Date of Degree
PhD (Doctor of Philosophy)
Molecular Physiology and Biophysics
Andrew F. Russo
Calcitonin gene-related peptide (CGRP) has been strongly implicated in the pathophysiology of migraine. CGRP levels are elevated during a migraine attack. Injection of CGRP can trigger a delayed migraine-like headache in migraineurs. Finally, CGRP receptor antagonists are effective antimigraine therapeutics. Consequently, a CGRP-sensitized mouse, nestin/hRAMP1 was genetically engineered to conditionally express a subunit of the CGRP receptor, hRAMP1, in neurons and glia. In response to CGRP, nestin/hRAMP1 mice demonstrated a significant decrease in time in the light zone of a dim light-dark box compared to vehicle-treated nestin/hRAMP1 mice and CGRP-treated control mice. This reflects photophobia-like behavior. Photophobia is a common symptom of migraine, where light exacerbates the headache pain. Furthermore, CGRP decreased motility in the dark zone, which may reflect exacerbation of pain by movement that is often experienced during a migraine. Wildtype mice have also demonstrated this CGRP-induced behavior, but required bright light and habituation to the chamber. While there is a difference in sensitivity in this assay between wildtype and nestin/hRAMP1 mice, it demonstrates that endogenous CGRP receptors are sufficient to convey this behavior. A common antimigraine drug, rizatriptan, attenuated the CGRP-induced behaviors in wildtype mice validating the assay as a migraine model. To explore the relative contributions of CGRP receptors on neurons versus glia, synapsin/hRAMP1 transgenic mice were genetically engineered to express hRAMP1 in neurons only. In contrast to the nestin/hRAMP1 mice, the synapsin/hRAMP1 mice did not show CGRP-induced light aversion upon naïve exposure to a dim chamber. This suggests that neuronal overexpression of hRAMP1 is insufficient to convey a heighted sensitivity to CGRP in the light aversion assay. As a first step to understanding the mechanism underlying CGRP-induced light aversion, a non-behavioral assay was developed to measure photic blink reflexes by measuring orbicularis oculi EMG responses in mice. Bright light increased orbicularis oculi activity, and an air puff induced a blink response. Interestingly. CGRP and bright light increased the duration of squinting following the air puff-induced blink. This pilot suggests that the trigeminal system plays a key role in mediating CGRP-induced light sensitivity. Overall, these studies propose a potential model for the mechanisms involved in migraine and photophobia in which CGRP likely acts through endogenous CGRP receptors on neurons and glia in the trigeminal system to trigger light sensitivity.
Behavior, CGRP, Migraine, Mouse model, Photophobia, Trigeminal
xx, 274 pages
Includes bibliographical references (pages 252-274).
Copyright 2014 Eric Alan Kaiser