hows are orexin neurons involved in the pathophysiology of migraine?
Orexin
Orexin can also be seen to play a role in the painful firing associated with trigemino vascular nocicpetion
-stimualtion of the dura and thus its trigeminal neurons is associated with the induction of pain in migraines.
- injecting orexin A is able to reduce the activtiy of both a-fibre and c-firbre nociceptive neurons here, but B will pottentiate firing.
- It is possible changes in orexin tone following hypothalmic activity in the prodromal phase cause these changes in the nociceptive circuits throughout the brain.
- Thus linking a hypersentivity that could explain photo/phonophobia. in migrainas they are mistook for nocicepetive stimuli.
Briefly discuss the role of 5HT in migraine pathogenesis
5HT
- role was known early on through studies reporting reduced platelet 5HT during attacks
- studies showing that 5ht inufsion could abort headaches from reserpine prevents packaging of 5HT into vessels could inudce attack.
- Was believed for a long term its benefits stemmed from action as a central vasoconstirctor. In particular with the taregtting of 5HT1B which prefetrentially express on central vasulature. But as the theory behind migraines has switched fro one of trigeminalvascular system to one of neurovascualr condition the knowledge of 5HT has supported this.
- Goadsby eta al 1998 showed stimulating the sinus electrical an trigeminal nerves to induce migraine. They found the infusion of 5HT after taking baseline recordings, was suffeicient to inhibit induced pottentials. This has a very samll effect on vasculature. This also could be prevented by the inhibition of 5HT1B anatagonists.
- This suggests that this migraine stems more from the nocicpetive outputs of the trigeminal nerves then vascular dilation.
- This brings gravity to the queerys that where held over why CGRP was the only vasoactive dilator increased in migraine attack whilst others like substance P were not.
- This has now led to the informing of the DIANS 5HT1f slective taregts. their receptors hav been reported on TCC and TRigeminal ganglion and in cats and rats they have been shown to have a infleunce on inhibiting Trigeminal firing and not vasculature. This is smething that is maintained even during HT1b/D inhibtion.
- Lasmiditan is the first to have shown to be effective in trial. offers a treatment withought the vascular side effects of triptans
This idea of these drugs having a nerual actionm brings light to the other studies implicating a hypersensitivity of these neruons into action. With reprots linking the loss of regions functional in the inhibtion of nocicpetive firing of trigeminal ganglion being seen between the prodromal and attack phases. and other reporting links to symptoms like Phtophobia.
Outline primary headaches, secondary headache and migraine.
Primary- This is when the headache is a core part of the pathology (migraines are a primary headache)
secondary- This is when the heachache is secondary to a core pathology, like a head injury.
Migraines-
- This biggest neurological cause of dysfunction in the worlds.
- It has varying incidence throughout life, tending to effect early age adults up to the 60s.
- 43% females, 18% chance in men.
- This can be linked to hormone cycling of oetrogen. studies has shown this decreases the 5-HT receptors and 5HT release whilst concomitantl increase CGRP release, hence lowering the migraine threshold. This is why we tend to see no gender difference until the onset of puberty.
- Study by teppert et al 2004- tracked ndividuals comingg in for prolonged heachaches for 3 months and using personal diary diagnosis by professionals. found that 76% had migraines and 18% where migraneurs, so over 90% coming in for heachaches wereatually expereincing migraines, so this is a wide reaching disorder.
Definition MIGRAINES ARE SYNDROMIC AND THUS: - a migraine must last 4-72 hours - must have 2 of the following * unilateral pain *pulsating pain * intermediate or severe pain that is worsened with movement - Must have 1 of th following * photophobia or phonophobia ( studies tracking cerbral blood flow using PET scans where able to observe increase blood flow in the auditory and visual cortical areas with the onset of migaine in individuals with right sided migraines. pottentially explains this link.) *nausea or vomiting
Disorder or 1 attack
In the case of a disroder it is repetitive
- This can e EPISODIC case where it occurs less that 15dya/month
- This can be chronic occuring more than 15day/month
Triggers
The is biological triggers associate with migraines
- Light or smells (Noseda)
- Hormones associated with the eostorus cyclee, also seen then in men you have sex change.
- skipping meals,
-sleep deprivation.
- stress
- chemicals- alcohol or nitroglycerine which is used in studies to induce migraines.
