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Ergot alkaloids block neurogenic extravasation in dura mater Proposed action in vascular headaches.

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Ergot Alkaloids Block Neurogenic
Extravasation in Dura Mater: Proposed
Action in Vascular Headaches
Kiyoshi Saito, MD, Stephen Markowitz, MD, and Michael A. Moskowitz, MD
Although the ergot alkaloids (ergots) are useful drugs for the acute treatment of migraine headaches, their mechanism
of action remains obscure. When administered to rats in clinically relevant doses, ergots blocked the development of
neurogenic plasma extravasation in dura mater. Plasma extravasation was induced by depolarization of perivascular
axons following capsaicin injection or unilateral electrical stimulation of the trigeminal nerve. The ergot action could
not be accounted for by vasoconstriction alone because neurogenic plasma leakage was not blocked by angiotensin or
phenylephrine. Furthermore, ergots did not block plasma extravasation induced by administering sensory neuropeptides that mediate enhanced permeability. We propose that the therapeutic effects of ergots in vascular headaches may
result from peripheral blockade of small fiber (C or A-delta)-dependent neurogenic inflammation within the dura
mater.
Saito K, Markowitz S, Moskowitz MA. Ergot alkaloids block neurogenic extravasation in dura mater:
proposed action in vascular headaches. Ann Neurol 1988;24:732-737
First introduced for the treatment of migraine and
cluster headache about 60 years ago, the ergots remain
one of the most effective abortive drug therapies for
these headaches [l, 2). Although the ergots are presumed to work by constricting painful dilated and
stretched cephalic vessels [3-51, evidence is lacking to
support fully either a vasodilator mechanism of headache pathogenesis or a vasoconstrictor mechanism of
drug action. Indeed, which of the many properties artributed to the ergots are important in relieving headache remains unclear [GI. The fact that they relieve
classic and common migraine as well as cluster headache suggests that they may work on a mechanism
common to all headaches. Despite the considerable
controversy as to the mechanism of drug action, there
is general agreement that cranial blood vessels and, in
particular, those vessels within the dura mater and leptomeninges are an important source for headaches
17-91, and that perivascular afferents transmit this
nociceptive information to the central nervous system
[lo, 111.
That afferent fibers subserve functions other than
transmission of sensory inputs has long been recognized. In particular, sensory nerves mediate certain
trophic interactions [12, 131 and proniote so-called
neurogenic inflammation [14- IS]. The term nearogenic inflammation has been coined to describe the lo-
cal vasodilation and plasma extravasation that occur
within the peripheral distribution of C-fibers following
electrical or chemical stimulation of these unmyelinated afferent fibers.
We have recently established that depotarization of
trigeminal small caliber axons induces neurogenic
plasma extravasation in the dura mater of rats [19]. In
this model, depolarization results in the release of
vasoactive substances such as substance P (SP), neurokinin A (NKA), and other contained neuropeptides
(such as calcitonin gene-related peptide) from perivascular sensory axons into the vessel wall, thus mediating
dilation and plasma extravasation. Depolarizatiom was
induced by electrical trigeminal stimulation or in travenous injection of capsaicin. Capsaicin is the pungent
ingredient in red peppers, which upon acute low dose
(0.5 mg/kg) intravenous administration selectively depolarizes primary sensory afferent C-fibers with the
development of neurogenic inflammation [20 1. By
contrast, when administered at high dose (50 mg/kg)
subcutaneously to neonatal animals within the first 24
hours of life, capsaicin selectively and permanently depletes animals of unmyelinated C-fibers and some
finely myelinated fibers [21, 221. As expected, adult
animals in whom C-fibers have been selectively destroyed at birth do not develop neurogenic plasma extravasation in the dura rnater [lc)].
From the Stroke Research Laboratory, Departments of Neurosurgery and Neurology, Massachusetts General Hospital, Harvard
Medical School, Boston, MA.
Received Mar 21, 1988, and in revised form May 3. Accepted for
publication June 1, 1988.
