy subjects served as controls. No significant difference between
the migraine groups for any of several parameters was detected, although the trend
was always towards more headaches in frequent migraineurs. Both migraineurs with
frequent and rare attacks experienced a headache that was significantly more severe,
longer lasting, and fulfilled the diagnostic criteria for migraine without aura
more often, compared to the healthy subjects (P = 0.0001). Conclusively, supersensitivity
to glyceryl trinitrate in migraineurs seems to be related to a basic - probably
genetically determined - pathophysiological mechanism involving nitric oxide,
and not to the environmental influences, which to a large extent determine the
expression of migraine." [Abstract]
Ashina, L. Bendtsen, R. Jensen, and J. Olesen
headache in patients with chronic tension-type headache
123: 1830-1837. 2000.
"An experimental model of headache offers unique
possibilities to study the mechanisms responsible for head pain. Using the glyceryl
trinitrate [GTN; nitric oxide (NO) donor] model of experimental headache, we studied
the intensity, quality and time profile of headache after infusion of GTN in 16
patients with chronic tension-type headache and in 16 healthy controls. Subjects
were randomized to receive intravenous infusion of GTN (0.5 microg/kg per minute
for 20 min) or placebo on two headache-free days separated by at least 1 week.
Headache intensity was measured on a 10-point verbal rating scale during 2 h of
observation and for the next 10 h after discharge from hospital. The primary endpoints
were the difference between the area under the curve (AUC-intensities x duration)
for headache recorded on the day of GTN treatment and on the day of placebo treatment
in patients, and in patients and controls on the days of GTN treatment. In patients,
the AUC on a GTN day [2221 (1572-3704); median with quartiles in parentheses],
was significantly greater than on a placebo day [730 (60-1678), P: = 0. 008].
On the GTN day, the AUC in patients [2221 (1572-3704)] was significantly higher
than in controls [43 (0-972), P: = 0.0001]. In patients, peak pain intensity occurred
8 h after infusion of GTN, whereas in controls it occurred 20 min after the start
of infusion. The present study demonstrates that an NO-induced biphasic response
with an immediate and a delayed headache is common to chronic tension-type headache
and migraine. Furthermore, the NO-induced delayed headache has the characteristics
of the primary headache disorder. This suggests that NO contributes to the mechanisms
of several types of primary headaches and that NO-related central sensitization
may be an important common denominator in the pain mechanisms of primary headaches."
I, Thomsen LL, Daugaard D, Ulrich V, Olesen J.
induces attacks of migraine without aura in sufferers of migraine with aura.
1999 Sep;19(7):660-7; discussion 626.
"Migraine with aura and migraine
without aura have the same pain phase, thus indicating that migraine with aura
and migraine without aura share a common pathway of nociception. In recent years,
increasing evidence has suggested that the messenger molecule nitric oxide (NO)
is involved in pain mechanisms of migraine without aura. In order to clarify whether
the same is true for migraine with aura, in the present study we examined the
headache response to intravenous infusion of glyceryl trinitrate (GTN) (0.5 microg/kg/min
for 20 min) in 12 sufferers of migraine with aura. The specific aim was to elucidate
whether an aura and/or an attack of migraine without aura could be induced. Fourteen
healthy subjects served as controls. Aura symptoms were not elicited in any subject.
Headache was more severe in migraineurs than in the controls during and immediately
after GTN infusion (p=0.037) as well as during the following 11 h (p = 0.008).
In the controls, the GTN-induced headache gradually disappeared, whereas in migraineurs
peak headache intensity occurred at a mean time of 240 min post-infusion. At this
time the induced headache in 6 of 12 migraineurs fulfilled the diagnostic criteria
for migraine without aura of the International Headache Society. The results therefore
suggest that NO is involved in the pain mechanisms of migraine with aura. Since
cortical spreading depression has been shown to liberate NO in animals, this finding
may help our understanding of the coupling between cortical spreading depression
and headache in migraine with aura." [Abstract]
M, Bendtsen L, Jensen R, Sakai F, Olesen J.
Possible mechanisms of
glyceryl-trinitrate-induced immediate headache in patients with chronic tension-type
Cephalalgia. 2000 Dec;20(10):919-24.
oxide (NO) plays an important role in the pathophysiology of primary headaches
including chronic tension-type headache (CTTH). Thus, a NO synthase inhibitor
reduces headache and muscle hardness while the NO donor glyceryl trinitrate (GTN)
causes more headache in patients than in healthy controls. Sensitization of myofascial
pain pathways is important in CTTH, and the aim of the present study was to investigate
if such mechanisms may also explain GTN-induced immediate headache in patients
with CTTH. In a randomized, double-blind, crossover study 16 patients with CTTH
and 16 healthy subjects received intravenous infusion of GTN (0.5 microg/kg per
min for 20 min) or placebo on two headache-free days separated by at least 1 week.
