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Analgesic triptan action in an animal model of intracranial pain A race against the development of central sensitization.

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Analgesic Triptan Action in an Animal
Model of Intracranial Pain: A Race against
the Development of Central Sensitization
Rami Burstein, PhD,1–3 and Moshe Jakubowski, PhD1
We have shown that the development of cutaneous allodynia (exaggerated skin sensitivity) during migraine is detrimental
to the anti-migraine action of the 5HTIB/ID receptor agonists known is triptans. Because cutaneous allodynia is a manifestation of sensitization of central trigeminovascular neurons, we examined whether triptan treatment can intercept
such sensitization before its initiation or after its establishment in our rat model for cutaneous allodynia induced by
intracranial pain. Single-unit recordings were obtained from spinal trigeminal neurons that proved to received convergent
inputs from the dura and facial skin. The effects of sumatriptan (300 ␮g/kg i.v.) on central sensitization induced by
topical application of inflammatory soup (IS) on the dura were determined when the drug was administered either 2 h
after IS (late intervention) or at the same time as IS (early intervention). Late sumatriptan intervention counteracted two
aspects of central sensitization: dural receptive fields, which initially expanded by IS, shrunk back after treatment;
neuronal response threshold to dural indentation, which initially decreased after IS, increased after sumatriptan. On the
other hand, late sumatriptan intervention did not reverse other aspects of central sensitization: spontaneous firing rate
and neuronal response magnitude to skin brushing which initially increased after IS, remained elevated after
sumatriptan; response threshold to heating of the skin, which initially dropped after IS, remained low after sumatriptan.
Early sumatriptan intervention effectively blocked the development of all aspects of central sensitization expected to be
induced 2 h after IS application: dural receptive fields did not expand; neuronal response threshold to dural indentation
and skin stimulation did not decrease; spontaneous firing rate did not increase. The early treatment results suggest that
triptan action provides a powerful means of preventing the initiation of central sensitization triggered by chemical
stimulation of meningeal nociceptors. The late treatment results suggest that triptan action is insufficient to counteract
an already established central sensitization. Thus, triptan action appears to be exerted directly on peripheral rather than
central trigeminovascular neurons.
Ann Neurol 2004;55:27–36
On the basis of our findings that a brief application
of inflammatory mediators to the rat dura sensitizes
both peripheral and central trigeminovascular neurons, we have proposed that during migraine, peripheral and central sensitization are manifested, respectively, as throbbing headache and cutaneous allodynia
(ie, pain resulting from a nonnoxious stimulus to normal skin).1 Our preclinical studies demonstrated that,
after sensitization, perivascular meningeal nociceptors,
as well as central trigeminovascular neurons that receive convergent input from the dura and skin, became hyperresponsive to low-force dural indentation
to which they were essentially mute before sensitization.2– 4 These preclinical studies further demonstrated that sensitized central trigeminovascular neu-
rons became extremely sensitive to otherwise mild
tactile and thermal stimulation of the periorbital skin.
Indeed, subsequent clinical studies showed that as
many as 75% of our patients developed cutaneous allodynia during migraine attacks.5,6
There are remarkable similarities between the temporal changes in the development of peripheral and
central sensitization in the rat, and their corresponding
clinical manifestations during the course of migraine.
The induction of peripheral sensitization in the rat occurs rapidly within 5 to 20 minutes after applying inflammatory soup (IS) onto the dura,2,7 whereas central
sensitization develops between 20 to 120 minutes before it becomes firmly established after IS.3 Similarly in
patients, throbbing transpires some 5 to 20 minutes
From the 1Departments of Anesthesia and Critical Care, Beth Israel
Deaconess Medical Center; and 2Department of Neurobiology and
the 3Program in Neuroscience, Harvard Medical School, Boston, MA.
Address correspondence to Dr Burstein, Department of Anesthesia
and Critical Care, Harvard Institutes of Medicine, Room 830, 77
Avenue Louis Pasteur, Boston, MA 02115.
E-mail: rburstei@caregroup.harvard.edu
Received Apr 11, 2003, and in revised form Jul 16. Accepted for
publication Jul 16, 2003.
