Migraine is a debilitating neurological condition involving the neuropeptide calcitonin gene-related peptide (CGRP). The overall objective of this project is to identify mechanisms by which CGRP triggers photophobia, a common symptom of migraine. Photophobia is a painful response to ordinarily non-painful levels of light. A useful tool for these studies is the nestin/hRAMP1 transgenic mouse, which is sensitized to CGRP actions. The mice have elevated nervous system expression of a subunit of the CGRP receptor called human receptor activity-modifying protein 1 (hRAMP1). Nestin/hRAMP1 mice have heightened responses to at least two sensory stimuli: touch and light. The light aversive phenotype is analogous to photophobia and is greatly enhanced by central administration of CGRP. The mice also display enhanced light aversive behavior following chemically induced mast cell degranulation and a mild stress paradigm. Stress is one of the most common triggers of migraine and also induces dural mast cell degranulation. There is evidence that migraine is a neural disorder that can be exacerbated by inflammatory signals: dural mast cells activate trigeminal nociceptive pathways, mast cell degranulation triggers migraine-like headaches, and anti-inflammatory drugs are commonly used for migraine. We hypothesize that CGRP can act in the thalamus to trigger light aversion following stress-induced neurogenic inflammation. This hypothesis is based on a recent finding that posterior thalamic neurons are sensitive to both dural and light stimulation. Furthermore, CGRP can activate dural mast cells, trigeminal neurons, and posterior thalamic neurons. Thus, there is a CGRP-dependent pathway for stress-induced mast cell activation to sensitize thalamic neurons to light, leading to photophobia.
The first aim will establish the contribution of mast cells in light aversive behavior. Light aversion in response to a chemical activator and a mild stress paradigm will be compared between nestin/hRAMP1 and control mice.
The second aim will identify whether the posterior thalamus is a CNS target of CGRP- and mast cell-induced light aversion. Complementary pharmacological and genetic strategies will be used.
These aims will provide insight to the mechanisms by which stress can trigger a migraine-like symptom in an animal model. Clearly, a host of genes will be involved in migraine in addition to CGRP. Hence, the hRAMP1-based strategy provides an innovative approach using the advantages of a defined mouse system for the study of complex diseases. The significance of the proposed studies is their translational potential, which is underscored by the prevalence of migraine, affecting almost 1 in every 5 women. 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. To address these issues, we have assembled an interdisciplinary team with expertise in CGRP, migraine, pain pharmacology, and mouse behavior. The impact of this proposal will be a validated preclinical model for translational studies to develop new therapeutics for migraine.

Public Health Relevance

Migraine represents a significant burden to society. The proposed experiments will provide insights on links between stress and a neuropeptide implicated in migraine. By identifying the relevant biological pathways, these studies could uncover novel therapeutic targets for migraine and other cranial pain states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075599-03
Application #
8476285
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Porter, Linda L
Project Start
2011-06-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$405,757
Indirect Cost
$134,418
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Mason, Bianca N; Kaiser, Eric A; Kuburas, Adisa et al. (2016) Induction of migraine-like photophobic behavior in mice by both peripheral and central CGRP mechanisms. J Neurosci :
Wang, Yan; Tye, Anne E; Zhao, Junli et al. (2016) Induction of calcitonin gene-related peptide expression in rats by cortical spreading depression. Cephalalgia :
Russo, Andrew F (2015) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol 55:533-52
Raddant, Ann C; Russo, Andrew F (2014) Reactive oxygen species induce procalcitonin expression in trigeminal ganglia glia. Headache 54:472-84
White, Stephanie; Marquez de Prado, Blanca; Russo, Andrew F et al. (2014) Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis. PLoS One 9:e106767
Kuburas, Adisa; Thompson, Stewart; Artemyev, Nikolai O et al. (2014) Photophobia and abnormally sustained pupil responses in a mouse model of bradyopsia. Invest Ophthalmol Vis Sci 55:6878-85
Russo, Andrew F (2014) Migraine meets membrane trafficking. Cephalalgia 34:851-2
Kaiser, Eric A; Russo, Andrew F (2013) CGRP and migraine: could PACAP play a role too? Neuropeptides 47:451-61
Russo, Andrew F; Recober, Ana (2013) Unanswered questions in headache: so what is photophobia, anyway? Headache 53:1677-8
Kaiser, Eric A; Kuburas, Adisa; Recober, Ana et al. (2012) Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT(1B/D) agonist. J Neurosci 32:15439-49

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