5. Aura Phase
Spasm of Cerebral Arteries
Headache Phase
Vasodilation of Cerebral Arteries
Wolf HG. Headache and Other Head Pain. 1963.
Pathophysiology of Migraine
Classic Vascular Theory of Migraine
9. Pathophysiology of migraine
Vascular theory-attributes the phenomenon of
vasodilatation.
Neurogenic theory- neuronal events, cortical spreading
depression.
Third theory - accommodate vascular modifications with
neuronal dysfunction.
10. Vascular theory
Harold G Wolff first one to explain
Vasoconstriction and ischemia accounts for symptoms of
migraine aura,
Reactive vasodilatation activate primary sensory
neurons.
Therapies provides evidence for this theory.
11. Cortical spreading depression
NMDA receptors involved in the genesis and propagation
of CSD. CSD was blocked by NMDA receptors
antagonists in various experimental models
Long lasting depression of
neuronal activity.
12. Wave of oligemia begins in
occipital cortex and spreads
forward at rate of 2-3 mm/min
– Begins with aura and persists
for hours after headache
– CBF changes not in distribution
of any cerebral artery
– Consistent with primary
neuronal event producing
secondary vascular changes
James MF et al. J Physiol. 1999;519:415-425.
Pathophysiology of Migraine
Cortical Spreading Depression
13. Hadjikhani N et al. Proc Natl Acad Sci USA. 2001;98:4687-4692.
Pathophysiology of Migraine
Imaging of Cortical Spreading Depression (CSD)
14. The key pathway for pain in migraine is the
trigeminovascular input from the meningeal
vessels, which passes through the
trigeminal ganglion and synapses on
second-order neurons in the
trigeminocervical complex (TCC).
These neurons in turn project in the
quintothalamic tract and, after decussating
in the brainstem, synapse on neurons in
the thalamus.
Important modulation of the
trigeminovascular nociceptive input comes
from the dorsal raphe nucleus, locus
coeruleus, and nucleus raphe magnus
15. Cortical spreading
depression
perivascular trigeminal and
parasympathetic nerve activation,
release of vasodilator mediators,
CGRP, neurokinen A, substance P
(pain signal)trigeminal
ganglion trigeminal
nucleus caudalis
trigeminocervical complex
16. Brain stem aminergic nuclei can modify trigeminal pain
processing
PET demonstrates brain stem activation in spontaneous
migraine attacks
Brain stem activation persists
after successful headache
treatment
Brain stem: generator or
modulator?
PET=positron emission tomography.
Weiller C et al. Nat Med. 1995;1:658-660.
Pathophysiology of Migraine
Brain Stem Involvement in Migraine
17. Pharmacological treatment of migraine includes
Acute (abortive) treatment
Preventive (prophylaxis) treatment
24. Recent findings
CGRP is widely distributed in the nervous system,
particularly at anatomical areas thought to be
involvedwith migraine, including the trigeminovascular
nociceptive system.
In studies, CGRP has been shown to be released during
severe migraine attacks, and effective triptan treatment
of an attack normalizes these levels.
CGRP administration triggers migraine in patients and
CGRP receptor antagonists can abort migraine.
Moreover, recent data demonstrate that CGRP
mechanism blockade either by small molecule receptor
antagonists or by monoclonal antibodies can have a
preventive effect in migraine.
25. Immunocytochemistry studies have shown
that up to half of the trigeminal neurons
produce CGRP within the trigeminal
system, at various sites including the
trigeminal ganglion, nerve endings and in
higher order neurons and glia
. Centrally, CGRP is therefore involved in
nociceptive transmission through second
and third order neurons, and pain
modulation in the brainstem, whereas
peripherally it mediates vasodilatation
through smooth muscle receptors
26. Although animal studies have shown the role of several
neuropeptides during trigeminovascular system
activation, including substance P, vasoactive intestinal
peptide (VIP) and pituitary adenylate cyclase activating
peptide (PACAP)
only CGRP and PACAP seem to be released when
durovascular structures are stimulated in the cat and in
humans. CGRP and PACAP, but not substance P, are
elevated in the cranial circulation during acute migraine
attacks
These elevated levels normalize after effective triptan
treatment of the migraine attack
27. CALCITONIN GENE-RELATED PEPTIDE AS
A TREATMENT TARGET IN MIGRAINE
CGRP may have a role in mediating some of the varied
painful and non-painful symptomatology of migraine
attacks. Additionally, CGRP-targeted therapies do not
seem to have the coronary vasoconstricting side-effects
that triptans doSix small molecule CGRP receptor
antagonists have been developed and five of them have
demonstrated clinical efficacy in acute migraine. This
class of drugs has acquired the stem name the gepants.
28. CGRP antagonist-BIBN4096BS(olcegapant)
CGRP mediates dilation of cerebral
vasculature and increases in cerebral
blood flow.
CGRP-induced vasodilation can activate
nociceptors on cerebral vessels.
In humans, intravenous human CGRP
administration induces migraine-like
headache in susceptible migraineurs
29. The gepants
A summary of these agents is detailed in Table for clarity.
Two compounds, telcagepant and MK-3207 have been
discontinued due to hepatotoxic side-effects,
olcegepant has been discontinuedasanoral formulation
was too difficult to develop
whereas two compounds B144370A and BMS- 927711
showed clinical efficacy in phase II studies MK-1602 has
no reported data as yet
33. Newer targets and drugs
Non-triptan 5-HT1 agonist,
5-HT1D agonists (PNU-109291 and
PNU- 142633) are potent inhibitors of
dural plasma protein extravasation
(PPE)
LY334370, which is a selective 5-HT1F
agonist, inhibits single cell firing in the
trigeminal nucleus caudalis (TNC)
34. Nitric oxide synthase inhibitor
An intravenous infusion of nitroglycerin
(NTG) releases NO, causes migraine in
more than 60% of migraineurs , and
activates trigeminal neurons in
experimental animals.
In a small RCT, 546C88, a non-selective
NOS inhibitor, was administered
intravenoulsy to migraineurs during an
acute attack (Lassen et al., 1998). The 2-hr
headache response rate was 67% (10/15)
on 546C88 versus 14% (2/14) on placebo