© 2003 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
27
after the onset of headache, whereas cutaneous allodynia starts between 20 and 120 minutes and becomes
firmly established only 120 to 240 minutes after the
onset of headache.6 According to our scenario, meningeal nociceptors become sensitized during migraine a
few minutes after their initial activation, resulting in
throbbing headache and its exacerbation by bending
over. The continued barrage of impulses arriving from
sensitized meningeal nociceptors gradually stimulates
the development of central sensitization in spinal trigeminovascular neurons, resulting in cutaneous allodynia in the same area as the referred head pain. Eventually, as we observed in the rat,3 central
trigeminovascular neurons change their physiological
properties and remain inveterately sensitized, independent of incoming impulses from meningeal nociceptors.
We recently have conducted a clinical study showing
that triptans (5HT1B/1D receptor agonists), the best
studied and most commonly used family of antimigraine drugs, can render migraine patients pain-free depending on whether or not they exhibited cutaneous
allodynia at the time of treatment.8 Patients who had
never developed allodynia were rendered pain-free by
triptan therapy at any time after the onset of migraine
pain. However, patients bound to develop cutaneous
allodynia during migraine were rendered pain-free and
allodynia-free if triptan therapy was given before, but
not after, the establishment of allodynia (ie, within 1
hour of the onset of pain). In this study, we used our
animal model of intracranial pain and cutaneous allodynia to determine (1) whether early sumatriptan administration can prevent the development of central
sensitization and cutaneous allodynia, and (2) whether
late sumatriptan administration can reverse inveterate
central sensitization and cutaneous allodynia.
Materials and Methods
Surgical Preparation
Male Sprague-Dawley rats (350 –500gm) were anesthetized
with urethane (1.2gm/kg, IP) and treated with atropine
(0.04mg, IP). The femoral vein was fitted with indwelling
cannula for later administration of sumatriptan. The trachea
was fitted with an indwelling metal tube for artificial ventilation, and the rat head was affixed in a stereotaxic apparatus. End-tidal CO2 and core temperature were continuously
monitored and kept within physiological range. The ventral
half of the occipital bone and the laminar process of C1 were
removed to lower a recording electrode into the trigeminal
nucleus caudalis. Dura mater overlying the dorsal surface of
the left hemisphere and transverse sinus was exposed by carefully removing the frontal and parietal bones. To keep the
moisture, we covered the exposed brainstem with mineral oil,
and the exposed dura was flooded with synthetic interstitial
fluid, consisting of 10mM Hepes, 5mM KCl, 1mM MgCl2,
5mM CaCl2, and 135mM NaCl, pH 7.3.
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Neuronal Identification and Selection
Central trigeminovascular neurons receiving converging input from the dura and facial skin were first identified by
mapping their intracranial and extracranial receptive fields,
using electrical stimulation of the dura and mechanical stimulation of the skin as we described elsewhere.3 Next, each
neuron was characterized for its baseline responses to a series
of stimuli. Dural stimulation was performed by indentation
with a series of calibrated von Frey hairs. Stimulation of the
facial skin included the following: brushing with paintbrush;
pressing with loose arterial clip; incremental heating using a
contact thermal stimulator. Each series of stimuli was repeated at least three times at 5 to 10-minute intervals, and
only neurons showing less than 10% variability in responses
were selected to be further studied. Selected neurons then
were sampled for their baseline rate of spontaneous firing
over a period of 10 minutes.
To induce sensitization in central trigeminovascular neurons, we bathed the hotspot of the dural receptive field for 5
minutes in IS (1mM histamine, serotonin, bradykinin,
0.1mM prostaglandin E2 in 10mM Hepes buffer, pH 5.5;
adapted from Steen and colleagues9,10). In the initial part of
the study, we found that application of IS onto the dura
produced activation in all neurons studied but resulted in
sensitization in 14 of 15 neurons that received both A␦- and
C-fiber input and in none of the six neurons that received
only A␦-fiber input. Therefore, we selected only neurons that
got activated upon IS application onto the dura and proved
to receive both A␦- and C-fiber input.
