Benchmark I kjk103

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Author: Kayla Kindig


Layout of Introduction:

1. What is a migraine, how widespread are they are.

2. Trigeminal nerve, proposed theories.

3. Problems with current treatments of migraine.

4. What is CGRP?

5. Hypothesis, potential roles of CGRP.


Introduction

Migraine is a type of headache that affects nearly ten percent of the population worldwide [1]. Migraine is described as an intense, throbbing pain in the head that is often unilateral, with associated symptoms such as nausea, sensitivity to light (photophobia), and sensitivity to sound (phonophobia)[2]. About 1/3 of migraine patients experience a form of visual disturbance just before the headache, called an aura, in which a blind spot migrates across the patient’s field of vision[3]. Known triggers of migraines include stress, lack of sleep, exercise, caffeine, and certain foods, though triggers vary between individuals [3]. Migraines can be chronic or episodic, in which migraines occur >15 days per month or <14 days per month, respectively[4]. Although there is some evidence to suggest that chronic and episodic migraines are distinct[5], it is common for patients who initially suffer episodic migraine to begin to experience chronic migraines over time[4]. A migraine headache can last for several hours or even days, with a fluctuating level of pain and associated symptoms[2].


Although the exact mechanism involved in migraine headache is largely unknown, there are key players and steps in the process that have been well-established. The trigeminal nerve is the fifth cranial nerve that relays sensory and motor information in the face and jaw, and also innervates blood vessels in the meninges[6]. Most structures of the brain are not pain sensitive, but the meninges are an exception[7]. The trigeminal nerve is thought to be capable of receiving or transmitting nociceptive information from the meninges[6]. Perhaps the most prevalent and long-held theory as to the cause of migraine headaches is the vascular theory. Due to the throbbing nature of the pain and early observations of vasoconstriction in response to alleviation of headache, it was proposed that headache pain was due to vasodilation of meningeal blood vessels[8]. It was thought that the stretching of the blood vessels was what caused the pain[8]. Migraine can be invoked experimentally by the injection of a vasodilator, such as nitroglycerin[9]. Another theory as to the cause of migraine headaches is more recent, and has been proposed as an explanation for the aura phase of headache in some individuals[10]. Cortical spreading depression (CSD) is a phenomena in which a wave of depolarization spreads across the brain from anterior to posterior and causes a cascade of other effects[11]. The speed of CSD propagation coincides approximately with the speed of aura progression across the visual field, and the ionic changes are thought to possibly explain the visual blind spot[10]. More recent evidence suggests CSD might be linked to trigeminal activation and therefore directly causes the headache pain[7], though this is contested[12]. It should also be noted that vascular changes have been demonstrated to occur concomitantly with CSD[13][14], suggesting a possible overlap in the theories. Regardless of the theory, the trigeminal nerve is considered to be involved in migraine, and presumably some kind of sensitization occurs to cause nociception in response to something as innocuous as blood vessel dilation or ionic changes.


Many treatments for migraine were discovered to work retroactively, or developed under the assumptions of vascular theory. For example, ergotamine is a vasoconstrictor developed from the ergot fungus of the genus Claviceps[15]. Derivatives of ergot were once used to assist with childbirth, but eventually became used to treat migraine headaches due to their vasoconstricting properties[15]. Later, a class of medications called triptans were developed to treat migraines. Triptans are serotonin agonists that target \text{5-HT}_\text{1B} and \text{5-HT}_\text{1D} receptors on cranial blood vessels and nerve endings to cause vasoconstriction[16]. While triptans are effective at reducing migraine symptoms [17], there are unpleasant side effects with prolonged use, such as “rebound headaches” that occur when the medication wears off [2][18]. Other side effects include feeling dizzy or lightheaded, nausea, and chest pain[18]. Additionally, triptans do not work satisfactorily for all migraine patients, and they become less effective over time[19]. Therefore, it is important to develop a migraine treatment that works well for most patients, retains its effectiveness over time, and has minimal side effects. Perhaps more importantly, there is a need to develop a preventative treatment for migraine; ergotamine and triptans are abortative treatments, and current preventative treatments are not migraine-specific[20]. Creating the best possible treatment relies on understanding the mechanism responsible for generating migraine pain.


