title: Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms.
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-HT1B/Dagonist 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.
authors.affiliation: Molecular and Cellular Biology Program.
authors.forename: Bianca N
authors.initials: BN
authors.lastname: Mason
authors.affiliation: Department of Molecular Physiology and Biophysics, and.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Kaiser
authors.affiliation: Department of Molecular Physiology and Biophysics, and.
authors.forename: Adisa
authors.initials: A
authors.lastname: Kuburas
authors.affiliation: Alder Biopharmaceuticals, Bothell, Washington 98011.
authors.forename: Maria-Cristina M
authors.initials: MM
authors.lastname: Loomis
authors.affiliation: Alder Biopharmaceuticals, Bothell, Washington 98011.
authors.forename: John A
authors.initials: JA
authors.lastname: Latham
authors.affiliation: Alder Biopharmaceuticals, Bothell, Washington 98011.
authors.forename: Leon F
authors.initials: LF
authors.lastname: Garcia-Martinez
authors.affiliation: Molecular and Cellular Biology Program, andrew-russo@uiowa.edu.|Department of Molecular Physiology and Biophysics, and.|Department of Neurology, University of Iowa, Iowa City, Iowa 52242.|Veterans Affairs Medical Center, Iowa City, Iowa 52246, and.
authors.forename: Andrew F
authors.identifier: 0000-0002-8156-5649
authors.initials: AF
authors.lastname: Russo
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003624:Darkness; D005260:Female; D007274:Injections, Intraperitoneal; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008881:Migraine Disorders / Q000523:psychology*; D009043:Motor Activity; D064231:Nestin / Q000235:genetics; D020795:Photophobia / Q000523:psychology*; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology
chemical_list: D064231:Nestin; C545505:Ramp1 protein, mouse; D058262:Receptor Activity-Modifying Protein 1; D017366:Serotonin Receptor Agonists; D018170:Sumatriptan; D015740:Calcitonin Gene-Related Peptide
keywords: CGRP; CGRP-blocking antibody; RAMP1; migraine; photophobia; transgenic mouse