Sumatriptan Treatment
Sumatriptan solution (300␮g/ml) was infused intravenously
at a rate of 15␮g/minute over 7 to 10 minutes, to a final
dose of 300␮g/kg body weight. The choice of injectable
sumatriptan treatment in this study was based on the evidence that, of all the triptans, this formulation provides the
highest therapeutic gain in migraine patients.11 Animal studies have shown that intravenous administration of
sumatriptan at doses ranging from 100 to 300␮g/kg produces constriction of dilated blood vessels,12,13 inhibition of
dural plasma protein extravasation,14 neurogenic inflammation,15 neurogenic vasodilatation,16 arterial blood flow,17 and
release of calcitonin gene–related protein18,19 and substance
P.20 The higher sumatriptan dose of 300␮g/kg was chosen to
maximize potential inhibitory action of the drug on central
sensitization and to minimize the probability of negative results due to lower ineffective dose.
Experimental Protocol
Two groups of neurons were used to examine whether intravenous infusion of the 5HT1B/1D receptor agonist
sumatriptan (GlaxoSmithKline, Research Triangle Park, NC)
can prevent the initiation of IS-induced central sensitization
(early treatment) or reverse ongoing central sensitization (late
treatment). Group 1 (n ⫽ 9) was designated for late
sumatriptan treatment. At 1 and 2 hours after the application of IS onto the dura, we remapped dural receptive field
size, reexamined neuronal responses to stimulation of dura
and skin, and resampled spontaneous firing rate. Resulting
values for each measure were then compared with the respec-
tive baseline values obtained before IS application to ascertain that central sensitization took place. As described in our
earlier work,3 mandatory criteria for central sensitization included expansion of receptive fields, enhanced sensitivity to
dural indentation, decreased thresholds and increased response magnitude to mechanical and thermal stimulation of
the skin, and increased spontaneous activity. Once central
sensitization was ascertained, sumatriptan was infused intravenously, and all measurements described above were repeated again at 3 and 4 hours after the application of IS (⫽
1 and 2 hours after administration of sumatriptan). Group 2
(n ⫽ 9) was designated for early sumatriptan treatment, such
that sumatriptan was infused intravenously at the same time
as IS was applied onto the dura. Resulting receptive field
size, neuronal response threshold or magnitude to each stimulus, and spontaneous firing rate were remeasured 1 and 2
hours later and compared with the respective baseline values
obtained before any treatment to determine whether or not
sumatriptan prevented the induction of central sensitization
by IS.
Statistical Analysis
Data are presented as mean ⫾ standard error and analyzed
using nonparametric statistics.21 Spontaneous activity and
neuronal responses to dural or skin stimulation were analyzed over three time points (0, 1, 2 hours), using Friedman
two-way analysis of variance. Post hoc paired comparisons
were performed using one-tailed Wilcoxon matched-pairs
signed ranks test. Level of significance was set at 0.05.
Results
Recording Sites and Cutaneous Receptive Fields of
Central Trigeminovascular Neurons
Recording sites and maps of cutaneous receptive fields
did not differ between neurons tested for early
sumatriptan intervention and those tested for late intervention (Fig 1). All identified recording sites were
localized to laminae IV and V of the first cervical segment. In most cases, cutaneous receptive fields were
restricted to the periorbital/ophthalmic area. This area
remained the most sensitive spot even in cases in which
the receptive field extended over the entire face.
Spontaneous and Inflammatory Soup–Induced
Activity of Central Trigeminovascular Neurons
Late sumatriptan intervention did not reverse the longterm increase in neuronal spontaneous firing induced
by IS (Fig 2A). Neuronal firing rate, which increased
sixfold ( p ⫽ 0.002) within 2 hours of IS application,
remained elevated fivefold after sumatriptan infusion
compared with the initial rate of spontaneous activity
( p ⫽ 0.008; see Fig 2C).
