# Perivascular mechanisms of CGRP-induced migraine symptoms

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $534,120

## Abstract

Perivascular mechanisms of CGRP-induced migraine symptoms
Project Summary
Migraine is a debilitating neurological condition involving the neuropeptide calcitonin gene-related peptide
(CGRP). It affects 15% of the population and is the second leading cause of years lived with a disability.
Indeed, over 40% of women will experience migraine during their lifetime. An exciting development is the
recent FDA approval of a new class of CGRP-targeted drugs designed to prevent migraine. However, a critical
need remains because these drugs do not work for all patients. To improve the efficacy of CGRP-based drugs
and pave the way for new drug development, we need to know more about how CGRP works in migraine. The
objective of this project is to identify the mechanisms by which CGRP acts at both peripheral and central sites
to trigger migraine-like symptoms. The scientific premise is that migraine involves increased sensitivity to
CGRP, which is supported by clinical studies that have shown CGRP is both required and sufficient to cause
migraine. During the past funding period, we developed transgenic mice that are sensitized to CGRP actions.
The CGRP-sensitized mice have elevated expression of a subunit of the CGRP receptor called human
receptor activity-modifying protein 1 (hRAMP1). We found that CGRP causes a migraine-like symptom
(photophobia) by distinct, but possibly overlapping actions in the central nervous system (CNS) and periphery.
Here we propose to measure migraine-like symptoms in wildtype and hRAMP1 transgenic mice, using light
aversion as an indicator of photophobia, and touch sensitivity and grimace as indicators of pain. We
hypothesize that CGRP acts at perivascular sites in the dura and thalamus to cause migraine-like symptoms of
photophobia and pain. Specifically, we propose that CGRP-induced vasodilation in the periphery alters the
trigeminovascular microenvironment, and that centrally it facilitates the action of CGRP as a neuromodulator in
the posterior thalamic region. The first aim will test whether peripheral CGRP mechanisms involve actions on
blood and lymphatic vessels and resident mast cells in the dura. The second aim will test whether central
CGRP mechanisms involve perivascular and neuromodulatory actions in the posterior thalamic nuclei.
Complementary genetic and pharmacological strategies will be used in both aims. These studies will provide
insight into the mechanisms that enable CGRP to act both centrally and peripherally, via the vasculature, to
affect sensory functions in a neurological disorder. Despite advances in our understanding of migraine over the
past decade, many questions remain unanswered, in part due to the paucity of appropriate animal models. The
use of our novel CGRP-sensitized hRAMP1 mice represents an innovative approach for challenging the
current dogma regarding the vascular roles of CGRP in the periphery and brain. The outcome of this proposal
will be the uncovering of perivascular CGRP actions in the ...

## Key facts

- **NIH application ID:** 9889178
- **Project number:** 5R01NS075599-07
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Andrew F Russo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $534,120
- **Award type:** 5
- **Project period:** 2011-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889178

## Citation

> US National Institutes of Health, RePORTER application 9889178, Perivascular mechanisms of CGRP-induced migraine symptoms (5R01NS075599-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9889178. Licensed CC0.

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