3 phases of migraine Note there tends to be a blurring of the phases with premonitory symtoms occuring sometimes throughout, most common being tirdness and neck stifness. and Photophobia can be seen at the end of the Prodromal phase.
Prodromal/ premonitor- This occurs before migraine attack and in peopl with migraine with auras it ccurs before auras. consists of common systoms:
-Tiredness
-yawning
- Cranial autonomic symptoms like nasal congestion or lacrimating eye.
- food cravings
- neck stiffness
- mood changes
- excessive urination or thirst. (polyuria and polydipsia)
-concentration impairment
Attack phase- This is the migraine phase- this is controlled by trigeminovascular system instigated by DURAL trigeminal afferents.
Postdromal- occuring after attack
- lasts around 2 days,
- Fatigue ( brain imaging shows hypoactivity)
- nech stifness,
- photo/phonophobia
Migraines with aura
This is a rarer from of the conditrion in which prior to migraines AURAs are expereince. 1/3 of patients
- These are neurolgical defects
- Fortification spectra are an example- jagged white lines that appear in vision and grow as migraine gets nearer.
- In recent times this have been associated more with a wave of depolarisaing energy going through the cortex observed in animals as the cortical spreading depression (CSD)
outline the premonitory symptoms of migraine and link these to biological pathophysiology where possible?
Maniyar et al 2004- They used H(15)O2 PET to track cerebral blood flow in the premonitory and migraine phases following the induction of migraine wih nitroglycerine. They observed changes in neural activity between the 2 pases. in particualr the HYPOTHALAMUS, PAG and VTA areas where activated in the premonitory phase but this left in the migraine phase. This suggests the play a role in the premonitory symptoms;
PAG- again this has descending inputs into the spinal crd and is a well estabilished modulator of pain being related to the placebo resposne.
- I also have been shwon to infleunce trigemino nociceptio in particualr those with dural inputs.
- Electrtical stimulation rats reuslts in inhibtion f niceptive firing. This can be stopped by silencing the firing of VPAG rat neurons by intorducing bicuculine a GABA A agonist.
- The activity here seems to be modulated by P/Q types calcium channels and it such currenaat have been associated wit mutant causes of familail migraineurs liek familail hemplegic migrain (Cav2.1)
Tiredness
- Orexins are a pepride produced by the hypothalamus.
- There are 2 froms A and B, A acts on OX1 and 2 but B only activates OX2.
- both receptors have a Gq, so exciatotory path but OX2 also has a Gi/o
- These orexin neruons plug into several areas active in the premonitory pahse. one such is the locus coeurlus and NA neurons. This is a region assoiated with arousal and inhibitory action may expalin tiredness.
Bartsch et al 2005.
- injecting orexin A is ale to reduce the activtiy of both a-fibre and c-firbre nociceptive neurons here, but B will pottentiate firing.
- It is possible changes in orexin tone folloing hypothalmic activity in the pordromal phase cause these changes in the npociceptive circuits throughout the brain.
- Thus linking a hypersentivity that could explain photo/phonophobia in migrainas they are mistook for nocicepetive stimuli.
Yawning- (dopamine)
- We see VTA activation and hyptohalamus that has A11 dopaminergic nucleus in the prodromal phase
- injection drove yawning.
- shows action of symptoms - apomorphine injection increased nausea, vominiting and sweating. always preceeded by yawning.
- The A11 is found at the posterior hypothalamus. And is thought to bethe sole input into the spinal cord.
- USE OF IMMUNOFLUOREscence has alread showed the presence of dopamine receptors at the TCC and the alteration of central noceptive firing=has be shwon.
- Best demonstarted in CHARBIT ET AL 2009. they sowed that the stimulation of the A11 inputs into the TC was able to inhbiti the evoked nocicpetive pottential of the TCC.
- This was attenuated by the addition of a D2 antagonist.
- Lesioning also had the opposite effect of fasciliatting firing.
- The same group showed that the Lesioning of the A11 negative effects on firing could be reversed by the infusion of a D2 AGONIST or a 5HT1B/C. this suggests that these dopamine neurons play an important role in cntrolling the acsneding nocieptiveinouts from the trigeminovascular system.
Food cravings
- Again linked to hypothalamic activity and the release of the eating peptide neuropeitde Y
- Individuals often have a craving of a sweat thing like chocolates.
- This often leads to unhinged diets as they associate foods with cravings.
