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Professor Anthony DickensonUniversity College London, UK
HQ/FRE/19/0129. Date of preparation: June 2019
Migraine Pathophysiology & New Pathophysiology Based Preventive Treatment Options.
Disclosures
In the past two years:
• Speaker: Teva, Grunenthal, Allergan, Janssen, Novartis
• Advisory boards: Regeneron, Sandoz, Teva
CGRP discovery – heralding a new era of migraine prevention
1. Arkless K, et al. Handbook of Experimental Pharmacology, 2018.2. Humphrey PPA. J Head Face Pain 2008;48:685–7.
CGRP, calcitonin gene-related peptide; CVD, cardiovascular; mAb, monoclonal antibody
• For acute attacks; effective in just ~70%• Associated with side effects• Contraindicated in CVD
Anti-CGRP monoclonal antibodies are the first drugs developed specifically for migraine prevention
Last major advance in migraine: triptans introduced2
1982 1993 2018 Today
CGRP shown to play a key role in
migraine pain1
First anti-CGRP mAb available for migraine prevention
Three anti-CGRP mAbs available; one in development
CGRP discovered1
1990s
Cortex – where and how much pain
Peripheral eventsTissue and nerve damage
Spinal events
Brain stem descending controls
Limbic areas – unpleasantness Central reward and co-morbidities
Peripheral channels and sensorsPeripheral sensitization
Wind-upImpact of the brainCentral sensitization
Key types of pain
Nociceptive painPain caused by
an inflammatory ornon-inflammatory
response to anoxious stimulus
Tissue damage
Chemical activation
Osteoarthritis
Neuropathic painPain initiated or causedby a primary lesion or
disease in theperipheral or central
nervous system
Nerve damage
Ion channel changes
Both types of pain
can co-exist
Post-surgical pains
Low back pain, cancer pain etcNociplastic
All pains are not the same…..
Migraine
Central and peripheral mechanisms
Akerman S, et al. Pharmacol Ther 2017;172:151–70.CSD, cortical spreading depression; LC, locus coeruleus; PAG, periaqueductal gray; RVM, rostral ventromedial medulla;
SPG, sphenopalatine ganglion; TCC, trigeminocervical complex; TG, trigeminal ganglion
CGRP
The Search for the Holy Grail?
NSAIDs
LidoGBP
Nociceptive painChemical activation
Neuropathic painElectrical events
But git actions, low ceiling
Topical, central side effects
CGRP
CortexLocation and
intensity
Limbic brainAffective aspects
of painFear, anxiety,
sleep
Spinal cordIntegrates, amplifies and modifiesincoming messages Output to brain
Incoming peripheral nerves• Convey touch, temperature• Convey painful messages - heat, mechanical, chemical• Are altered by tissue and nerve damage
Descending controlsAllow top-down processesto enhance pain - link mood, sleep and pain
CGRP
ongoing painevoked pains
Allodynia – central sensitisation
Speaker’s own material
A-beta fibres – tactile sensations C and A-delta fibres – nociceptors – heat, mechanical and chemicals
CGRP: A key transmitter at both ends of pain fibres
Usoskin D, et al. Nat Neurosci 2015;18;145–53.Todd AJ. Nat Rev Neurosci 2010;11:823–36.
CGRP found in 46% C – fibres, 33% of A-delta fibres
O'Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH.Pharmacol Rev. 2012 Oct;64(4):939-71
Image adapted from Edvinsson L, et al. Nat Rev Neurol. 2018;14(6):338–350.
Peripheral release of CGRP can be monitored…in migraine and induced by triggersrs
Image adapted from Cady RK, et al. Headache. 2009;49(9):1258–1266. Image adapted from Fanciullacci M, et al. Brain. 1997;120(Pt 2):283–288.
NO and CGRP
Headache 52(9):1411-27 Messlinger K1, Lennerz JK, Eberhardt M, Fischer MJ.
CGRP and NO actions talk to each other
And does vasodilatation activate mechano pain receptors?
Release and /or changes in CGRP
• Whiplash – x 5 elevation of CGRP in plasma• Burn pain – increased CGRP levels in skin• CRPS – role in inflammation but not pain
• Severe Back Pain - + CGRP fibre innervation of disc• Pelvic pain – increased CGRP in neurites • Endometriosis - increased CGRP in neurites
Ebbinghaus, et al. (2015). Interleukin‐6‐dependent influence of nociceptive sensory neurons on antigen‐induced
arthritis. Arthritis Research & Therapy. 17. 10.1186/s13075‐015‐0858‐0.
Expression of calcitonin gene-related peptide in the infrapatellar fat pad in knee osteoarthritis patientsJun Aikawa, et al.Journal of Orthopaedic Surgery and Research. 201712:65
CGRP is likely important in other pain states ‐ central and peripheral actions but accessible?
