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The Journal of Neuroscience, July 8, 2009, 29(27):8798-8804; doi:10.1523/JNEUROSCI.1727-09.2009

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Neurobiology of Disease
Role of Calcitonin Gene-Related Peptide in Light-Aversive Behavior: Implications for Migraine

Ana Recober,1 Adisa Kuburas,2 Zhongming Zhang,2 John A. Wemmie,3,5 Michael G. Anderson,2,4 and Andrew F. Russo2

Departments of 1Neurology, 2Molecular Physiology and Biophysics, 3Psychiatry, and 4Ophthalmology and Visual Sciences, University of Iowa, and 5Department of Veteran's Affairs Medical Center, Iowa City, Iowa 52242

Correspondence should be addressed to Dr. Andrew F. Russo, Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, 5-432 BSB, 51 Newton Road, Iowa City, IA 52242. Email: andrew-russo{at}uiowa.edu

Migraine is a chronic neurological disorder characterized by recurrent episodes of severe unilateral throbbing head pain and associated symptoms, such as photophobia. Our current understanding of the mechanisms underlying migraine has been hampered by limitations in ascertaining migraine symptoms in animal models. Clinical studies have established the neuropeptide calcitonin gene-related peptide (CGRP) as a key player in migraine. Here, we establish a genetic model of photophobia by engineering increased sensitivity to CGRP in mice. These transgenic mice (nestin/hRAMP1) display light-aversive behavior that is greatly enhanced by intracerebroventricular injection of CGRP and blocked by coadministration of the CGRP receptor antagonist olcegepant. This behavior appears to be an indicator of photophobia and cannot be fully explained by gross abnormality of ocular anatomy or differences in general anxiety or motor activity. Our findings demonstrate that a single gene, receptor activity-modifying protein 1 (RAMP1), can be a modifier of photophobia and, by extension, suggest that genetic or epigenetic modulation of RAMP1 levels may contribute to migraine susceptibility. Moreover, they validate CGRP hypersensitive mice as a tool for exploring the neurobiology and novel therapies for migraine and other disorders involving photophobia.

Received April 9, 2009; revised May 14, 2009; accepted June 1, 2009.

Correspondence should be addressed to Dr. Andrew F. Russo, Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, 5-432 BSB, 51 Newton Road, Iowa City, IA 52242. Email: andrew-russo{at}uiowa.edu






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