- NPY is associated with pain. apeptite control and circadian rhythm it has 6 subtypes of recepor in mice and 5 in humans.
This has also been shown to inhibit dural stimualtion induced Trigeminovascualr sytem activity when NPY Y1 agonists where applied to the rats brain. This particualry inhibited to the second order neurons.
- Martin oliviera, 2016 injected NPY and found it inhibited nociceptive trigemino vascular transmission in a dose dependant manner.
Cranial autonomic symptoms
TENTORAIL NERVE branch of the trigeminal nerve afferents.
- These run along the dura and over the tentorium to collect in the tentorial nerve.
- Stimualting this is what causes the cranial autonomicc reflex of lacrimation of the eye, sweatinge,e.t.c
Concentration impairment
polyurea and polydipsia
neck stifiness
mood changes
Describe migraines with and link to CSD.
Migraines with aura
This is a rarer from of the conditrion in which prior to migraines AURAs are expereince. 1/3 of patients
- These are neurolgical defects
- Fortification spectra are an example- jagged white lines that appear in vision and grow as migraine gets nearer.
- In recent times this have been associated more with a wave of depolarisaing energy going through the cortex observed in animals as the cortical spreading depression (CSD)
* This has not yet been shown in humans but the use of a transcranial magentic stimulation device which release a pulse to dsurpts and stop this wave of energy prroves effective in these patients, observing the thalamus shows normalised firing.
Studies have shown.- Using 113 XE to track blood flow thatr aura could be associated with a wave like change in CBF. In addition, neural activity using BOLD Fmri in induced auras or individuals able to get to clinic in early stages. That those with visual auras presnted with similar activiy in the visual cortex to what would be predicited or is seeen in the rabbit cortex. This including a signal spread with a defined temporal characteristic.
CSD has been linked to gentic deficits
- mutation in the casein kinase portein has been associated ith this. (involved in marking per2 for dgredation)
- These are importnat in the reualtion of the biologivcal clock;
- The are seen in migraines with aura comorbid witr famial advanced sleep phase syndrome.
- Moddeling this mutation in mice and stimulating the using FOS immunocytochemistyr to track activity
- observe a higher basal level of Fos and more frewuent occurence of CSDs .
Support form Familail Hemiplegic migraines.
familial condition. mutations are found on Chromosome 19
- These include muations in CACN1a- the PQ TYPE caclium channel.
-Mice KNCK INs for the muation, show: they found this produced a model with reduced threshold for CSDs
unsurprisingly these individuals have increased risk of aura often expereincing weakness down one side.
simillar muations include
- ATP1A2- Na/K pump
- SCN1A- voltage gated sodium channel
Outline the circuits meadiating the pain phase of migraines?
This stems from th action in the trigeminovascular system
- Trigenminal ganglia innervate the dural blood vessels, as weel as the arrachnoid including the suppperior sagtal sinus and the middle menigeal artery.
- Stimualting these regions, in particualr the DURA causes pain, much like migraines.
- These trigeminal ganglion innervates these areas voa unmyelinated c0 brebres and myelinated A-fibres.
- These nociepetive neruons contsaing CGRP a vasoacive peptide whic will cause vasolidalation of these aareas when released with stimualtion.
The TENTORAIL NERVE branch of the trigeminal nerve afferents.
- These run along the dura and over the tentorium to collect in the tentorail nerve.
- Stimualting this is what causes the cranial autonomicc refelex of lacrimation, sweatinge,e.t.c
trigeminal afferents project also to the trigeminocervical complex in C2 and C1
*This has reflex connections with the superior salivatory nucleus in the pons, a glutamatergic synapse that excites projections to the sphenopalatine ganglion in the pterygopalatine fosaa.
- From here they provide the parasy,apthetic innervation to the blood vessels to cause vasodialtion
Second-order neurons from the TCC ascend in the quintothalamic (trigeminothalamic) tract synapsing on third-order thalamocortical neurons. Direct and indirect ascending projections also exist to the locus coeruleus (LC), periaqueductal grey (PAG), and hypothalamus. The third-order thalamocortical neurons in turn synapse on a diffuse network of cortical regions including the primary and secondary motor (M1/M2), somatosensory (S1/S2), and visual (V1/V2) cortices.