Role of CGRP in peripheral and central pain mechanisms
Copyright © 2018 International Association for the Study of PainIyengar S, et al. Pain 2017;158:543–59.
AC, adenylyl cyclase; AMPA, amino-3-hydroxyl-5-methylsoxazole-4-propionic acid; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate;
NOS, nitric oxide synthase; pERK, phosphorylated extracellular signal-regulated kinase; PGE2, prostaglandin E2; PK, protein kinase
PERIPHERAL SENSITISATION CENTRAL SENSITISATION
Peripheral sensitisation: contribution to the pathophysiology of chronic migraine
Reduced threshold for stimulation of the peripheral sensory neurons1
1. Dodick D, Silberstein S. Headache 2006;46(Suppl 4):S182–91.2. Strassman AM, et al. Nature 1996;384:560–4.3. Schlereth T, Birklein F. Neuromolecular Med 2008;10:141–7.
The peripheral processes are very differentCentral controls more common
Result: sensitisation of nociceptive neurons3
Release of neurotransmitters such as CGRP within the periphery can amplify and sustain the inflammatory response
May be due to chemical irritation of peripheral trigeminal fibres byinflammatory mediators1,2
CGRPα-GFP+ DRG neurons respond to agonists that evoke pain and itch sensationReleased from C-fibres activate A-delta fibres
McCoy ES, et al. PLOS ONE 2012;7(5): e36355. DRG, dorsal root ganglion; GFP, green fluorescent protein;
PrimaryThermal and mechanical
PeripheralSecondaryMechanicalNot peripheral spreadCENTRAL
Secondary - Mechanical hypersensitivity - increased area of response….
CGRP axons terminate in dorsal spinal / trigeminal cord
McCoy ES, et al. PLOS ONE 2012;7(5): e36355.
J Neurosci. 2017 Nov 1; 37(44): 10587–10596.Fremanezumab—A Humanized Monoclonal Anti-CGRP Antibody—Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal NociceptorsAgustin Melo-Carrillo,1,2 Andrew M. Strassman,1,2 Rony-Reuven Nir,1,2 Aaron J. Schain,1,2 Rodrigo Noseda,1,2Jennifer Stratton,3 and Rami Burstein 1,2
A-delta fibres play a major role inmechanical pain
Wind‐up ‐ temporal summationLong‐term potentiation
Peripheral and descending pathways converge …
Spinal mechanisms -central hypersensitivity
++++++Early A – delta/C‐fibre inputs
Subsequent inputs
Altered pain states
Tactile, cold
Central sensitization
Enhanced responses to low and highthreshold stimuli - increased receptive fieldswithin nerve territory or area of damage
Can be induced in healthy volunteersby acute intense peripheral stimulation
Is seen in patients with peripheralneuropathy and OA
Stimulus no.1 6 12 16
Increased excitability
Iannetti et alPNAS 2006
Spinal mechanisms of central hypersensitivity spread upwards and change the brain
Edvinsson L, et al. Nat Rev Neurol 2018;14:338–50. CALCRL, calcitonin receptor-like receptor; RAMP, receptor activity modifying protein; RCP, receptor component protein
Stopping pain where it starts………
Peripheral release of CGRP
Acts on its receptor on vascular smooth muscle DILATION
Release from C-fibres –receptor on A-delta fibres PAIN
Edvinsson L, et al. Nat Rev Neurol 2018;14:338–50.
CGRP and pain; targets in migraine
Gray A. The Pharmaceutical Journal. 2016. Russell FA, et al. Physiol Rev. 2014;4:1099–142.
Don’t forget the ganglion…
BDNF, brain-derived neurotrophic factor; GABA, gamma-aminobutyric acid; mGluR, metabotropic glutamate receptor; SC, Schwann cellsMesslinger K. J Headache Pain 2018;19:22
Edvinsson L, et al. Nat Rev Neurol 2018;14:338–50
CNS
Spinal trigeminal nucleus
Dorsal horn of spinal cord at
C1 and C2
CNS
Dorsal pons Hypothalamus
Thalamus
Initiation
Headache phaseTrigeminal ganglion acts as
migraine pain amplifier
Trigeminal ganglion
CGRP circuitsActivation of
trigeminal ganglion• Gepants• Anti-CGRP antibodies• Anti-CGRP receptor
antibodies
Activation of trigeminovascularpain pathway
Ascending CNS pain pathways
Headachepain
Blood–brainbarrier
Pain needs a peripheral drive for central processing
• Pain is a sensory and emotional response
• Spinal – thalamic – cortical pathways –sensory
• Spinal – limbic brain projections – affective
• Anxiety and psychosocial issues in chronic pain
• Huge limbic input through LPb
• The brain is driven by the periphery but has a major impact on peripheral inputs
CVLM, caudal ventrolateral medulla; LPb, lateral paracore bundle; NTS, nucleus tractus solitaries; PAG, periaqueductal greyImages adapted from Todd AJ., Nat Rev Neurosci 2010;11:823–836. Text refers to the Speaker’s own opinion.