Muscle hardness, myofascial tenderness, mechanical and heat pain thresholds were
measured at baseline and at 60 min and 120 min after start of infusion. In patients,
GTN infusion resulted in a biphasic response with immediate headache and more
pronounced delayed headache. A similar but less pronounced response was seen in
controls. There was no difference between GTN and placebo regarding muscle hardness,
myofascial tenderness or pressure and heat pain thresholds in either patients
or controls (P>0.05). The unchanged sensitivity of pericranial myofascial pain
pathways indicates that peripheral and central sensitization is not involved in
the mechanisms of GTN-induced immediate headache." [Abstract]
P, Micieli G, Buzzi MG, Marcheselli S, Castellano AE, Rossi F, Nappi G.
correlates of early and delayed responses to sublingual administration of isosorbide
dinitrate in migraine patients: a transcranial Doppler study.
"In normal subjects or migraine patients, nitrates
induce a non-specific early headache caused by vasodilation of intracranial arteries.
In migraineurs a delayed headache response to nitrates may have a typical clinical
profile of a spontaneous migraine attack. The cerebral vasomotor changes of this
delayed response require further study. Isosorbide dinitrate (IDN), an exogenous
nitric oxide (NO) donor, was given at a dose of 5 mg sublingually and a bilateral
transcranial Doppler device was used to monitor bilateral mean velocity (Vm) changes
at the middle cerebral artery (MCA) after IDN administration and until delayed
headache occurred. Spontaneous migraine-like headache occurred only in migraine
patients during the delayed phase after IDN and was accompanied by a prolonged
arterial vasodilation compared to normal subjects. This vasomotor response was
more evident on the customary side of the head pain of a spontaneous migraine
attack. Our findings suggest a particular vasomotor response to nitrates in migraine
patients. This response is associated with the nitrate-induced headache and it
is not evident in healthy pain-free controls during the delayed phase after administration
of an NO donor. Owing to the short half-life of NO, the neurotransmitter released
by IDN, and because of the late onset of headache, we believe the mechanism is
unlikely to be vascular in origin, but may have a neurogenic component."
LL, Iversen HK, Brinck TA, Olesen J.
Arterial supersensitivity to
nitric oxide (nitroglycerin) in migraine sufferers.
1993 Dec;13(6):395-9; discussion 376.
"The sensitivity to nitroglycerin-induced
dilatation of large intracranial arteries was studied in 17 patients with migraine
without aura, 17 age and sex-matched healthy subjects and 9 patients with episodic
tension-type headache. Nitroglycerin in the doses of 0.015, 0.03, 0.25 microgram/kg/min
was successively infused for 15 min per dose. Blood velocity (Vmean) in the middle
cerebral artery (MCA) was recorded with transcranial Doppler before and at the
end of every infusion period, and 30 and 60 min after end of the last infusion.
In all three groups Vmean decreased with increasing doses (p < 0.001). The
response was more pronounced in migraine patients at the two higher doses (p <
0.05). Since nitroglycerin acts as an exogenous source of nitric oxide (NO), these
data support that NO supersensitivity may be an important molecular mechanism
of migraine pain." [Abstract]
J, Iversen HK, Thomsen LL.
Nitric oxide supersensitivity: a possible
molecular mechanism of migraine pain.
"Nitroglycerin, which may be regarded as a prodrug for
nitric oxide, induces a mild to moderate headache in healthy subjects. In order
to study whether migraine patients are more sensitive to nitric oxide than non-migrainous
subjects, four different doses of intravenous nitroglycerin were given in a double
blind design to 17 migraine patients, 17 age and sex matched healthy controls
and 9 subjects with tension-type headache. The nitroglycerin-induced headache
was significantly more severe in migraine sufferers, lasted longer and fulfilled
diagnostic criteria for migraine more often. We have previously shown a similar
supersensitivity to histamine which in human cerebral arteries activates endothelial
H1 receptors and causes endothelial production of nitric oxide. Migraine patients
are thus supersensitive to exogenous nitric oxide from nitroglycerin as well as
to endothelially produced nitric oxide. It is suggested that nitric oxide may
be partially or completely responsible for migraine pain." [Abstract]
P, D'Alo S, Stirparo G, Rinaldi C, Cifone MG, Giacovazzo M.
of nitric oxide synthase by nitric oxide donor compounds in migraine.
J Clin Lab Res. 1998;28(2):135-9.
"A controlled study was performed to
assess the involvement of the nitric oxide pathway in migraine pathophysiology.