- These could be related to the increase cerbral blood flow and incorporation of photphobia e.t.c seen in mgrains.
such connections demostarted in imaging
- PET imaging studies demonstrate evidence of activation of hypothalamic nuclei (209), and activation in the ACC, frontal cortex, visual and auditory cortices, as well as the thalamic nuclei contralateral to the side in which the pain is experienced
Outline the current and upcoming therepautic targets of Migraine? provide evidence where possible
Non-specific
- Clasic NSAIDS like ibuprofen
- apsirn
- Antiemetics like dompeirdone- a dopamine agonist atempting to resotre its inhibition of downstream trigeminovascualr circuits.
5HT agonists - aim is to drive constriction and counter the vsodilation associated with nociception ERGOTAMINE- agonist of 5HT recpetors TRIPTAN= -key examples is sumatriptan - These target receptor 1D and 1B There are now DITANS - these are 1f selective- these do not affect vasculatre and instead inhibit trigeminal neurons going aganst this idea of migraines being a neruinfakamtory issue. - example is Lasmiditan.
Novel targets
GEPANTS- CGRP anatgonists
-interest coming from superior sagital sinus stimulation causing pain and increasing CGRP. these are released by rtrigeminal nerves and are vasodilators.
- anatgonists inhibit action also on nerves, in thalamus, periauedctal grey and trigeminal nerves.
- These anatgonists have been shown to have no effect on cerebral blood flow but have been ,more effective than placebo in treating migraine with Rimegepant and Ubrogepant going forward to clinical trials.
Targetting CGRP has also offered hope for preventaitive treatments
- Likes of b-blockers and anticonvulsants like valproate had reduced number of hedaches but not stopped them.
CGRP Mabs
-Telcagepant a gepant discontinued due to off target issues effecting the liver had proven to have preventaitve effects in parralela studies prompting MABS
- ,MAB code U- human, z- humanised, n- neuronal
*EPTINEZUMAB-
* GALCANEZUMAB
* FREMANEZUAMB (Teva’s)
*erenuzumab (NOVARTIS)
these have now been approved
These all target CGRP and are nmot bothers whether is is the CGRP form of to the caclitonin like recptor bound to bind to a modulator like RAMP1 to make CGRP. ( in the end they are the same) ERENUZUMAB IS THE ONLY ONE SELCTIVE TAREGTTING THE CLC/RAMP1 form
/ ALL have shown a greater efficay then placebo with varied placebo action being related to the method of application, e..g tablet lower than infusion.
- also those you have failed previously and thus may be be negative actually had lower scores than those you had never failed.
- They almost nmp side effects
- No changes in BP
- No formation of anti-drug antibosies
- n injection site reactions.
- only 2-4% drop out rate. much better than topirimate a current tretament.
Outline chemical and hromanal, then vascular contribution to migraine ?
Chemical and hormonal
Maniyar et al 2004- They used H(15)O2 PET to track cerebral blood flow in the premoniroty and migraine phases following the induction of migraine wih nitroglycerine. They observed changes in neural activity between the 2 pases. in particualr the HYPOTHALAMUS, PAG and VTA areas where activated in the premonitory phase but this left in the migraine phase. This suggests the play a role in the premonitory symptoms; is the loss of activity key here.
Orexin
Orexin can also be seen to play a role in the painful firing associated with trigemino vascular nocicpetion
-stimualtion of the dura and thus ists trigeminal neurons is associated with the induction of pain in migraines.
- injecting orexin A is ale to reduce the activtiy of both a-fibre and c-firbre nociceptive neurons here, but B will pottentiate firing.
- It is possible changes in orexin tone folloing hypothalmic activity in the pordromal phase cause these changes in the npociceptive circuits throughout the brain.
- Thus linking a hypersentivity that could explain photo/phonophobia in migrainas they are mistook for nocicepetive stimuli.
Dopamine and the A11 hypothalamic nucleus
- associated with yawning as injection drove this.
- shows action of symptoms - apomorphine injection increased nausea, vominiting and sweating. always preceeded by yawning.
- the A11 hypothalamic nucleus is the primary input of the dopaminergic neurons into the spinal cord and trigeminovascular system .
- lesioning the input to the spinal cord will fascilitate dural noxious input firing.
- alternatively stimulating the A11 has shown attentuationof firing in the trigeminocervocal centre through the action of D2 receptors.
