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by Amynah Pradhan, PhD

This work by Mengya Wang, a trainee in Andrew Russo’s lab at the University of Iowa, investigates the role of CGRP in the cerebellum, and how it relates to migraine-associated symptoms. Human imaging studies reveal alterations in the cerebellum in migraine patients1-3, suggesting a role for this brain region in migraine pathophysiology. There is an abundant expression of both CGRP peptide and its corresponding receptor in the cerebellum4-6. However, it is unclear what role CGRP plays in this brain region. Mengya Wang examined the role of this pro-migraine peptide in the cerebellum using preclinical mouse models. She confirmed that CGRP and its receptor were highly expressed in the mouse cerebellum. Additionally, injection of CGRP into the fastigial nucleus of the cerebellum resulted in light aversion, increased anxiety-like behavior, and allodynia. This group also performed preliminary studies that revealed a projection from the cerebellum to the posterior thalamic area, a region associated with pain processing and light aversion. This study highlights how much there is to still learn about the CGRP system in the brain. The role of CGRP in migraine has primarily focused on peripheral regions and the trigeminocervical complex, yet there is high expression of this peptide in other brain regions, the function of which is not clearly understood. This preclinical study opens the possibility that CGRP in the cerebellum may contribute to migraine pathophysiology.  For example, CGRP in this region may play a role in vestibular symptoms associated with migraine, such as vertigo. In addition, this work contributes to the growing body of evidence indicating that the cerebellum is part of the brain’s pain matrix. The cerebellum is connected to many regions that regulate pain processing, and may play an important role in emotional and motor responses to pain7. Future studies may focus on fully characterizing the CGRP expressing circuits that project from the cerebellum to other brain regions to regulate light aversion, anxiety, and allodynia. It may also be of interest to determine if CGRP or its receptor expression is altered in the cerebellum in models of chronic migraine, post-traumatic headache, or medication overuse headache. This is a preclinical study and so therefore cannot immediately inform patient treatment or prognosis. However, it is important to encourage the fundamental science of migraine, as discoveries in this area can form the building blocks for subsequent translational and clinical insight.

 


References

  1. Bilgiç B, Kocaman G, Arslan AB, et al. Volumetric differences suggest involvement of cerebellum and brainstem in chronic migraine. Cephalalgia. 2016;36:301-308.
  2. Mehnert J, May A. Functional and structural alterations in the migraine cerebellum. J Cereb Blood Flow Metab. 2019;39:730-739.
  3. Qin Z, He XW, Zhang J, et al. Structural changes of cerebellum and brainstem in migraine without aura. J Headache Pain. 2019;20:93.
  4. Eftekhari S, Salvatore CA, Johansson S, Chen TB, Zeng Z, Edvinsson L. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res. 2015;1600:93-109.
  5. Hostetler ED, Joshi AD, Sanabria-Bohórquez S, et al. In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232. J Pharmacol Exp Ther. 2013;347:478-486.
  6. Warfvinge K, Edvinsson L, Pickering DS, Sheykhzade M. The Presence of Calcitonin Gene-Related Peptide and Its Receptors in Rat, Pig and Human Brain: Species Differences in Calcitonin Gene-Related Peptide Pharmacology. Pharmacology. 2019;104:332-341.
  7. Moulton EA, Schmahmann JD, Becerra L, Borsook D. The cerebellum and pain: passive integrator or active participator? Brain Res Rev. 2010;65:14-27




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