Thirteen patients with migraine without aura and seven clinically healthy subjects
(C) were selected. All of the migraine patients were studied both before, during
an asymptomatic phase (t0), and 1 h after the administration of 5 mg isosorbide
dinitrate, a nitric oxide donor able to induce an experimental migraine attack
(t1). The nitric oxide levels were analyzed as nitrite accumulation in serum samples,
in peripheral blood mononuclear cell extracts, and culture supernatants. Basal
nitrite levels in serum samples and peripheral blood mononuclear cell culture
supernatants or migraine patients and healthy subjects indicated that migraine
patients possess an activated nitric oxide synthesis pathway (t0 vs. CF = 8.16,
P < 0.01 and F = 16.2, P < 0.01, respectively). As expected, in the migraine
patients treated with the nitric oxide donor, a marked increase of nitrite levels
was observed in sera (t1 vs. t0 P < 0.05, t = 3.05). In contrast, during the
nitric oxide donor-induced migraine attacks a statistically significant decrease
of nitrite levels in peripheral blood mononuclear cell culture supernatants was
observed (t1 vs. t0 P < 0.01, t = -4.03), whereas a significant increase of
nitrite in total cell extracts was detected (t1 vs. t0 P < 0.001, t = -6.89).
These preliminary data suggest that nitric oxide could be involved in the neurovascular
modifications leading to a migraine attack." [Abstract]
C, Thomsen LL, Birk S, Olesen J.
Migraine can be induced by sildenafil
without changes in middle cerebral artery diameter.
2003 Jan;126(Pt 1):241-7.
"Migraine is considered a neurovascular disease
involving dilatation of cerebral arteries. Nitric oxide (NO) donors induce dilatation
of cerebral and extracranial arteries and migraine, but NO has several mechanisms
of action in addition to its cyclic guanosine monophosphate (cGMP)-mediated vasodilatation.
We examined whether sildenafil (Viagra), a selective inhibitor of cGMP-hydrolysing
phosphodiesterase 5 (PDE5), which acts exclusively by increasing cGMP, can induce
migraine and dilatation of cerebral arteries. We included 12 patients with migraine
without aura in this double-blind, placebo-controlled crossover study, in which
placebo or sildenafil 100 mg was administered orally on two separate days. Blood
flow velocity in the middle cerebral artery (V(mca)) was recorded by transcranial
Doppler ultrasonography and regional cerebral blood flow in the territory of the
middle cerebral artery (rCBF(mca)) was measured using SPECT (single photon emission
computed tomography) and xenon 133 inhalation. Radial and temporal artery diameters
were studied using high-frequency ultrasonography. Headache response, tenderness
of pericranial muscles, blood pressure and heart rate were measured repeatedly.
We found that migraine attack was induced by sildenafil in 10 of 12 migraine patients
and by placebo in two of 12 patients (P = 0.01). V(mca) (P = 0.1) and rCBF(mca)
(P = 0.93) remained unchanged after sildenafil. Temporal (P = 0.47) and radial
(P = 0.87) artery diameter and pericranial tenderness (P = 0.16) were unaffected
by sildenafil. Systolic and diastolic blood pressures were unchanged but heart
rate increased from a mean of 62 +/- 2 to 74 +/- 3 beats/min (P = 0.01) after
sildenafil. Our results demonstrate that migraine may be induced via a cGMP-dependent
mechanism, and we show for the first time that this occurs without initial dilatation
of the middle cerebral artery. We propose that triggering mechanisms may reside
within the perivascular sensory nerve terminals or the brainstem. However, other
sites of action may also be possible and future studies are needed to elucidate
this. In the clinical use of sildenafil, patients who have migraine should be
informed about the risk of migraine attacks." [Abstract]
Thomsen LL, Brennum J, Iversen HK, Olesen J.
of a nitric oxide donor (glyceryl trinitrate) on nociceptive thresholds in man.
"Several animal studies suggest that nitric oxide
(NO) plays a role in central and peripheral modulation of nociception. Glyceryl
trinitrate (GTN) exerts its physiological actions via donation of NO. The purpose
of the present study was to examine the effect of this NO donor on nociceptive
thresholds in man. On two different study days separated by at least a week 12
healthy subjects received a staircase infusion of GTN (0.015, 0.25, 1.0, 2.0 micrograms/kg/min,
20 min each dose) or placebo in a randomized double-blind crossover design. Before
the infusion and after 15 min of infusion on each dose, pressure pain detection
and tolerance thresholds were determined by pressure algometry (Somomedic AB,
Sweden) in three different anatomic regions (finger, a temporal region with interposed
myofascial tissue and a temporal region without interposed myofascial tissue).
