Andrew Russo

University of Iowa, USA

Abstract

[O14] A potential preclinical migraine model: cgrp-sensitized mice

Andrew F. Russo*, Adisa Kuburas*, Eric Kaiser*, Ann Raddant*, Ana Recober+
Departments of *Molecular Physiology and Biophysics, +Neurology, University of Iowa, Iowa City, IA, USA

The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine. However, a major challenge for studying CGRP actions is the lack of animal models for migraine. Clinical studies suggested that migraineurs may be more sensitive to CGRP than people who do not suffer from migraine. We therefore generated a double transgenic mouse that is sensitized to CGRP. The mice have elevated expression of a subunit of the CGRP receptor, human receptor activity-modifying protein 1 (hRAMP1). An hRAMP1 expression cassette was selectively activated in the nervous system by cre recombinase expressed from the nestin promoter. RAMP1 is required for receptor trafficking to the cell surface and subsequent binding of CGRP. CGRP mRNA and peptide levels were elevated in nestin/hRAMP1 mice brain tissue and cerebrospinal fluid, respectively, which is consistent with a positive feedback loop observed in primary cultures. The nestin/hRAMP1 mice have increased CGRP-induced neurogenic inflammation and two associated symptoms of migraine: photophobia and mechanical allodynia. The greater light aversive behavior compared to littermate controls is not simply due to increased anxiety. The light aversion was greatly enhanced by intracerebroventricular administration of CGRP. CGRP had little or no effect on motility in the light zone, but, interestingly, once in the dark, the mice moved much less than controls. The CGRP-induced light aversion was attenuated by co-administration of the CGRP receptor antagonist olcegepant or the triptan drugs rizatriptan and sumatriptan. These findings suggest that CGRP acts as a neuromodulator to increase sensory responses and that regulation of a single gene, hRAMP1, could potentially contribute to migraine susceptibility.

Keywords: calcitonin gene-related peptide (CGRP), migraine, photophobia, transgenic mouse, receptor activity-modifying protein 1 (RAMP1)

Biography

Dr. Russo received his Ph.D. in Biochemistry from the University of California, Berkeley with Dr. Daniel E. Koshland, Jr.  He did postdoctoral training in molecular neurobiology at the University of California, San Diego.  Dr. Russo is currently a Professor of Molecular Physiology and Biophysics and Director of the Biosciences Program at the University of Iowa. The primary focus of Dr. Russo’s research is to understand the molecular basis of migraine.