- equally serotnergic migraine treatemnts have been shown to infleunce dopamine intercation and the A11 has dopamine neurons they may be wroking to rest dopamine action
- Those acting on 5HT1B/D and D2 agonists where able to stop this pottention.
This suggests dopamine plays a basal role of a tonic inhibitoion of trigeminal nociceptive traffick and a loss of this in migraine, fasciliatting smotkms like allodynia through the dirtubuted trigeminal system.
NPY and the hypothalamus
- This is linked to the food craving behvaiour of the prmonitory state.
- Martin oliviera, 2016 injected NPY and found it inhibited nociceptive trigemino vascular transmission in a dose dependant manner.
- This has also been shown to inhibit dural stimualtion induced Trigeminovascualr sytem activity when NPY Y1 agonists where applied to the rats brain. This particualry inhibited to the second order neurons.
- Hence, another peptide that palys a role in pain control which could b lossed in nociception.
CGRP
- caclitonin gene rgulated protein is released at the ends of nociceptive trigeminal projections to vsculature and plays a key role in the vasoldialtion of vasculature in pain.
- however action of argetting these in drugs suggests vasculature is not that impornmat and it is dysregualtionation at central neuronal synapses.
GEPANTS- CGRP anatgonists
-interest coming from superior sagital sinus stimulation causing pain and increasing CGRP. these are released by rtrigeminal nerevand are vasodilators.
- anatgonists inhibit action also on nerves, in thalamus, periauedctal grey and trigeminal nerves.
- These anatgonists have been shown to have no effect on cerebral blood flow but have been ,more effective than placebo in treating migraine with Rimegepant and Ubrogepant going forward to clinical trials.
5HT
role was known early on through studies reporting reduced platelet 5HT during attacks and studies shoing that reserpine prvents packaging into vessels could inudce attack.
- role of vasodilation supported by use of 5HT1 receptors the nhibitory and thus vasoconstictor
5HT agonists
- aim is to drive constriction and counter the vsodilation associated with nociception
ERGOTAMINE- agonist of 5HT recpetors
TRIPTAN=
-key examples is sumatriptan
- These target receptor 1D and 1B
There are now DITANS
- these are 1f selective- these do not affect vasculatre and instead inhibit trigeminal neurons going aganst this idea of migraines being a neruinfakamtory issue.
- example is Lasmiditan.
Outline the typical migraine triggers?
The is biological triggers associate with migraines
- Light or smells
- Hormones associated with the eostorus cyclee, also seen then in men you have sex change.
- skipping meals,
- sleep deprivation.
- stress
- chemicals- alcohol or nitroglycerine which is used in studies to induce migraines.
rowing evidence of lights role of controling thalamocortical dysregulation associated with migraines.
- NOSEDAet al 2010- they found that in blind patients that light could still trigger auras.
- testing in mice and using single unit neuron reocrding and tracing of neural cnnections they found thalamic neurons thats activity was both senstive to inputs from the dura (the origin of migraine linked tirgeminal afferents) and sensitive to light modulation.
- These neurons where fed by inputs from Retinal ganglion neuons observed with non- image producing siganlling.
- They believe this may modulate the dural inputs to play a role in light triggering migraine onset.
outline read study on te pottential of acid sensing ion channels as a pottential therpaeutic target in Migraines?
A study by Holland et al 2012
- The were investigating novel therpeutics fro migraines with aura
- They were investiagting the efficacy of Amiloride a sodium channel blocker in inhibiting the CSD.
- The sort out to investigat a novel therapeutic mechanism acting on acid sensing ion channel ( proton gated channels that can flux Na and Ca.)
- They used needle pricks or K+ application in cortices to induce CSD.
- They found that 20mg/kg-1 was sufficient to stop
6/9 CSDs in control mice but on 1/8 in ASIC1a KO mice. suggesting was key to function
To investigate the trigeminovascualr effects they stimulated the dura and gave a amiloride bolus to test the vascualr effects over an hour.
- The foun amiloride attentuated dilation of the middle meningeal artery.
- and reduced nocicpetive firing.
Finally in human trial of 7 pateints who had been rpeviously refractory
- 4/7 showed success.
- be care full as only succesful reported no side effects, and ailiure and success does not correlated with age, gender, or dose. s placebo could have been in play.
But this overall signall that ASICs could be a pottential novel target.
A NOTE FOR MIGRAINe
see paper in notes
