Term Paper Proposal kjk103

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Author: Kayla Kindig


Background

Approximately 10% of people worldwide suffer from migraine headaches [1], and yet their exact pathophysiology is unknown. Migraines are characterized by an intense throbbing or pulsing head pain that is often unilateral, accompanied by symptoms such as nausea, photophobia, and phonophobia [2]. Regardless of the specific mechanism, the trigeminal nerve is thought to be involved in migraine headache in some way, because most of the brain is not pain sensitive, but the meninges are, and they are densely innervated by trigeminal axons [3]. The trigeminal nerve is the cranial nerve responsible for motor and sensory function in most of the face and jaw, and also transmits cephalic pain [4][3]. It has been proposed that projections of the trigeminal nerve that innervate blood vessels in the meninges can be stimulated by vasodilation in these blood vessels, somehow leading to nociception [5]. There is evidence, however, that vascular changes during migraine may not be responsible, or at least not solely responsible for the pain. Another prominent theory as to the generation of migraine pain is cortical spreading depression(CSD), a wave of depolarization that spreads across the brain, changing ionic composition of the interstitial space and releasing neurotransmitters that lead to stimulation of pain [6]. Vascular changes have been reported to occur along with cortical CSD [7] [8], which suggests that the two theories are not be mutually exclusive. Neither CSD or vascular changes alone can fully explain headache pain, as there must be a reason as to why these processes occur in the first place, and why they are capable of causing pain at all. A neuropeptide called calcitonin gene related peptide (CGRP) is a potent vasodilator[9], and has been shown to be released just before CSD [7], thus implicating it in two major migraine theories. The central hypothesis of this review is that CGRP plays a role in causing the pain of migraine headache.


Arguments for the Hypothesis

Upon its discovery in neural tissue, CGRP mRNA was found in highest concentration in the trigeminal ganglion, followed by the lateral medulla, midbrain, and hypothalamus [10]. This distribution led researchers to speculate that CGRP was involved in nociception. Release of CGRP and substance P was observed in the external jugular vein (EJV) after stimulation of the trigeminal nerve [11], but only CGRP was found in substantial concentrations in the EJV of humans during migraine attacks [12]. Administration of anti-migraine drugs sumatriptan and dihydroergotamine reduced cerebral blood flow (CBF) and decreased the amount of CGRP in the EJV of cats, and sumatriptan was observed to reduce CGRP in the EJV and relieve headache in humans [13]. Furthermore, CGRP infusion has been demonstrated to induce a delayed migraine attack in migraine patients [14]. More support for the involvement of CGRP in migraine comes from the discovery that components of the CGRP receptor complex CLR and RAMP1 are expressed in the brainstem of the rhesus monkey [15], and the brainstem has been shown to activate during migraine attacks and stay active after headache relief by medication [16]. Additionally, CGRP antagonists (both small molecules and antibodies) have proven successful at reducing the frequency and severity of migraine attacks in clinical trials [17][18][19]. The mechanism of action for CGRP could either be indirect, a result of its vasodilating properties, or CGRP could be directly involved in sensitizing the neurons so that the threshold for pain is lowered, which could cause nociception to be triggered by previously harmless stimuli, such as dilation of blood vessels [20].


Arguments against the Hypothesis

Some studies have found no difference in CGRP levels in the EJV during migraine attacks without aura [21]. Additionally, vasodilators other than CGRP, such as nitroglycerin, are capable of inducing migraines [22], suggesting that vasodilation is sufficient for migraine headache production and the mechanism is not specific to CGRP. It is possible that CGRP may act during migraine, but not during the actual headache pain phase, which could explain its presence in the blood during migraine. For example, CGRP could play a role in generating aura, which is a painless visual disturbance that preceeds a migraine headache in approximately 1/3 of migraine patients [23], though CGRP injection can induce a migraine without aura [14]. It is also possible that CGRP only mediates or causes common symptoms that often occur together with migraine, such as photophobia, phonophobia, and nausea; mice that have one of the CGRP receptor components overexpressed show sensitivity and aversion to light [24]. The injection of CGRP only induces a migraine in people who experience migraine (not healthy volunteers) [14], so it is possible that the effect is due to the stress of injection.