Early sumatriptan intervention effectively prevented
the long-term increase in spontaneous activity seen in
the late intervention group, although it did not block
neuronal activation (the initial burst in neuronal firing)
that typically takes place upon IS application (see Fig
Fig 1. Recording sites and cutaneous receptive fields of trigeminovascular neurons in the late (A) and early (B) intervention groups. The photomicrographs of electrolytic lesions show
the recording locations of neurons in the deep laminae (IV, V)
of the dorsal horn at first cervical segment. The schematic
mapping of facial receptive fields (light gray areas) show that
the periorbital skin contains the most sensitive region of the
receptive field (dark gray area). Numbers identify individual
cases.
2B). Neuronal firing rate did not increase; in fact, it
decreased slightly ( p ⫽ 0.048; see Fig 2D).
Dural Receptive Fields of Central
Trigeminovascular Neurons
Late sumatriptan intervention effectively reversed ISinduced expansion of dural receptive field. In 89% of
the cases, dural receptive field expanded within 2 hours
of IS application and contracted back 1 to 2 hours after sumatriptan infusion; with the exception of two
cases (Cases 2 and 34), dural receptive field returned to
its original, presensitization size (Fig 3A).
Burstein and Jakubowski: Sumatriptan and Sensitization
29
Fig 2. Spontaneous and ISinduced firing of central trigeminovascular neurons. (A) Mean
firing rate of a neuron sampled
at 1-hour intervals before (baseline/green) and after (red) application of IS, and again after
a delayed administration of
sumatriptan (blue). Notice that
spontaneous activity increased
from a baseline of 2 spikes/sec to
28 spikes/sec 4 hours after IS
application and remained elevated at 18 spikes/sec after
sumatriptan infusion. (B) Mean
firing rate of a neuron sampled
before (baseline/green) and after
(purple) simultaneous application of IS and sumatriptan. Notice that spontaneous activity
increased transiently (from 0.1
to 10 spikes/sec) for only 20
minutes. (C, D) Summary of
spontaneous firing rate (mean ⫾
SE) in late (n ⫽ 9) and early
(n ⫽ 9) sumatriptan intervention groups, respectively.
Early sumatriptan intervention prevented the expansion of dural receptive fields seen in the late intervention group. In 78% of the cases, dural receptive field
size remained unchanged; the remaining 22% (Cases
12 and 30) expanded transiently (see Fig 3B).
Sensitivity of Central Trigeminovascular Neurons to
Dural Indentation
To one degree or another, late sumatriptan intervention reversed IS-induced increase in neuronal sensitiv-
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ity to dural indentation. In 56% of the cases, neuronal
threshold increased back to its presensitization value, in
33% it increased only partially, and in the remaining
11% the threshold did not increase at all (Fig 4A).
Overall, neuronal threshold for dural indentation plummeted significantly ( p ⬍ 0.001) within 2 hours of IS
application and then increased significantly ( p ⫽ 0.005)
within 2 hours of sumatriptan infusion (see Fig 4C).
Early sumatriptan intervention effectively prevented
IS from inducing increased neuronal sensitivity in all
Fig 3. Dural receptive fields of individual central trigeminovascular neurons. (A) Receptive field sizes mapped before (baseline/green)
and after (red) the application of IS, and again after a delayed administration of sumatriptan (blue). Notice that dural receptive
fields that expanded by IS, contracted back to their original size by sumatriptan. (B) Receptive field sizes mapped before (baseline/
green) and after (purple) simultaneous application of IS and sumatriptan. Notice that dural receptive fields did not expand. Numbers on top identify individual cases. Inset depicts meningeal sinuses.
cases. In fact, neuronal threshold for dural indentation
slightly increased (rather than decreased) in 57% of the
cases (see Fig 4B), and the overall increase in threshold
approached the level of significance ( p ⫽ 0.056; see
Fig 4D).
Sensitivity of Central Trigeminovascular Neurons to
Mechanical Stimuli at the Periorbital Skin
Late sumatriptan intervention did not reverse ISinduced increase in neuronal sensitivity to mechanical
stimulation at the periorbital skin (Fig 5A). There was
a twofold increase in neuronal response magnitude to
brush ( p ⫽ 0.004) and pressure ( p ⫽ 0.005) within
2 hours of IS application, and sumatriptan infusion
produced no change in these elevated responses (see
Fig 5C).