Relative to placebo, the three higher GTN doses induced a decrease in both detection
and tolerance thresholds in the temporal region with interposed myofascial tissue
(p = 0.003 detection and p = 0.002 tolerance thresholds, Friedman). No such changes
were observed in the other two stimulated regions. These results could reflect
central facilitation of nociception by NO. However, we regard convergence of nociceptive
input from pericranial myofascial tissue and from cephalic blood vessels dilated
by NO as a more likely explanation of our findings." [Abstract]
Sarchielli P, Alberti A, Codini M, Floridi A, Gallai
Nitric oxide metabolites, prostaglandins and trigeminal vasoactive
peptides in internal jugular vein blood during spontaneous migraine attacks.
"Despite evidence emerging from the experimental
model of nitroglycerin-induced headache, the endogenous increase in nitric oxide
(NO) production during migraine attacks is only speculative. It has been hypothesized
that there is a close relationship between activation of the L-arginine/NO pathway
and production of certain vasoactive and algogenic prostaglandins during spontaneous
migraine attacks, but this suggestion also needs to be confirmed. In the present
study the levels of nitrites, the stable metabolites of NO, were determined with
high performance liquid chromatography (HPLC) in the internal jugular venous blood
of five patients affected by migraine without aura examined ictally. These samples
were taken within 30 min, 1, 2, and 4 h from the onset of the attack and at the
end of the ictal period. At the same time, the plasma levels of calcitonin gene-related
peptide (CGRP), neurokinin A (NKA), prostaglandin E2 (PGE2) and 6 keto PGF1alpha,
the stable product of PGI2, were assessed with radioimmunoassay (RIA) kits in
the same samples. The levels of the intracellular messengers, cGMP and cAMP, were
also measured with the RIA method. Nitrite, cGMP, CGRP and NKA levels reached
their highest values at the first hour, then they tended to decrease progressively
and returned, after the end of attacks, to values similar or below those detected
at the time of catheter insertion (ANOVA, statistical significance: P<0.001;
P<<0.002; P<0.002; P<0.003, respectively). PGE2 and 6 keto PGF1alpha,
as well as cAMP levels also significantly increased at the first hour but reached
a peak at the 2nd hour and remained in the same range until the 4th and 6th hours.
Then their values tended to decrease after the end of attacks, becoming lower
than those measured immediately after catheter positioning for internal jugular
venous blood drawing (ANOVA: P<0.002, P<0.004, P<0.001, respectively).
Our results support early activation of the L-arginine/NO pathway which accompanies
the release of vasoactive peptides from trigeminal endings and a late rise in
the synthesis of prostanoids with algogenic and vasoactive properties which may
intervene in maintaining the headache phase." [Abstract]
G, Zicari A, Favilla M, Lipari M, Martelletti P.
of nitric oxide synthase and cyclooxygenase in peripheral monocytes of asymptomatic
migraine without aura patients.
Cephalalgia. 2000 Mar;20(2):100-6.
reports indicate that nitric oxide (NO) could be involved in migraine without
aura (MWA), an extremely diffuse clinical event. Since monocyte may be a relevant
source of NO, we analysed monocyte activation in MWA patients, in a period in
which they were free of symptoms. NO basal production by MWA peripheral monocytes
was significantly higher than in healthy subjects (91.25+/-8.6 microM/10(6) cells
vs. 22.6+/-3.2 microM/106 cells). Interestingly, even the release of prostaglandin
E2 (PGE2), was higher in MWA patients than in healthy subjects (3137+/-320 pg/10(6)
cells vs. 1531+/-220 pg/10(6) cells). The incubation of monocytes from healthy
subjects and MWA patients with N-nitro-L-arginine methyl ester caused a marked
decrease of both NO and PGE2 release. We hypothesise that NOS and cyclooxygenase
pathways in monocytes are linked and are, in MWA patients, up-regulated, even
in a symptoms-free period. NO and PGE2 hyperproduction could therefore be involved
in the neurovascular modifications leading to migraine attacks." [Abstract]
AE, Micieli G, Bellantonio P, Buzzi MG, Marcheselli S, Pompeo F, Rossi F, Nappi
Indomethacin increases the effect of isosorbide dinitrate on cerebral
hemodynamic in migraine patients: pathogenetic and therapeutic implications.
"Intracerebral vascular reactivity induced by the
nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more
major and longer-lasting in migraine patients who develop delayed headache in
response to the drug. The headache is purportedly due to neuronally-mediated vascular
mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in
NO generation. Indomethacin also decreases cerebral blood flow by constricting
precapillary resistance vessels. In the present study, the hemodynamic effects
of indomethacin were evaluated in migraine patients and healthy controls by means
of transcranial Doppler monitoring. Indomethacin caused a significant decrease
in mean flow velocity in the middle cerebral artery. This was an additional effect
to the mean velocity decrease induced by IDN. The interactions between the two
drugs suggest that their effects on cerebral hemodynamics (and pain) may be of
relevance both in understanding the role of NO in migraine pathogenesis and in
evaluating symptomatic treatments for migraine attacks." [Abstract]
U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez del Rio M, Letourneau R, Theoharides
TC, Waeber C, Moskowitz MA.
