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Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms
Journal article   Open access   Peer reviewed

Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms

Bianca N Mason, Eric A Kaiser, Adisa Kuburas, Maria-Cristina M Loomis, John A Latham, Leon F Garcia-Martinez and Andrew F Russo
The Journal of neuroscience, Vol.37(1), pp.204-216
01/04/2017
DOI: 10.1523/JNEUROSCI.2967-16.2016
PMCID: PMC5214631
PMID: 28053042
url
https://doi.org/10.1523/JNEUROSCI.2967-16.2016View
Published (Version of record) Open Access

Abstract

The neuropeptide calcitonin gene-related peptide (CGRP) is a key player in migraine. Although migraine can be treated using CGRP antagonists that act peripherally, the relevant sites of CGRP action remain unknown. To address the role of CGRP both within and outside the CNS, we used CGRP-induced light-aversive behavior in mice as a measure of migraine-associated photophobia. Peripheral (intraperitoneal) injection of CGRP resulted in light-aversive behavior in wild-type CD1 mice similar to aversion seen previously after central (intracerebroventricular) injection. The phenotype was also observed in C57BL/6J mice, although to a lesser degree and with more variability. After intraperitoneal CGRP, motility was decreased in the dark only, similar to motility changes after intracerebroventricular CGRP. In addition, as with intracerebroventricular CGRP, there was no general increase in anxiety as measured in an open-field assay after intraperitoneal CGRP. Importantly, two clinically effective migraine drugs, the 5-HT agonist sumatriptan and a CGRP-blocking monoclonal antibody, attenuated the peripheral CGRP-induced light aversion and motility behaviors. To begin to address the mechanism of peripheral CGRP action, we used transgenic CGRP-sensitized mice that have elevated levels of the CGRP receptor hRAMP1 subunit in nervous tissue (nestin/hRAMP1). Surprisingly, sensitivity to low light was not seen after intraperitoneal CGRP injection, but was seen after intracerebroventricular CGRP injection. These results suggest that CGRP can act in both the periphery and the brain by distinct mechanisms and that CGRP actions may be transmitted to the CNS via indirect sensitization of peripheral nerves. The neuropeptide calcitonin gene-related peptide (CGRP) is a central player in migraine pathogenesis, yet its site(s) of action remains unknown. Some preclinical studies have pointed to central sites in the brain and brainstem. However, a peripheral site of action is indicated by the ability of intravenous CGRP to trigger migraine in humans and the efficacy of CGRP receptor antagonists that evidently do no penetrate the CNS in effective amounts. Resolving this issue is particularly important given recent clinical trials showing that anti-CGRP monoclonal antibodies can reduce and even prevent migraine attacks. In this study, we report that CGRP can act in both the brain and the periphery of the mouse to cause migraine-like photophobia by apparently distinct mechanisms.
 Darkness Calcitonin Gene-Related Peptide - pharmacology Mice, Inbred C57BL Anxiety - psychology Injections, Intraperitoneal Male Calcitonin Gene-Related Peptide - administration & dosage Receptor Activity-Modifying Protein 1 - genetics Motor Activity Serotonin Receptor Agonists - pharmacology Animals Sumatriptan - pharmacology Migraine Disorders - psychology Light Calcitonin Gene-Related Peptide - antagonists & inhibitors Nestin - genetics Female Mice Photophobia - psychology

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