Research Papers:

17-β-Estradiol induces spreading depression and pain behavior in alert female rats

Alexander J. Sandweiss, Karissa E. Cottier, Mary I. McIntosh, Gregory Dussor, Thomas P. Davis, Todd W. Vanderah and Tally M. Largent-Milnes _

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Oncotarget. 2017; 8:114109-114122. https://doi.org/10.18632/oncotarget.23141

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Alexander J. Sandweiss1, Karissa E. Cottier1, Mary I. McIntosh1, Gregory Dussor2, Thomas P. Davis1, Todd W. Vanderah1 and Tally M. Largent-Milnes1

1Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA

2School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, USA

Correspondence to:

Tally M. Largent-Milnes, email: [email protected]

Keywords: migraine; trigeminal; headache; neuroendocrine; aura

Received: June 15, 2017     Accepted: November 26, 2017     Published: December 09, 2017


Aims: Test the putative contribution of 17-β-estradiol in the development of spreading depression (SD) events and head pain in awake, non-restrained rats.

Main Methods: Female, Sprague-Dawley rats were intact or underwent ovariectomy followed one week later by surgery to place electrodes onto the dura to detect epidural electroencephalographic activity (dEEG). dEEG activity was recorded two days later for 12 hours after systemic administration of 17-β-estradiol (180 μg/kg, i.p.). A separate set of rats were observed for changes in exploratory, ambulatory, fine, and rearing behaviors; periorbital allodynia was also assessed.

Key Findings: A bolus of 17-β-estradiol significantly elevated serum estrogen levels, increased SD episodes over a 12-hour recording period and decreased rearing behaviors in ovariectomized rats. Pre-administration of ICI 182,780, an estrogen receptor antagonist, blocked 17-β-estradiol-evoked SD events and pain behaviors; similar results were observed when the antimigraine therapeutic sumatriptan was used.

Significance: These data indicate that an estrogen receptor-mediated mechanism contributes to SD events in ovariectomized rats and pain behaviors in both ovariectomized -and intact- rats. This suggests that estrogen plays a different role in each phenomenon of migraine where intense fluctuations in concentration may influence SD susceptibility. This is the first study to relate estrogen peaks to SD development and pain behaviors in awake, freely moving female rats, establishing a framework for future preclinical migraine studies.

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