Delayed inflammation in rat meninges:
implications for migraine pathophysiology.
Brain. 2001 Dec;124(Pt
"Nitric oxide (NO) has been implicated in migraine pathogenesis
based on the delayed development of typical migraine headache 4-6 h after infusing
the NO donor nitroglycerin [glyceryl trinitrate (GTN)] to migraineurs. Furthermore,
inhibiting the synthesis of NO by treatment with a NO synthase (NOS) inhibitor
attenuates spontaneous migraine headaches in 67% of subjects. Because NO has been
linked to inflammation and cytokine expression, we investigated the delayed consequences
of brief GTN infusion (30 min) on the development of meningeal inflammation in
a rat model using doses relevant to the human model. We found dose-dependent Type
II NOS [inducible NOS (iNOS)] mRNA upregulation in dura mater beginning at 2 h
and an increase in the corresponding protein expression at 4, 6 and 10 h after
infusion. Type II NOS immunoreactivity was expressed chiefly within resident meningeal
macrophages. Consistent with development of a delayed inflammatory response, we
detected induction of interleukin 1beta in dura mater at 2 and 6 h and increased
interleukin 6 in dural macrophages and in rat cerebrospinal fluid at 6 h after
GTN infusion. Myeloperoxidase-positive cells were rarely found. Leakage of plasma
proteins from dural blood vessels was first detected 4 h after GTN infusion, and
this was suppressed by administering a specific Type II NOS inhibitor [L-N(6)-(1-iminoethyl)-lysine
(L-NIL)]. In addition to cytokine induction, macrophage iNOS upregulation and
oedema formation after GTN infusion, dural mast cells exhibited granular changes
consistent with secretion at 4 and 6 h. Because iNOS was expressed in dural macrophages
following topical GTN, and in the spleen after intravenous injection, the data
suggest that the inflammatory response is mediated by direct actions on the dura
and does not develop secondary to events within the brain. Our findings point
to the importance of new gene expression and cytokine expression as fundamental
to the delayed response following GTN infusion, and support the hypothesis that
a similar response develops in human meninges after GTN challenge." [Abstract]
P, Stirparo G, Morrone S, Rinaldi C, Giacovazzo M.
intercellular adhesion molecule-1 (ICAM-1), soluble ICAM-1 and interleukin-4 by
nitric oxide expression in migraine patients.
J Mol Med.
"The mechanisms of the postulated "sterile"
inflammation in migraine were studied utilizing flow cytometry (intercellular
adhesion molecule 1, ICAM-1; interleukin-1 receptor, IL-1R) and enzyme-linked
immunosorbent assay (soluble intercellular adhesion molecule 1, sICAM-1; interleukin-4,
IL-4). Twenty patients suffering from migraine without aura, 20 healthy subjects,
and 10 patients suffering from episodic tension headache were selected. All of
the migraine patients were studied during a migraine crisis experimentally induced
by the administration of isosorbide dinitrate (a nitric oxide donor), and 10 out
the 20 were also studied during a spontaneous migraine attack. A sharp decrease
in the expression of ICAM-1 (F=5.09, p<0.001 and F=2.46, p<0.05, respectively),
sICAM-1 1 (F=6.21, p<0.0001 and F=3.99, p<0.007, respectively) and serum
IL-4 (F=6.23, p<0.001 and F=3.64, p<0.01, respectively) were observed in
experimentally induced and spontaneous migraine attacks. There was no change with
respect to IL-IR 1 receptor expression values. The two control groups, tested
with the same experimental procedure, showed no changes in ICAM-1 and IL-1R or
in in sICAM-1 and IL-4. Our data suggest that migraine patients are more sensitive
to exogenous NO than controls. In addition, our results indicate that experimental
migraine crisis, induced by an NO donor, is mediated by the inhibition of IL-4
and subsequently of ICAM-1. It is likely that the described ICAM-1 downregulation
inhibits during a migraine attack the critical step of transendothelial migration
into the cerebral tissues of activated leukocytes, as proposed in the "sterile
inflammation" hypothesis." [Abstract]
A, Anuntasethakul T, Maneesri S, Phansuwan-Pujito P, Patumraj S, Kasantikul V.
nitric oxide supersensitivity in the cerebral microcirculation.