Calcitonin gene-related peptide (CGRP) is a neuropeptide created by alternative processing of the calcitonin gene[21]. In neural tissue, it is found in highest concentration in the trigeminal nerve[21]. The distribution led its initial discoverer to propose it was involved in nociception[21]. CGRP was eventually observed to be a potent vasodilator, which potentially implicated it in vascular theory[22]. It is also shown to be released in the brain prior to CSD[13]. CGRP antagonists are capable of reducing allodynia in mice after hemisection of the spinal cord[23]. CGRP activates a receptor complex that consists of a G-protein coupled receptor called calcitonin receptor-like receptor (CRLR or CLR), a receptor activity modifying protein (RAMP1), and a receptor component protein (RCP)[24]. Expression of mRNA of the receptor complex for CGRP has been observed in the brainstem of monkeys[25], which has been shown to activate during migraine headache[26].


The distribution and potential function of CGRP suggests it may play a causative role in the pain of migraine headache. Its action could be primarily vascular, or it could be involved directly with relaying nociceptive information, or it could act to sensitize the trigeminal nerve to innocuous stimuli. If CGRP plays a role in generating migraine pain, this could allow for a greater understanding into the cause of migraine headache, and give researchers a new target for migraine medications that may have greater specificity and effectiveness than current medications.


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. ↑ 2.0 2.1 2.2 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 "NINDS Migraine Information Page". National Institute of Neurological Disorders and Stroke. National Institutes of Health. Retrieved 20 October 2016. 
  4. ↑ 4.0 4.1 Burshtein, R.; Burshtein, A.; Burshtein, J.; Rosen, N. (2015). "Are episodic and chronic migraine one disease or two?". Current Pain and Headache Reports. 19 (12): 53. 
  5. ↑ Schewdt, T.; Chong, C.; Wu, T.; Gaw, N.; Fu, Y.; Li, J. (2015). "Accurate classification of chronic migraine via brain magnetic resonance imaging.". Headache. 55: 762–777. 
  6. ↑ 6.0 6.1 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. 
  7. ↑ 7.0 7.1 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. 
  8. ↑ 8.0 8.1 Graham, J.; Wolff, H. (1938). "Mechanism of migraine headache and action of ergotamine tartrate.". Archives of Neurology and Psychiatry. 39: 737–763. 
  9. ↑ 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. 
  10. ↑ 10.0 10.1 Lauritzen, M. (1994). "Pathophysiology of the migraine aura. The spreading depression theory.". Brain. 117: 199–210. 
  11. ↑ Leão, A. (1944). "Spreading depression of activity in cerebral cortex.". Journal of Neurophysiology. 7: 159–390. 
  12. ↑ Ebersberger, A.; Schaible, H.; Averbeck, B.; Richter, F. (2001). "Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache?". Annals of Neurology. 49 (1): 7–13. 
  13. ↑ 13.0 13.1 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. 
  14. ↑ 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. 
  15. ↑ 15.0 15.1 Schumann, Gail. "Ergot of rye". apsnet.org. The American Phytopathological Society. Retrieved 25 October 2016. 
  16. ↑ Feniuk, W.; Humphrey, P. (1992). "The development of a highly selective 5-HT, receptor agonist, sumatriptan, for the treatment of migraine". Drug Development Research. 26: 235–240. 
  17. ↑ Tfelt-Hansen, P. (1998). "Efficacy and adverse events of subcutaneous, oral, and intranasal sumatriptan used for migraine treatment: a systematic review based on number needed to treat". Cephalalgia. 18: 532–538. 
  18. ↑ 18.0 18.1 "Triptans". NPS Medicinewise. National Prescribing Service Limited. Retrieved 26 October 2016. 
  19. ↑ Ferarri, M.; Roon, K.; Lipton, R.; Goadsby, P.J. (2001). "Oral triptans (serotonin 5-HT1B/1D) agonists) in acute migraine:A meta-analysis of 53 trials". Lancet. 358: 1668–1675. 
  20. ↑ Martin, Laura. "Which Drugs Can Keep My Migraines Away?". Migraines & Headaches Health Center. WebMD. Retrieved 26 October 2016. 
  21. ↑ 21.0 21.1 21.2 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. 
  22. ↑ 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. 
  23. ↑ Bennett, A.; Chastain, K.; Hulsebosch, C. (2000). "Alleviation of mechanical and thermal allodynia by CGRP8-37 in a rodent model of chronic central pain". Pain. 86 (1-2): 163–175. 
  24. ↑ Poyner, D.; Sexton, P.; Marshall, I.; Smith, D.; Quirion, R.; Born, W.; Fischer, J.; Muff, R.; Foord, S. (2002). "International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors". Pharmacology Review. 54 (2): 233–246. 
  25. ↑ 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. 
  26. ↑ 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. 
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