Early sumatriptan intervention effectively prevented
IS from inducing such increased neuronal sensitivity
to mechanical skin stimuli (see Fig 5B). Neuronal
response magnitude to brush and pressure did not
show any significant increase from baseline values (see
Fig 5D).
Sensitivity of Central Trigeminovascular Neurons to
Thermal Stimulation of the Periorbital Skin
Of the 18 neurons studied, 2 (1 of each group) were
heat insensitive and therefore were excluded from the
analysis. Three additional neurons in the late intervention group failed to exhibit a decrease in heat threshold
after IS application and therefore could not be tested
for potential inhibitory effects of late sumatriptan infusion.
Late sumatriptan intervention did not reverse ISinduced increase in neuronal sensitivity to heat stimuli
at the periorbital skin (Fig 6A). Neuronal response
threshold for heat decreased by 4 to 6°C ( p ⫽ 0.008)
within 2 hours of IS application and remained low after sumatriptan infusion compared with the initial heat
threshold value ( p ⬍ 0.05; see Fig 6C).
Early sumatriptan intervention prevented IS from in-
Burstein and Jakubowski: Sumatriptan and Sensitization
31
Fig 4. Response threshold of central
trigeminovascular neurons to dural
indentation. (A) Response threshold to
dural indentation of 2 neurons sampled
at 1-hour intervals before (baseline/
green) and after (red) application of
IS, and again after a delayed administration of sumatriptan (blue). Notice
that response thresholds plummeted
after IS application and recovered completely in one case and only partially in
the other after sumatriptan administration. (B) Response threshold to dural
indentation of two neurons sampled at
1-hour intervals before (baseline/green)
and after (purple) simultaneous application of IS and sumatriptan. Notice
that the response threshold remained
unchanged in one case and increased in
the other. (C, D) Summary of response
threshold to dural indentation
(mean ⫾ SEM) in late (n ⫽ 9) and
early (n ⫽ 9) sumatriptan intervention
groups, respectively.
ducing such increased neuronal sensitivity to heat (see
Fig 6B), and neuronal response threshold remained unchanged ( p ⬎ 0.07; see Fig 6D).
Discussion
This study demonstrates that the effects of sumatriptan
on spinal trigeminovascular neurons depends on
whether the drug is given before or after the establishment of central sensitization and cutaneous allodynia.
Late sumatriptan intervention effectively reversed measures of central sensitization that depend on peripheral
input from the meninges (ie, enlarged dural receptive
field and increased sensitivity to dural indentation), but
not those that reflect intrinsic activity (ie, increased
spontaneous firing and increased sensitivity to periorbital skin stimulation). These results suggest that
sumatriptan acts peripherally to block transmission of
pain signals from the dura but does not act directly on
the central neurons in spinal trigeminal nucleus. Such
peripheral blockade of signal transmission from the
dura to the central trigeminovascular neurons is also
compatible with our finding that early sumatriptan intervention effectively prevented the induction of all of
the above measures of central sensitization.
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Effects of Sumatriptan on Sensitization in Central
Trigeminovascular Neurons
This is the first study to our knowledge to test the
effects of any triptan on long-lasting sensitization of
central trigeminovascular neurons. Critical to meaningful interpretation of sumatriptan action was the integration of intracranial and extracranial sensitivities in
the same central trigeminovascular neuron.