"OBJECTIVE: To investigate the relationship between
hyposerotonin and cranial microvascular responses to nitric oxide (NO). BACKGROUND:
Although the mechanism underlying NO supersensitivity in migraine is still unclear,
an alteration of the serotonin system is a possible explanation. METHODS: Wistar
rats were divided into control and hyposerotonin groups. Serotonin was depleted
by intraperitoneal injection with 300 mg/kg of para-chlorophenylalanine (PCPA),
a tryptophan hydroxylase inhibitor. Three days after PCPA pretreatment, the animals
were prepared for assessment of their NO-induced vasomotor response using glyceryl
trinitrate (GTN: 8 to 10 mg/kg, intravenously) as an NO donor. Pial circulation
was visualized by the intravital fluorescein videomicroscopic technique. Images
of vessels at 0, 5, 15, 30, and 60 minutes post GTN infusion were digitized and
measured. At the end of monitoring, the rat brains were removed for ultrastructural
study of the brain microvessels. RESULTS: Infusion of GTN produced dose-dependent
pial arteriolar dilatation. This vasodilator effect was significantly increased
in the PCPA-treated groups, especially at 30 and 60 minutes. The percentage change
from baseline diameter at 30 minutes after the 8-mg/kg GTN infusion was 42.6 +/-
3.1 for the hyposerotonin group and 16.8 +/- 2.9 for the control group (P<.001).
Electron microscopic study revealed that exposure to the NO donor produced considerable
changes in cerebral microvessels, characterized by focal ballooning of endothelial
cells, increased microvillous formation, and increased endothelial pinocytosis.
These anatomical changes were significantly more prominent in the hyposerotonin
group. CONCLUSIONS: A hyposerotoninergic condition can facilitate the NO-induced
physiological and pathological responses in meningeal and cerebral microvessels
and, therefore, is a possible explanation for the supersensitivity to NO observed
in patients with migraine." [Abstract]
P, Alberti A, Russo S, Codini M, Panico R, Floridi A, Gallai V.
oxide pathway, Ca2+, and serotonin content in platelets from patients suffering
from chronic daily headache.
Cephalalgia. 1999 Nov;19(9):810-6.
alteration in serotonin concentration has been found in patients with chronic
headache caused by abuse of analgesic substances as well as an up-regulation of
5HT2 platelet receptors, which has been correlated with chronicization of the
headache. In a previous study we demonstrated an increase in L-arginine/nitric
oxide (NO) pathway activity in platelets from patients affected by migraine with
or without aura, particularly during attacks. In the present research we assessed
the variations in platelet L-arginine/NO pathway and cyclic guanosine monophosphate
(cGMP) levels in 32 patients affected by chronic daily headache (CDH) (8 M, 24
F, age range 34-50 years) both during and between attacks. In these same patients,
the platelet aggregation to different collagen concentrations (0.3, 1, 3 micrograms/ml)
was determined as well as the intracellular platelet calcium concentration using
fluorescence polarization spectrometry. These parameters were compared with those
of an age- and sex-matched control group (n = 25; n = 10, n = 15, age range 35-51
years). A reduction found in platelet aggregation response to each collagen concentration
used (p < 0.001) was coupled with an increased NO and cGMP production (NO:
p < 0.0001; cGMP: p < 0.001). This was accompanied by a significant increase
in intracytosolic Ca2+ (p < 0.0001) concentration and a reduced platelet serotonin
content compared to those in control individuals (p < 0.0002). Changes in the
above platelet parameters were accentuated more in patients with analgesic abuse
than in CDH patients with no drug abuse. These findings suggest the occurrence
of an activation of cGMP-Ca2+ mediated events in CDH patients with analgesic abuse.
This physiologic compensatory mechanism, which intervenes in overcoming the increase
in cytosolic Ca2+ levels, is not as efficient at limiting serotonin depletion
by platelet dense bodies. A similar depletion in the central serotoninergic pathway
can be assumed in the same patients." [Abstract]
C, Blandini F, Costa A, Preza E, Nappi G.
of monoaminergic transmission in the rat.
"When administered to migraine patients, nitroglycerin
induces a spontaneous-like migraine attack, with a latency of several hours. Nitroglycerin
acts directly and/or indirectly on the central nervous system, through the release
of nitric oxide (NO). Systemic administration of the drug to the rat causes neuronal
activation in selected subcortical areas, particularly in monoaminergic nuclei
of the brainstem. In this study, we sought to investigate whether this activation
correlates with changes in monoaminergic neurotransmission. For this purpose,
we evaluated the tissue levels of catecholamines and serotonin in the hypothalamus,
mesencephalon, pons and medulla of rats treated with systemic nitroglycerin or
vehicle, at different time points (1, 2 and 4 h). We also evaluated the peripheral
sympathetic response to the drug by measuring the concentrations of plasma catecholamines.
