Post on 29-Aug-2020
OrexinDr. Philip R Holland
Dept of Basic & Clinical Neuroscience
King’s College London
PathophysiologyDunuelle et al. 2007 Afridi et al. 2005
Afridi et al. 2005Holland. Cephalalgia. 2014
Endogenous Pain Modulation
Holland. Cephalalgia. 2014
Attack Phases
Migraine Triggers/Premonitory Symptoms
Kelman. Cephalalgia. 2007; Giffin et al. Neurology, 2003
Reported Migraine Triggers Premonitory Symptoms
Hypothalamic Involvement
Imaging the Premonitory Phase
Maniyar et al., Brain 2014
Hypothalamus Brainstem-PAG
Pathway Integration in Migraine
Noseda et al., PLOS1 2014
The Orexins
Holland & Goadsby. Headache 2007
Orexinergic Projections
The Orexins: Sleep wake
Holland. Cephalalgia. 2014
The Orexins: Appetite
Gonzalez et al., Curr Biol 2016
The Orexins: Nociception
Loss of orexin neurons enhances pain responses
Inutsuka et al., Scientific Rep 2016
Orexins & Cluster Headache
Barloese et al., J Headache & pain 2015
Orexins & MigraineDunuelle et al. 2007
Differential modulation of trigeminal thermal nociceptive responses
Bartsch et al., Pain 2004
Orexins & Migraine
Differential modulation of dural responsive trigeminovascular neurons
Bartsch et al., Pain 2004
Orexins & Migraine (PAG)
Afridi et al. 2005
Holland et al., Unpublished
Orexins & Trigeminovascular Processing
% b
asel
ine
chan
ge
1 2 0
1 4 0
1 6 0
1 8 0
O rex in A 3 0 µ g k g-1
O rex in A 3 0 µ g k g-1
& O X1R A n tago n is t
O rex in A 3 0 µ g k g-1
& C G R P 8 -3 7
O re x in A C G R P d ila tio n
**
tim e (m in )
0 2 0 4 0 6 0
% b
asel
ine
chan
ge
2 0
4 0
6 0
8 0
1 0 0
1 2 0
*
*
*
*
OxA inhibits neurogenic dural vasodilation
Dual Orexin Receptor Antagonists
Hoffmann et al. Neurobiol Dis. 2015.
NDV TCC
Inhibits trigeminovascular activation
Dual Orexin Receptor Antagonists
Inhibits Cortical Spreading Depression
Hoffmann et al. Neurobiol Dis. 2015.
DORA Clinical Trial
Chabi et al. Cephalalgia. 2015.
No significant reduction in migraine days
The Orexins: Sleep wake
Holland. Cephalalgia. 2014
Orexin Interactions
Sakurai. Nat Rev Neurosci, 2007
Pathway Integration in Migraine
Noseda et al., PLOS1 2014
Acknowledgements
King’s College London, UK