Address correspondence to Dr Moskowitz, Stroke Research Iaboratory, Massachusetts General Hospital, Boston, MA 02 1 14.
732 Copyright 0 1988 by the American Neurological Association
We now present results demonstrating that those
ergots therapeutically useful in the management of vascular headaches (ergotamine tartrate {ET), dihydroergotamine EDHE), and methysergide {MDE)) also
block neurogenic plasma extravasation in the dura mater by a mechanism that is axon dependent. These
studies have been reported previously in preliminary
form {23, 23a).
Materials and Methods
Sprague Dawley male rats (150-250 gm) were housed under
diurnal lighting conditions and allowed food and water ad
libitum. Anesthetized with an intraperitoneal injection of
pentobarbital (60 mg/kg), they were injected with 100 pCi/
kg of '*'I-bovine serum albumin ('251-BSA; New England
Nuclear, Boston, MA; 100 pCi/ml saline) via the right
femoral vein 5 minutes before electrical stimulation or injection of capsaicin (Polysciences, Warrington, PA), as previously described [19]. For electrical stimulation, nonconcentric bipolar electrodes were lowered under stereotactic
control into both trigeminal ganglia. The test side was stimulated for 5 minutes using paired rectangular pulses of opposite polarity; five pulses were administered per second, each
of 5 milliseconds duration at a current of 1 mA. For chemical
stimulation, 0.5 mg/kg of capsaicin (0.5 mg/ml capsaicin vehicle) was injected into the left femoral vein. For controls,
capsaicin vehicle (ethanol-Tween 80-saline at 10: 10 :80),
saline, or phosphate-buffered saline (1 mykg) was injected;
the effects of these three did not differ from one another
119, 231. After 5 minutes of electrical stimulation or 10
minutes after injection of capsaicin, animals were perfused
via the left cardiac ventricle with saline at a pressure of 120
mm Hg for 2 minutes. The dura mater was dissected as
follows: For the experiments involving electrical stimulation,
the entire supratentorial dura was taken, exclusive of the
superior sagittal sinus and that portion damaged by the penetrating electrode. For the capsaicin experiments, the entire
supratentorial dura mater was dissected. The dura was then
weighed and counted for the amount of extravasated '*'IBSA (cpdmg wet weight tissue), which was expressed either as the ratio of the radioactivity between the stimulated
and the unstimulated side in the electrically stimulated group
or as a percentage of the mean value for vehicle-injected
controls in the capsaicin group. Radioactivity in the dura
mater was also determined in a group of animals receiving an
injection of lZ51-BSAonly.
Plasma extravasation was also induced in the dura mater by
an intravenous injection of SP (Peninsula Labs, San Carlos,
CA; 1 nmoYkg or 0.1 nmoykg) or NKA (Peninsula Labs; 1
nmoYkg) as reported previously 119, 24, 251. The protocol
described above was followed, except that SP or NKA was
injected via a femoral vein ( 1 mVkg) instead of capsaicin.
Extravasated radioactivity was expressed as a percentage of
the mean value for vehicle-injected controls. Stock solutions
of SP (in 0.01 N acetic acid) and NKA (in 2 N acetic acid)
were separated in aliquots, stored at - 70°C and diluted with
saline (SP) or phosphate-buffered saline (NKA) before use.
For ergot pretreatment, animals were injected with ET
(Sandoz, East Hanover, NJ) or DHE (Sandoz; supplied as
D.H.E. 45R ampules El mg/ml)) (0.5, 5.0, 50, or 100 pg/kg)
via the external jugular vein (0.5 mYkg), or MDE (Sandoz; 1
mg/kg) intraperitoneally (1 mYkg) 10 minutes before stimulation. One group of animals received 50 pg/kg MDE intraperitoneally (0.5 mVkg) four times a day for 3 days prior
to stimulation. ET and MDE were dissolved in 5% dimethylsulfoxide (1 mg/ml) and diluted with saline before the experiments.