Nitroglycerin caused an early (1 h) increase in cerebral (pons) and plasma levels
of norepinephrine, followed by a delayed (4 h) decrease in medullary and pontine
levels of serotonin. The initial noradrenergic activation may reflect the autonomic
response to the rapid cardiovascular effects of the drug, while the delayed response
may result from the interaction of nitroglycerin-released NO and 5-HT in central
areas devoted to the modulation of nociception. These data might therefore help
to clarify the mechanisms underlying the delayed migraine attack observed in migraine
sufferers after systemic administration of nitroglycerin." [Abstract]
Srikiatkhachorn A, Suwattanasophon C, Ruangpattanatawee
U, Phansuwan-Pujito P.
2002 Wolff Award. 5 -HT2A receptor activation
and nitric oxide synthesis: a possible mechanism determining migraine attacks.
"OBJECTIVE: To determine the effect of the
5-HT2A receptor in control of spinal nociception, cerebral circulation, and nitric
oxide synthase (nNOS) expression in trigeminovascular neurons. BACKGROUND: The
plasticity of the 5-HT2A receptor is a possible factor determining the course
of migraine. Up-regulation of this receptor has been demonstrated to correlate
with the increasing frequency of migraine attacks and may underlie the development
of chronic daily headache. METHODS: Adult male Wistar rats were divided into groups
receiving the 5-HT2A agonist, 1,2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI),
nitroglycerin, or normal saline. The tail flick test and chemical nociception-evoked
Fos-expression in dorsal horn neurons were used as indicators of nociception.
Regional cerebral blood flow was monitored using laser Doppler flowmetry. Expression
of Fos and nNOS was studied using immunohistochemical method. RESULTS: Administration
of DOI led to the shortening of tail flick latency (1.3 +/- 0.2 and 7.2 +/- 0.6
seconds for DOI-treated and control groups, respectively). The number of Fos-immunoreactive
neurons was also greater in the DOI-treated group compared with the control group.
DOI also produced long-lasting cerebral hyperemia (123% of baseline value) associated
with the enlargement of perivascular nNOS-immunoreactive nerve fibers and increased
nNOS-immunoreactive neurons in trigeminal ganglia and trigeminal nucleus caudalis.
These findings resembled those observed in the rats exposed to nitroglycerin.
CONCLUSION: Our results suggest that activation of the 5-HT2A receptor leads to
an enhancement of NO production in trigeminovascular pathway. NO may trigger migraine
attacks by inducing cerebral vasodilation and sensitizing the perivascular nociceptors
and central nociceptive neurons in trigeminovascular system. Up-regulation of
this pronociceptive receptor can increase headache attacks and contributes to
the development of chronic daily headache." [Abstract]
KW, Nelson DL, Dieckman DK, Wainscott DB, Lucaites VL, Audia JE, Owton WM, Phebus
Neurogenic dural protein extravasation induced by meta-chlorophenylpiperazine
(mCPP) involves nitric oxide and 5-HT2B receptor activation.
"The compound m-chlorophenylpiperazine (mCPP),
which is known to trigger migraine-like head pain in some subjects, was evaluated
for its ability to induce dural plasma protein extravasation (PPE) in guinea pigs.
Intravenous mCPP dose-dependently increased PPE. This effect was inhibited by
non-selective 5-HT2 receptor antagonists (methysergide, LY53857, LY215840), by
a peripherally restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B
selective receptor antagonist (LY202146). These data suggests that peripheral
5-HT2B receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor
L-NAME and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting
a role for nitric oxide (NO) and the trigeminal system, respectively. NO release
has been linked to activation of the 5-HT2B receptor on the vascular endothelium.
However, LY202146 did not block PPE induced by electrical stimulation of the trigeminal
ganglion. These data are consistent with activation of peripheral 5-HT2B receptors
initiating PPE and the theory that selective 5-HT2B antagonists might be effective
prophylactic therapies for migraine." [Abstract]
L, Wolzt M, Graselli U, Findl O, Strenn K, Simak S, Kastner J, Eichler HG, Singer
Nitric oxide synthase inhibition in the histamine headache model.
