Benchmark IV kjk103

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Author: Kayla Kindig


Conclusion

The cause of migraine headaches remains to be determined, though important structures and substances have been identified and investigated. One potential mechanism by which migraine headache might be generated is the sensitization of the trigeminal nerve [1], which would lower the threshold of meningeal nociceptors and cause a pain response without the presence of noxious stimuli. CGRP has been found in correlation with migraine[2][3][4][5], and thus has been a subject of extensive testing. The central hypothesis of this review is that CGRP causes migraine headache pain by sensitizing meningeal trigeminal afferents. In favor of this hypothesis is evidence such as the application of CGRP receptor antagonists reducing thermal and chemical allodynia in hemisected rat models of neuropathic pain[6], behavior indicative of pain following injection of CGRP[6], reduced paw withdrawal threshold in CGRP injected rats[7], increased neuronal firing of WDR neurons after application of CGRP[8], and increased withdrawal threshold in arthritic mice upon application of a CGRP receptor antagonist[9]. Thus, there is sufficient evidence to suggest that CGRP is capable of neuron sensitization. Further evidence in support of the hypothesis comes from studies directly analyzing the effect of CCGRP on the trigeminal nerve or the meninges, which include reduced firing of spinal trigeminal nucleus neurons in response to thermal stimulus after application of a CGRP receptor antagonist to the dura mater[10], and increased firing of cat trigeminal neurons after application of CGRP that can be reduced by application of CGRP receptor antagonists[11]. Evidence against the hypothesis includes a study that found no elevation of CGRP levels in EJV blood during migraine headache[12], which negates the correlation of CGRP with migraine. Additional evidence opposing the hypothesis is the finding that CGRP alone was not sufficient to cause facial rubbing behavior that indicates a lowered trigeminal pain threshold[13], and that application of nitroglycerin causes elevated neuronal activity that cannot be reduced if a CGRP antagonist is applied afterwards[14]. These studies call into question the necessity and sufficiency of CGRP in causing neuronal sensitization.


The evidence in favor of the hypothesis is somewhat more compelling than that against it. The original study claiming that CGRP levels were elevated during migraine[2] has been used as a rationale for further investigation of CGRP in migraine parthenogenesis in that it supports correlation of CGRP with migraine. However, the result that CGRP levels were not elevated in the EJV blood during migraine[12], which was obtained using a more suitible control than the previous study, does not allow us to conclude that CGRP does not play a role in migraine, merely that it is not elevated in the blood. The study by Capuano et al. in 2014 used nitroglycerin to evoke trigeminal sensitization, though they used behavioral assessments to determine sensitization and injected compounds into the facial whisker pad, which would contain trigeminal projections but would also contain blood vessels upon which nitric oxide could also act. Ramacharndran et al. (2014) measured trigeminal activation via cfos expression, and determined that nitroglycerin increases neuron activation, which cannot be reduced by application of a CGRP receptor antagonist after nitroglycerin application, but can be reduced if the antagonist is applied before nitroglycerin. This does not negate the sufficiency of CGRP as much as it suggests that nitric oxide also functions in the pathway and that there could be positive feedback in which CGRP increases production or binding of nitric oxide. Studies supporting the hypothesis demonstrate both behavioral evidence of neuron sensitization and direct evidence via electrophysiological recording of neurons, both in spinal cord nociceptors[6][7][8][9] and in parts of the trigeminal nerve[10][11]. These studies have shown that application of CGRP increases neuron sensitization, and that application of a CGRP receptor antagonist decreases sensitization.