Other groups of animals were pretreated with the vasoconstrictors phenylephrine (Sigma Chemical Co, St Louis,
MO) or angiotensin I1 (Sigma) or a long-acting opioid agonist, lofentanil (Janssen Pharmaceutica Inc, New Brunswick,
NJ) 1261. Phenylephrine (0.03, 0.1, 1.0, or 3.0 mg/kg) was
injected intraperitoneally (1 mVkg in saline) 10 minutes before stimulation. In some animals, lofentanil (10 pghl
saline) was also injected 10 minutes before capsaicin. In
some cases, naloxone (Sigma; 10 mg/ml saline) was administered 5 minutes prior to lofentanil. Angiotensin I1 (2 pg/ml)
was continuously infused (50 kYkg/min) through a femoral
vein 127) starting 2 minutes before capsaicin injection for the
duration of the experiment.
Data were expressed as mean
standard error of the
mean. Values from pretreated animals were compared with
the nonpretreated group by Student's t test, and probability
values less than 0.05 were considered significant.
*
Results
Both electrical and chemical stimulation significantly
increased leakage of radiolabeled albumin from dural
blood vessels (Fig 1). Mean counts per minute (cpm) in
dura mater o n the unstimulated side did not differ
statistically between treated and untreated animals and
averaged 10.9
0.5 c p d m g tissue for both groups.
In untreated animals, the mean leakage was 22.7
2.3 cpmlmg tissue o n the stimulated side and 12.3 ?
0.6 cpmlmg tissue o n the unstimulated side following
electrical stimulation at a current intensity of 1 mA. At
lower current intensities (< 0.9 mA for 5 minutes), no
significant plasma extravasation was observed in the
dura. When expressed as a ratio of the stimulated to
unstimulated side, electrical trigeminal stimulation increased plasma extravasation almost twofold, 1.8
0.1. By contrast, n o extravasation was observed in
brain under the same stated conditions 1191.
Intravenously administered capsaicin also promoted
the leakage of tracer in dura mater when examined 10
minutes following injection. T h e dura maters from
capsaicin-treated animals exhibited a 25% increase in
extravasated protein as compared with vehicle-injected
animals. T h e average count in vehicle controls was 7.2
& 1.0 c p d m g tissue. As previously described [19),
the extravasation was not measurable in adult animals
in whom small-diameter sensory fibers were depleted
by capsaicin treatment as neonates {19, 21, 22).
Pretreatment with ET o r D H E blocked the effects
of capsaicin at doses of 5 pgkg and above and electrical stimulation at doses of 50 pg/kg and above (Fig l A ,
B). That higher doses of the ergots were required to
*
*
*
Saito et a1 Ergot and Neurogenic Inflammation 733
T
Pretreatment with Ergots Does Not Black Plasma
Extravasation in the Dura Mater Induced by Substance P (SPI
or Neurokinin A (NKA)"
Inducing Agent
Pretreatment
~
SP (1 nmoYkg)
SP (0 1 nrnoYkg)
NKA (1 nmol/kg)
N
~______
~
None
Ergotarnine (1 rngikg IP)
DHE
(1 mg/k.g 1P)
None
DHE
(50 g/kg IV)
None
Ergotarnine (1 mgkg IP)
(1 rngikg IP)
DHE
Percent
ofControlh
18
14
8
8
I
8
8
4
165
143
136
132
121
144
144
134
t 11
-+ 14
?
?
?
10
6
6
2 10
k
10
t 1
"Data expressed as mean ? SEM.
bGroups pretreated with ergots did not differ from nonpretreated
groups by Student's t test.
DHE = dihydroergotarnine.