When given after the establishment of central sensitization (late intervention), sumatriptan effectively reversed increased intracranial sensitivity of central trigeminovascular neurons (ie, enlarged dural receptive
field; increased sensitivity to dural indentation). On
face value, this could have been mistaken as evidence
that sumatriptan directly counteracts ongoing sensitization of central trigeminovascular neurons, perhaps
through postsynaptic inhibition. Conversely, late treatment did not reverse the increased spontaneous firing
of the same sensitized central trigeminovascular neurons, nor did it reverse their increased extracranial sensitivity (ie, increased sensitivity to mechanical and thermal stimulation of the periorbital skin), suggesting that
sumatriptan cannot counteract ongoing central sensitization. Considering that central trigeminovascular neurons process afferent signals from intracranial and
Fig 5. Response magnitude of
central trigeminovascular neurons to mechanical stimulation
of the periorbital skin. (A) Responses induced by brush and
pressure in a neuron studied at
1-hour intervals before (baseline/green) and after (red) application of IS, and again after
a delayed administration of
sumatriptan (blue). Notice that
response magnitudes increased
after IS application and remained elevated after delayed
sumatriptan administration. (B)
Responses induced by brush and
pressure in a neuron studied at
1-hour intervals before (baseline/green) and after (purple)
simultaneous application of IS
and sumatriptan. Notice that
response magnitudes did not increase from baseline. (C, D)
Summary of response magnitudes
(mean ⫾ SEM) to brush (top)
and pressure (bottom) in late
(n ⫽ 9) and early (n ⫽ 9)
sumatriptan intervention groups,
respectively. Gray bars in C and
D indicate spontaneous activity
in the 10-second interval that
preceded the stimulus.
extracranial organs simultaneously, it is far more reasonable to conclude that sumatriptan acts peripherally
to block information flow from the dura to central trigeminovascular neurons, rather than inhibiting the latter directly.
When sumatriptan was administered at the same
time as IS was applied onto the dura (early interven-
tion), it invariably prevented the induction of every aspect of central sensitization that we measured. Thus,
central trigeminovascular neurons showed no expansion of dural receptive field, no increase in sensitivity
to dural indentation, no long-term increase in spontaneous firing, and no increase in response magnitude to
mechanical and thermal skin stimulation. On face
Burstein and Jakubowski: Sumatriptan and Sensitization
33
Fig 6. Response thresholds and
magnitudes of central trigeminovascular neurons to thermal
stimulation of the periorbital
skin. (A) Responses induced by
raising skin temperature from 35
to 50°C in a neuron studied at
1-hour intervals before (baseline/green) and after (red) application of IS, and again after
a delayed administration of
sumatriptan (blue). Gray area
(also in B) marks the interval
between the onset of heating and
the response threshold at baseline
(green panel). Notice that response thresholds decreased from
46 to 42°C after IS application
and remained at 42°C after
delayed sumatriptan administration. Notice also that response
magnitudes increased after IS
application and remained elevated after delayed sumatriptan
administration. (B) Responses
induced by increasing skin temperature from 35 to 50°C in a
neuron studied at 1-hour intervals before (baseline/green) and
after (purple) simultaneous application of IS and sumatriptan.
Notice that response thresholds
and magnitudes did not change
from baseline. (C, D) Summary
of response magnitudes (mean ⫾
SEM) to heat in late (n ⫽ 5)
and early (n ⫽ 8) sumatriptan
intervention groups, respectively.
value, these findings could be mistaken as evidence that
sumatriptan acts directly on trigeminovascular neurons
in the dorsal horn. Viewed together with the late intervention results, however, the more likely interpretation is that early sumatriptan intervention averted the
initiation of central sensitization by blocking noxious
signals generated in sensitized meningeal nociceptors
from reaching central trigeminovascular neurons in the
dorsal horn.