References

  1. ↑ Stovner, L.J.; Hagen, K.; Jensen, R.; Katsarava, Z.; Lipton, R.; Scher, A.I.; Steiner, T.J.; Zwart, J.A. (2007). "The global burden of headache: a documentation of headache prevalence and disability worldwide". Cephalalgia. 27: 193–210. 
  2. ↑ Linde, M.; Mellberg, A.; Dahlof, C. (2006). "The natural course of migraine attacks: A prospective analysis of untreated attacks compared with attacks treated with a triptan.". Cephalalgia. 26: 712–721. 
  3. ↑ 3.0 3.1 Bolay, H.; Reuter, U.; Dunn, A.; Huang, Z.; Boas, D.; Moskowitz, M. (2002). "Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model.". Nature Medicine. 8 (2): 136–142. 
  4. ↑ Bartsch, T.; Goadsby, P.J. (2003). "Increased responses in trigeminocervical nociceptive neurons to cervical input after stimulation of the dura mater.". Brain. 126: 1801–1813. 
  5. ↑ O'Connor, T.; van der Kooy, D. (1986). "Pattern of intracranial and extracranial projections of trigeminal ganglion cells.". The Journal of Neuroscience. 6 (8): 2200–2207. 
  6. ↑ Lafreniere, R.; Cader, Z.; Poulin, J.; Andres-Enguix, I.; Simoneau, M.; Gupta, N.; Boisvert, K.; Lafreniere, F.; McLaughlan, S.; Dube, M.; Marcinkiewicz, M.; Ramagopalan, S.; Ansorge, O.; Brais, B.; Sequieros, J.; Pereira-Monteiro, J.; Griffiths, L.; Tucker, S.; Ebers, G.; Rouleau, G. (2010). "A dominant negative mutation in the TRESK potassium channel is linked to familial migraine with aura.". Nature Medicine. 16 (10): 1157–1161. 
  7. ↑ 7.0 7.1 Wahl, M.; Schilling, L.; Parsons, A.; Kaumann, A. (1994). "Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide in the pial artery dilatation elicited by cortical spreading depression.". Brain Research. 637: 204–210. 
  8. ↑ Teplov, V.; Shatillo, A.; Nippolainen, E.; Grohn, O.; Giniatullin, R.; Kamshilin, A. (2014). "Fast vascular component of cortical spreading depression revealing in rats by blood pulsation imaging.". Journal of Biomedical Optics. 19 (4). doi:10.1117/1.JBO.19.4.046011. 
  9. ↑ McCulloch, J; Uddman, R.; Kingman, T.; Edvinsson, L. (1986). "Calcitonin gene-related peptide: Functional role in cerebrovascular regulation". Proceedings of the National Academy of Sciences USA. 83: 5731–5735. 
  10. ↑ Rosenfeld, M.; Jean-Jaque, M.; Amara, S.; Swanson, L.; Sawchenko, P.; Rivier, J.; Vale, W.; Evans, R. (1983). "Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing.". Nature. 304 (5922): 129–135. 
  11. ↑ Goadsby, P.J.; Edvinsson, L.; Ekman, R. (1988). "Release of vasoactive peptides in the extracerevral circulation of humans and cat during activation of the trigeminovascular system.". Annals of Neurology. 23: 193–196. 
  12. ↑ Goadsby, P.J.; Edvinsson, L.; Ekman, R. (1990). "Vasoactive peptide release in the extracerebral circulation of humans during migraine attacks.". Annals of Neurology. 28: 183–187. 
  13. ↑ Goadsby, E.; Edvinsson, L. (1993). "The trigeminovascular system and migraine:Studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats.". Annals of Neurology. 33: 48–56. 
  14. ↑ 14.0 14.1 14.2 Lassen, L.; Haderslev, P.; Jacobsen, V.; Iversen, H.; Sperling, B.; Olesen, J. (2002). "CGRP may play a causative role in migraine.". Cephalalgia. 22: 54–61. 
  15. ↑ Eftekhari, S.; Gaspar, R.; Roberts, R.; Chen, T.; Zheng, Z.; Villarreal, S.; Edvinsson, L.; Salvatore, C. (2016). "Localization of CGRP receptor components and receptor binding sites in Rhesus monkey brainstem: A detailed study using in situ hybridization, immunoflourescence, and autoradiography". The Journal of Comparative Neurology. 524: 90–118. 
  16. ↑ Weiller, C.; May, A.; Limmroth, V.; Juptner, M.; Kaube, H.; Schayck, R.; Coenen, H.; Diener, H. (1995). "Brain stem activation in spontaneous human migraine attacks.". Nature Medicine. 1 (7): 658–660. 
  17. ↑ Verheggen, R.; Bumann, K.; Kaumann, A. (2002). "BIBN4096BS is a potent competitive antagonist of the relaxant effects of alpha-CGRP on human temporal artery: comparison with CGRP(8-37)". British Journal of Pharmacology. 136: 120–126. 
  18. ↑ Bigal, M.; Walter, S. (2014). "Monoclonal antibodies for migraine: preventing calcitonin gene-related peptide activity". Central Nervous System Drugs. 28: 389–399. 
  19. ↑ Ho, T.; Mannix, L.; Fan, X.; Assaid, C.; Furtek, C.; Jones, J.; Lines., C.; Rapoport, A. (2008). "Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine". Neurology. 70 (16): 1304–1312. 
  20. ↑ Durham, P.; Vause, C. (2010). "Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonists in the Treatment of Migraine". Central Nervous System Drugs. 24 (7): 539–548. 
  21. ↑ Tvedskov, J.; Lipka, K.; Ashina, M.; Iversen, H.; Schifter, S.; Olesen, J. (2005). "No increase of calcitonin gene-related peptide in jugular blood during migraine". Annals of Neurology. 58: 561–568. 
  22. ↑ Schooman, G.; Grond, J.; Kortmann, C.; Keest, J.; Terwindt, G.; Ferrari, M. (2008). "Migraine headache is not associated with cerebral or meningeal vasodilation". Brain. 131: 2192–2200. 
  23. ↑ "NINDS Migraine Information Page". National Institute of Neurological Disorders and Stroke. National Institutes of Health. Retrieved 20 October 2016. 
  24. ↑ Recober, A.; Kaiser, E.; Kuburas, A.; Russo, A. (2010). "Induction of multiple photophobic behhaviors in a transgenic mouse sensitized to CGRP". Neuropharmacology. 58: 156–165. 
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