A
B
F i g I. Pretreatment with ergots blocks the plasma extravasation
induced by (Aj electrical stimulation (1 mA, 5 minutes) ofthe
trigeminal ganglion or (B) intravenously administered capsaicin
(0.5 mglkg). In A data are expressed as the ratio of the radioactivity between the stimulated and the unstimulated side. Data
from 23 aninials represent the untreated group. The numben
of animals in the ergotamine tartrate and dihydroergotamine
(DHE) groups were 8 (100 pglkg) and 6 (50 pglkg), and 8 (50
pglkg) and 5 (5 pglkg), respectively. Data from 6 animals represent each of the methysergide-treated groups. In B data are expressed as a percentage of the mean value for vehicle-injected controls. Data from 12 animals represent the untreated group. The
numbers of animals treated,with ergotarnine tartrate were 7 (50
pglke), 7 (5 pglkg), and 4 (0.5 pglkgl; the numbers treated
with DHE were 8 (50 pgtkd. 8 (S pglkg), and 9 (0.5 kglkg);
and the numbers treated with methysergide were 17 (chronic)
and 4 (1 mglkg acute). = p < 0.05; = p < 0.01 as
compared with the nonpretreated group.
+
734 Annals of Neurology
++
block the electrically induced albumin leakage possibly
reflects the larger spectrum of sensory fibers activated
and the greater plasma extravasation resulting from
electrical stimulation as compared with that induced by
capsaicin. Acute MDE administration was not effective, even at a dose of 1 mglkg. Chronic pretreatment
with MDE (50 p d k g IP four times a day for 3 days),
however, effectively blocked plasma extravasation induced by electrical or chemical stimulation.
The table shows that SP or NKA enhanced the leakage of plasma protein in the dura mater. The lowest
effective dose for SP and NKA was 0.1 nmol/kg and
1 .O nmoVkg, respectively. Leakage resulted from the
direct tachykinin action on the vasculature, since the
tachykinins promoted an equivalent amount of extravasation in animals treated with capsaicin as neonates
[191. Neither ET nor D H E pretreatment blocked the
SP-induced or NKA-induced response, even when administered in amounts much greater than those required to block neurogenic plasma extravasation. So,
for example, DHE completely blocked plasma extravasation in the dura mater when given intravenously at
concentrations of 5 pglkg 10 minutes prior to capsaicin
administration, but was ineffective against SP administration even when injected at a dose of 1 mglkg.
Neither phenylephrine nor angiotensin I1 blocked
the capsaicin-induced albumin leakage in the dura mater (Fig 2). When tested over a range of concentrations, no blockade was observed with either phenylephrine or angiotensin 11. In fact, high doses of
phenylephrine, known to be associated with severe hypertension, increased extravasation. Similarly, pretreatment with phenylephrine (0.1 mgikg) did not block
electrically induced plasma extravasation (2.0 k 0.3, n
= 5). The effect of angiotensin infusion was not tested
in the electrical stimulation model. Pretreatment with
lofentanil blocked capsaicin-induced extravasation of
tracer by a naloxone-sensitive mechanism (see Fig 2).
Vol 24 No 6 December 1988
**
T
*
0
c
2
P
8
P
i
Fig 2. Pretreatment with the vasoconstrictors, phenylephrine (n
= 4 per group) and angiotensin I1 (n = 4) did not block the
effect of capsaicin (0.5 mglkg, n = 12) on plasma extrauasation. Lofentanil ( n = S ) attenuated the capsaicin-induced extravasation. an effect reversible by naloxone (n = 9). Data are
expressed as apercentage ofthe mean SEM. ** = p < 0.01
as compared with nonpretreated group.
*
Discussion
Neurogenic inflammation provides one of the earliest
tissue responses to local injury, accelerating and modulating the development of the inflammatory processes. Tissues at portals of entry including those that
line the respiratory tract, integument, and genitourinary tract exhibit this phenomenon. The dura mater
can now be added to this list. Insofar as plasma extravasation is an invariant feature of neurogenic inflammation 118, 28) it can be used as a reliable indicator of
neurogenic inflammation and developed in the dura
mater following depolarization of the trigeminal nerve
by chemical or electrical stimulation.