Baron R. et al, Ann Neurol 2013;74:630–36
Peripheral input drives central sensitisationand changes descending controls
Two main ascending pathwaysSensory and affective
The brain needs to know about peripheral inputs – sensory and affective pathwaysCancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus
Spino-thalamic tract for intensity and location – cortexParabrachial inputs into the limbic brain – fear, aversion etc: Nature Reviews Neuroscience volume14, pages502–511 (2013) J Clin Invest DOI: 10.1172/JCI43498 Nature Neuroscience 20(7) · June
Limbic SystemAmygdala
Hypothalamus
Periaqueductal grey PAG
Rostroventral medial medulla RVM
Mood, fear, anxiety, ragepanic, sleep-wake….
Locus coeruleus
On-CellOff-Cell
Neutral Cell
Inhibitory controls excitatory controls
Noradrenaline 5HT
Noradrenaline and 5-HT AND THE CONTROL OF PAIN
PAIN
Alpha-2 adrenoceptor
Same circuitsimaged in humans
Descending inhibitions Descending excitationsCHANGED IN PERSISTENT PAINS
Protects Promotes
NA
Noradrenaline 5-HT
Alpha2 AR 5HT2/3R
One pain inhibits anotherDiffuse Noxious Inhibitory ControlsConditioned pain modulation
Through descending inhibitions
A marker for intrinsic pain modulation
Strong CPM - less pain after exerciseNormal CPM - 94% of the healthy populationReduced CPM - predicts chronic post-surgical painReduced CPM - patients with migraine, tissue and nerve damage
Anterior cingulate Left CE amygdalakappa opioid
medial prefrontal cortex
dorsal reticular nucleusopioid
Locus coeruleus RVM
Diffuse Noxious Inhibitory ControlsConditioned Pain Modulation
NA 5HT
- +
Parabrachialnucleus
Spinal cordLamina ISpinal cord
Lamina VAlpha-2 R 5HT3R
PAG
Image adapted from Mainero C, et al. Ann Neurol. 2011;70(5):838–45. Image adapted from Benarroch EE. Neurology. 2011;77(3):281–287.
Migraine changes the brain…….
Encoding of danger by parabrachial CGRP neurons
C A Campos et al. Nature 555, 617–622 (2018) doi:10.1038/nature25511
Rapid control of CGRPPBN neurons before and during painful stimuli – and touch and feeding…and are part of recall of a pain memory….
Does the brain talk to the periphery? And how??
Progress in Neurology and PsychiatryAnti-CGRP monoclonal antibodies: breakthrough in migraine therapeuticsRATNA KRISHNASWAMY, BILAL HAIDER MALIK, SAFEERA KHAN, DEEPTI GUPTA, MUHAMMAD ISLAM, SHRAWAN KUMAR MANDAL, IAN H RUTKOFSKY AUGUST 7, 2019 VOLUME 23.03 JULY-SEPTEMBER 2019
Images adapted from Akerman S, et al. Pharmacol Ther. 2017;172:151–170.
Central and peripheral mechanisms
CGRP
Causes dilatation – activation of mechanosensitive pain receptors?Released from C- fibres – activates A- delta fibresPeripheral sensitization – drives danger systemsFavours central sensitization – meets a changed CNS – more pain -facial allodynia
Altered central processingCentral sensitization from withinFailed descending inhibitions
PERIPHERAL AND CENTRAL PROCESSINGIS THERE CROSS-TALK??
• Multiple studies have confirmed that release of calcitonin gene-related peptide (CGRP) is increased during acute migraine attacks.
• In the trigeminal ganglion, CGRP is expressed in C-fibres and its receptor is expressed in Aδ-fibres; these types of fibres are involved in different aspects of pain perception.
• The trigeminal ganglion is central to the trigeminovascular reflex, which is triggered to protect against vasoconstriction; triggering of this system in patients with migraine leads to the perception of pain.
• The trigeminal ganglion and dura are not behind the blood–brain barrier; therefore, they are likely to be the targets of gepants and antibodies in migraine treatment.
• In clinical trials, CGRP receptor antagonists, anti-CGRP antibodies and anti-CGRP receptor antibodies were efficacious in migraine prophylaxis, supporting a role for CGRP in migraine pathophysiology.Edvinsson L, et al. Nat Rev Neurol. 2018;14(6):338–350.