Future studies should be done to further support or refute the hypothesis, specifically with regards to the sufficiency of CGRP. Since CGRP, nitric oxide, and substance P have all been suggested to have a role[14], it would be advantageous to test their function in trigeminal sensitization separately to determine if CGRP is sufficient and if the others occur further down the same pathway. For these experiments, it would be necessary to block CGRP with a receptor antagonist such as olcegepant or CGRP8-37 to see if nitric oxide and substance P can elicit the same effects on their own, which is similar to what Ramacharndran et al. did in their 2014 study in which they found that nitroglycerin-induced neuronal activation was blocked with pretreatment of olcegepant. Then nitric oxide synthase should be blocked with L-NAME to see if CGRP is still able to elicit sensitization, and then substance P should be blocked, such as with substance P receptor inhibitor L-733060 to see if CGRP can elicit the same effect. To determine if these substances are in the same pathway, one should be blocked while the remaining two are applied to see if their effects are linearly additive, indicating that they function in separate pathways, or if they saturate at a certain level, indicating that they act in the same pathway. It would be advantageous to perform these experiments on projections of the trigeminal nerve as opposed to other neurons in order to assess their immediate relevance, and direct measures of neuron sensitization should be used, such as electrophysiological measurements or cfos expression. Recording from neurons does have its drawbacks in that animals usually must be anesthetized, which can potentially confound the data, so it may be useful to supplement direct measurements with behavioral evidence in freely moving awake animals. Most importantly, experimenters should use human subjects where possible, since even the best animal model is still just a model, and humans are the subject for which treatments will ultimately be necessary. While it may be impractical or unethical to record directly from neurons in the human brain, perhaps magnetic resonance imaging could be of use to determine activation in particular areas of the brain. Additionally, while it is unlikely to be safe for researchers to block substance P or CGRP in the human brain due to possible side effects, experiments have already been conducted in which CGRP or nitric oxide are injected into awake human patients, so it should be plausible to try administering both at the same time.



References

  1. ↑ Strassman, A.; Raymond, S.; Burstein, R. (1996). "Sensitization of meningeal sensory neurons and the origin of headaches". Nature. 384: 560–564. 
  2. ↑ 2.0 2.1 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. 
  3. ↑ 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. 
  4. ↑ Bigal, M.; Walter, S. (2014). "Monoclonal antibodies for migraine: preventing calcitonin gene-related peptide activity". Central Nervous System Drugs. 28: 389–399. 
  5. ↑ 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. 
  6. ↑ 6.0 6.1 6.2 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. 
  7. ↑ 7.0 7.1 Sun, Q.; Tu, Y.; Lawand, B.; Yan, J.; Lin, Q.; Willis, W. (2004). "Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization". Journal of Neurophysiology. 92: 2859–2866. 
  8. ↑ 8.0 8.1 Gu, X.; Yu, L. (2007). "The colocalization of CGRP receptor and AMPA receptor in the spinal dorsal horn neuron of rat: A morphological and electrophysiological study". Neuroscience Letters. 414: 237–241. 
  9. ↑ 9.0 9.1 Adwanikar, H.; Ji, G.; Li, W.; Doods, H.; Willis, W.; Neugebauer, V. (2007). "Spinal CGRP1 receptors contribute to supraspinally organized pain behavior and pain-related sensitization of amygdala neurons". Pain. 132 (1-2): 53–66. 
  10. ↑ 10.0 10.1 Fischer, M.; Koulchitsky, S; Messlinger, K. (2005). "The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus". The Journal of Neuroscience. 25 (25): 5877–5883. 
  11. ↑ 11.0 11.1 Storer, R.; Akerman, S.; Goadsby, P. (2004). "Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat". 142. 142: 1171–1181. 
  12. ↑ 12.0 12.1 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. 
  13. ↑ Capuano, A.; Greco, M.; Navarra, P.; Tringali, G. (2014). "Correlation between algogenic effects of calcitonin-gene-related peptide (CGRP) and activation of trigeminal vascular system, in an in vivo experimental model of nitroglycerin-induced sensitization". European Journal of Pharmacology. 740: 97–102. 
  14. ↑ 14.0 14.1 Ramachandran, R.; Bhatt, D.; Ploug, K.; Hay-Schmidt, A.; Jansen-Olesen, I.; Gupta, S.; Olesen, J. (2014). "Nitric oxide synthase, calcitonin-gene related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation.". Cephalalgia. 34 (2): 136–147. 
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