Based on the integration of the findings above, we
propose that the sumatriptan reduces the transmission of
sensory signals from the dura to the dorsal horn by acting directly on meningeal nociceptors. Such action may
be exerted on the nociceptor’s peripheral branch (in the
dura), or its cell soma (in the trigeminal ganglion), or its
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central branch (in the spinal cord). We also propose that
sumatriptan cannot generate enough inhibition to significantly counteract inveterate sensitization in central trigeminovascular neurons, presumably because these neurons do not express the 5HT1B/1D receptor or,
alternatively, the receptor may be present but its activation falls short of generating functional inhibition when
the neurons are sensitized. Finally, we rule out the possibility that the failure of sumatriptan to counteract inveterate central sensitization was caused by poor penetrability through the blood–brain barrier, because
triptans with much higher lipophylicity than
sumatriptan are as equally as ineffective in terminating
migraine pain in the presence of cutaneous allodynia as
we report in the accompanying clinical study.8
Effects of Triptans on Nonsensitized Central
Trigeminovascular Neurons
Unlike this study, which tested the effects sumatriptan
on neurons undergoing a long-lasting state of sensitization that simulates migraine-like pathophysiology, other
studies have examined the effects of triptans on naive,
nonsensitized central trigeminovascular neurons. In
those studies, intravenous administration of triptans
such as sumatriptan,22 zolmitriptan,23 naratriptan,24 or
rizatriptan25,26 reduced evoked potential magnitude and
firing probability of central trigeminovascular neurons in
response to electrical stimulation of meningeal blood
vessels. Collectively, those studies have led the authors to
propose that the therapeutic actions of triptans in alleviating migraine headache are caused by direct inhibition
of central23,27 and/or peripheral25,28 trigeminovascular
neurons. Note that these studies reflect the physiological
properties of trigeminovascular neurons only under normal conditions, rather than the pathophysiological
changes they undergo during migraine attack.
Cumberbatch and colleagues28 showed that the
triptan L-741-604 interfered with calcitonin gene–related peptide–induced amplification of responses of
central trigeminovascular neurons to vibrissal air puffs
and concluded that this triptan can inhibit central sensitization. However, the increased neuronal responses
to vibrissal stimulation lasted a mere 6 minutes, a period of time too short for the development of central
sensitization, which should run for hours after termination of the triggering stimulus, independent of incoming impulses from peripheral trigeminovascular nociceptors.3 Short of fulfilling additional criteria for
central sensitization (ie, expansion of dural and facial
receptive fields, decreased threshold of mechanical and
thermal skin stimulation, long-lasting increase in spontaneous activity), Cumberbatch and colleagues appear
to have studied nonsensitized trigeminovascular neurons, and their results have no bearing to triptan action
on central sensitization.
Physiological and Clinical Correlates and Conclusions
We propose that the responses of individual trigeminovascular neurons in our animal model of intracranial
pain and cutaneous allodynia correspond to the neurological symptoms of migraine attacks in patients in
three ways. Correlate 1: expansion of dural receptive
fields and increased neuronal sensitivity to dural indentation correspond to the throbbing and exacerbation of
pain by bending over. Correlate 2: increased spontaneous activity corresponds to the pain intensity. Correlate
3: increased neuronal sensitivity to brushing and heating of the rat periorbital skin corresponds to mechanical and thermal allodynia in the patient periorbital
skin of the referred pain area.
Based on these correlates, we propose the following
interpretations for the neuronal action of sumatriptan.
The peripheral action of sumatriptan that blocks transmission of pain signals from the dura to the central
trigeminovascular neurons can explain our observations
in migraine patients8 that the drug is highly effective,
whether given early or late into the attack, in terminating throbbing and eliminating the exacerbation of pain
upon bending over (correlate 1). This peripheral action
also explains the results of our clinical study8 that early
sumatriptan intervention is effective in terminating migraine pain (correlate 2) and blocking the development
of cutaneous allodynia (correlate 3), because it disrupts
the input necessary for the development of central sensitization. The evidence that the peripheral action of
sumatriptan cannot counteract the inveterate, ongoing
sensitization in the central trigeminovascular neurons
can explain the failure of late sumatriptan intervention
to terminate migraine pain (correlate 2) or reverse the
exaggerated skin sensitivity (correlate 3) in attacks already associated with allodynia.8
That the benefits of triptan therapy is limited to the
early stages of a migraine attack among allodynic patients8 is consistent with the evidence that triptans can
prevent the initiation of central sensitization which depends on incoming impulses from meningeal nociceptors but cannot abort ongoing central sensitization
once it became self-sustained. This limitation of
triptans calls for new migraine drugs designed to reverse the hyperexcitable state of central trigeminovascular neurons in the later stages of migraine by bringing their membrane potential back to its normal
resting value.
This work was supported by a grant from GlaxoSmithKline (48573,
R.B.) and by the National Institutes of Health (NIDCR, DE13347,
R.B., and NINDS, NS35611, R.B.).
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