"Histamine has been widely used experimentally
to induce headache in healthy subjects and migraine in migraineurs. There is evidence
that the vascular effects of histamine are at least partially mediated by nitric
oxide (NO). Hence we hypothesized that subjective symptoms and hemodynamic effects
of histamine could be reduced by systemic NO-synthase inhibition. We therefore
studied the effect of pretreatment with N-monomethyl-L-arginine (L-NMMA), a competitive
inhibitor of NO-synthase, or placebo on headache, flush and discomfort scores
during histamine infusion. Additionally, blood flow velocities in the middle cerebral
and the ophthalmic artery and ocular fundus pulsations were measured. Whereas
L-NMMA blunted the effect of histamine in the ophthalmic artery and the ocular
circulation, NO-synthase inhibition did not mitigate subjective symptoms. Histamine
did not affect mean blood flow velocities in the middle cerebral artery. Hence,
we conclude that NO-synthase inhibition reduces the histamine-induced vascular
effects in the ocular circulation, but is not sufficient to attenuate or abort
the subjective symptoms provoked by histamine infusion." [Abstract]
S, Williamson DJ, Kaube H, Goadsby PJ.
The role of histamine in dural
Brain Res. 2002 Nov 22;956(1):96-102.
pain of migraine is often throbbing suggesting an important role for the cranial
blood vessels and their innervation by the trigeminal nerve. It is proposed that
clinically effective anti-migraine compounds, such as 5-HT(1B/1D) agonists, have
actions that include inhibiting calcitonin gene-related peptide (CGRP) release
from trigeminal nerves. Human studies suggest that histamine can induce migraine
possibly by activating nitric oxide (NO) synthase to promote endogenous NO production.
The present studies investigated the effect of histamine and its antagonists on
the cranial blood vessels using intravital microscopy to assess directly the diameter
of dural arteries in sodium pentobarbitone anaesthetised rats. Electrical stimulation
of a closed cranial window produces, by local depolarisation of nerves, dural
vessel dilation that is monitored continuously on-line using video-microscopy
and a video dimension analyser. Histamine infusion caused immediate and reproducible
dilation of meningeal blood vessels (103.5+/-6%; n=40) that could be blocked by
H(1)- (mepyramine) and H(2) (famotidine)-receptor antagonists (P<0.05), as
well as a nitric oxide synthase inhibitor (N(G)-nitro-L-arginine methylester;
P<0.05). Neurogenic dural vasodilation was not inhibited by H(2)-receptor antagonists,
but was significantly inhibited by a H(1)-receptor antagonist at the high dose
of 10 mg/kg. The present studies demonstrate that histamine is likely to activate
NO synthase to promote NO production. There is also evidence that H(1)-receptors
may be present on trigeminal neurones as the H(1)-receptor antagonist inhibited
neurogenic vasodilation, albeit at a large dose." [Abstract]
LH, Thomsen LL, Kruuse C, Iversen HK, Olesen J.
blockade does not prevent nitroglycerin induced migraine. Support for the NO-hypothesis
Eur J Clin Pharmacol. 1996;49(5):335-9.
has previously been shown that in migraine sufferers infusion of glyceryl trinitrate
(GTN) and histamine causes an immediate headache during the infusion and a genuine
migraine attack one to several hours after the infusion. This identical time profile
indicates a common mechanism of action. To evaluate whether GTN causes headache
via liberation of histamine, we studied the effect of GTN 0.5 micrograms.kg-1.min-1
for 20 min in seven migraine sufferers, once after pretreatment with the histamine-1
(H1)-receptor blocker mepyramine (0.5 mg.kg-1) and once without pretreatment.
This mepyramine dose is known to completely abolish histamine-induced headache.
After pretreatment with mepyramine five patients experienced migraine, and without
pretreatment six patients did so. The median peak headache score was 7 on a 0-10
scale with and without mepyramine pretreatment. The arterial responses, evaluated
with transcranial Doppler, were also unaffected by the mepyramine pretreatment.
Our results demonstrate that neither headache nor arterial dilatation due to GTN
infusion is caused by histamine release. In all likelihood the common mediator
of migraine induction by GTN and histamine is nitric oxide." [Abstract]
LH, Thomsen LL, Olesen J.
Histamine induces migraine via the H1-receptor.
Support for the NO hypothesis of migraine.
1995 Jul 31;6(11):1475-9.
"In primates, histamine activates cerebral endothelial
H1-receptors leading to formation of nitric oxide (NO). Twenty migraine patients
received pretreatment with placebo or the histamine-H1-receptor antagonist, mepyramine,
in a randomized, double blind fashion, followed in both groups by i.v. histamine
(0.5 microgram kg-1 min-1 for 20 min). Headache characteristics were subsequently
observed for 12 h. In patients given placebo histamine caused immediate headache
during the infusion followed by a delayed migraine attack fulfilling IHS criteria
for migraine without aura. The temporal profile of induced headache was exactly
the same as after glyceryl trinitrate. Mepyramine pretreatment abolished both
immediate headache and delayed migraine attacks. Our results suggest that a migraine
attack can be caused by NO formation in the endothelium of cerebral arteries."