Vermeer 2014

Comparisons of the effects of estradiol or bisphenol A treatment in a multibehavioral model of migraine in rat

Lydia M.M. Vermeer Ph.D.1, Eugene Gregory M.S. 1, Kenneth E. McCarson, Ph.D.2, Nancy E.J. Berman, Ph.D. 1
1Anatomy and Cell Biology Department, 2Pharmacology, Toxicology & Therapeutics Department, University of Kansas Medical Center, Kansas City, KS 66160

Objectives: To determine how proestrous estradiol treatment altered migraine-like behaviors and establish behavioral and gene differences between BPA and estradiol exposure. Background: Clinical studies have demonstrated that migraine is experienced by women three times more frequently than men, and estrogen has been implicated to play a role. Our lab has demonstrated that bisphenol A (BPA) exposure increases migraine-like behaviors; including, reduced locomotor activity, increased bouts of low mobility, increased light and noise aversion, altered facial grooming indicative of allodynia, and enhanced acoustic startle reflex as compared to vehicle-exposed rats. Dural stimulation in BPA-treated rats increased ERK gene expression and activation in the brainstem trigeminal nucleus and dura. (Vermeer, et al., 2013, Toxicol Sci.).

Methods: The established multibehavioral model of migraine was used to assess migraine-like behaviors following exposure to estradiol. Total locomotor activity, bouts of low mobility, light and noise aversion, evoked facial grooming, and acoustic startle reflex were examined. RT-PCR and western blot analysis of the brainstem trigeminal nucleus and dura was used to measure ERK1/2 and CGRP mRNA levels and ERK activation.

Results: Rats exposed to proestrous levels of estradiol exhibited decreased total locomotor activity and enhanced acoustic startle reflexes similar to BPA-exposed rats. Behavioral data suggest that BPA treatment produced more pronounced noise aversion effects than estradiol treatment. Following BPA exposure, ERK gene expression in the brainstem trigeminal nucleus was increased 14-fold and 10-fold for ERK1 and 2, respectively compared with estradiol treatment. Conversely, estradiol treatment caused these markers to be significantly increased as compared to BPA exposure in dura samples. It is important to note that total pERK levels in both trigeminal nucleus and dura samples were similar following exposure to BPA or estradiol. CGRP mRNA was significantly lower in estradiol treatment as compared to BPA samples in both trigeminal nucleus and dura.

Conclusions: Overall, these results indicate that estradiol treatment has the ability to alter migraine severity and duration, with some significant differences as compared to BPA
treatment. The mechanisms linking estrogen receptor activation to pain are complex due to the number of pathways that estrogen can signal through. These results demonstrate that both estradiol and BPA have the ability to alter nociception which may have implications for migraine pathogenesis.