The document discusses the pathophysiology of migraines. It outlines three main theories: [1] the vascular theory which attributes migraines to vasodilation, [2] the neurogenic theory which points to neuronal events like cortical spreading depression, and [3] a combined neurovascular theory. Newer research highlights the role of CGRP, which is involved in trigeminal pain processing and vasodilation. CGRP antagonists and monoclonal antibodies show promise as preventive migraine treatments.

1. Outline
 Migraine
 Pathophysiology
 Theories
 Vascular theory
 Neurogenic theory
 Neurovascular theory
 Newer targets and drugs

2. Pathophysiology of Migraine

3. TGVS=trigeminal vascular sensitization.
Adapted from Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-398.
Vasodilation
Neurogenic
Inflammation
Headache
Pain
Abnormal cortical
activity
Hyperexcitable brain
(Ca++, Glu, Mg++)
Cortical Spreading Depression
Activation/Sensitization of TGVS
Abnormal brain
stem function
Excitation of brain
stem, PAG, etc.
Central Sensitization
Pathophysiology of Migraine
Proposed Mechanisms of Migraine Headache

4. Pathophysiology of Migraine
Migraine Mechanisms
Iadecola C. Nature Medicine. 2002;8:111-112.

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

6. CBF=cerebral blood flow.
Laurizen M. Brain. 1994;118:199-210.
Pathophysiology of Migraine
Blood Flow During Aura and Headache Phase

8. Neuropeptide
Release
Central
Sensitization
Pain Signal
Transmission
Vasodilatation
Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(suppl 3):S12-S19.
Pathophysiology of Migraine
Trigeminovascular Migraine Pain Pathways
Preventive medication target
Acute medication target

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

19. Preventive medication

20.  NEWER DRUGS

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

32. compound Treatment class Clinical phase
Telcagepant [MK0974)- CGRP receptor antagonist Phase 111
Olcegepant [BIBN4096BS)- CGRP receptor antagonist phase II
B144370- CGRP receptor antagonist phase II
Lasmiditan 5-HT 1F receptor agonist Phase 111
Tezampanel (LY-293558) AMPA and kainate receptor antagonist phase 111

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