Pretreatment with ET or DHE blocked the stimulation-induced neurogenic plasma extravasation. The
clinical relevance of these observations is suggested by
the finding that (1) ET and D H E blocked extravasation
in doses similar to those used in the treatment of migraine headaches, and (2) MDE effectively blocked
extravasation only when administered chronically.
Whether the difference between acute and chronic administration reflects the presence of higher tissue
levels or the actions of an active metabolite remains to
be determined. MDE was reported to possess antiinflammatory properties in humans when tested intradermally against injections of manganese butyrate
"291.
Though vasoconstriction is one of the best charac-
terized actions of the ergots, the role of vasoconstriction in the treatment of headache remains unclear. Despite the fact that ET constricts both resistance and
capacitance vessels and that D H E is less potent and
constricts mainly capacitance vessels 130, 3 11, both are
effective in the treatment of headache. The inability of
the vasoconstrictors phenylephrine and angiotensin to
block neurogenic plasma extravasation suggests that
the relationship between vasoconstriction and ergot
therapeutic actions is complex. Furthermore, neither
ET nor DHE pretreatment blocked the ability of the
tachykinins to promote plasma extravasation by directly affecting the vasculature (so-called nonneurogenic plasma extravasation). Taken together, these
findings suggest that vasoconstriction is not the major
mechanism by which ergots block neurogenic plasma
extravasation. Indeed, there is little evidence to support a role for vasodilation as the pain-generating
mechanism in vascular tissues during migraine headaches. The data reported here raise the possibility that
ergot alkaloids alter the ability of the sensory nerves to
promote inflammation, perhaps by interfering with the
release of mediators in much the same way as has been
suggested in the case of opiates 126, 32). Indeed,
pretreatment with lofentanil blocked the capsaicininduced albumin leakage by a naloxone-sensitive
mechanism (see Fig 2). Lofentanil and other opiates
inhibit the presynaptic release of neuropeptide mediators and inhibit neurogenic inflammation 126, 32).
Neurogenic inflammation is increasingly being implicated in the pathogenesis of a variety of diseases
133-3 51, and a relationship between neurogenic inflammation and vascular headaches has been postulated 19, 36-39). Perivascular inflammation may play
an important role in the pathogenesis of headache. Indeed, neurogenic inflammation can be induced in a
cephalic distribution in humans and animals 128, 40,
41). In this regard, the dura offers a most attractive
locus. The dural vessels have been proposed to play a
central role in headache pathogenesis 171; they are
among the few pain-sensitive intracranial tissues and
contain the structures important to the development
of neurogenic inflammation, namely fenestrated postcapillary venules surrounded by a network of unmyelinated C-fibers 142-44).
Although this is an attractive hypothesis, the mechanisms by which neurogenic inflammation may be
implicated in headache pathogenesis remain to be
elucidated. The recent demonstration that the rat dura
contains Ruffini-like stretch receptors and unmyelinated C-fibers 1441 provides the morphological basis for
pain transduction from this tissue. It is possible that
consequences of neurogenic inflammation such as local
fluid accumulation and sensitization of polymodal
nociceptors 145) underlie the painful sensation of
headache. The ability of ergot derivatives, which lack
Saito et al: Ergot and Neurogenic Inflammation 735
inherent analgesic properties, to prevent the development of neurogenic plasma extravasation in the dura
mater not only suggests an action directly on the primary afferent fibers but in itself adds further weight to
the notion that d u a l inflammation may be important
in headache pathogenesis. Indeed, recent unpublished
data from our laboratory indicate that indomethacin
and aspirin inhibit plasma extravasation in the dura
mater induced by electrical stimulation of the rrigeminal nerve. The molecular mechanisms responsible for
ergot action now need to be elucidated based on structure-activity relationships to open the way for the
emergence of a more specific headache pharmacology.
This work was supported by grants from the National Institute of
Neurological and Communicative Disorders and Stroke (NS 21558,
NS 10828).
We wish to acknowledge the helpful advice of Frank W. Marcow,
PhD, Ann Arbor, MI.
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Saito e t al: Ergot and Neurogenic Inflammation 737
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