Vermeer 2013

The effect of bisphenol A exposure in a multibehavior model of rat migraine

Lydia M.M. Vermeer, Ph.D.1, Eugene Gregory, M.S.1, Kenneth McCarson, Ph.D.2,3, Nancy E.J. Berman, Ph.D.1,3

1Anatomy and Cell Biology, 2Pharmacology, Toxicology, and Therapeutics, 3Institute for Neurological Disorders, The University of Kansas Medical Center, Kansas City, KS 66160

Migraine is a debilitating neurological condition which can be accompanied by nausea, photo- and phonophobia and is aggravated by routine activities. Clinical studies have demonstrated that migraine is experienced by women three times more frequently than men. While the mechanism behind this sex-difference is not well understood, estrogen has been implicated to play a role. Studies have established that estrogen receptors are found in trigeminal pain neurons and that estrogen exposure can lead to increased primary afferent activity, increased response of nociceptors to capsaicin, and lead to increased allodynia (i.e. facial pain). Therefore, these results suggest that estrogen can modulate sensitization to pain. Xenoestrogens are chemicals found in the environment that exhibit estrogen-like activities. Bisphenol A (BPA), a building block in plastics manufacturing, is one of the most ubiquitous and pervasive xenoestrogens. It is estimated that over 90% of Americans have PBA in their bodies and this chemical has been shown to mimic natural estrogen including the ability to bind to and activate estrogen receptors (such as ERα and GPR30, found in trigeminal nociceptors). The full consequences of BPA exposure on migraine pathogenesis have never been previously explored; therefore, it is hypothesized that BPA exposure leads to an increase in migraine intensity and duration through activation of estrogen receptors and downstream nociceptive pathways.

The work presented here utilizes a multibehavior model of migraine in rat. Ovariectomized, female animals are surgically implanted with a cranial cannula used to induce migraine-like symptoms via inflammatory soup application. Following BPA exposure, rats preform a series of behavioral tasks modeled after the International Headache Classification (ICHD-2) used to diagnose migraine in humans.  Behavioral tasks include: total locomotor activity, light and sound aversion, evoked grooming, and startle reflex. Preliminary results indicate that rats exposed to BPA and given a dural application of inflammatory soup demonstrate significantly higher migraine-like symptoms than non-BPA exposed rats; including, decrease locomotion, increase light and sound aversion, and increased startle. Furthermore, it is interesting to note that control rats (dural application of vehicle) exposed to BPA also demonstrate changes in pain sensitization as compared to rats with no BPA exposure (decreased locomotor activity and changes in grooming behaviors). Overall, these results demonstrate that BPA exposure exacerbates migraine-like symptoms, and also leads to increased pain-related behavior in control rats, indicating that BPA has the ability to alter nociception.

The mechanisms linking estrogen receptor activation to pain are likely complex due to the number of pathways that estrogen can signal through. Further studies are needed to fully examine how BPA exposure alters pain sensitization. Currently, analyses for change in expression of several estrogen and pain-related genes are being carried out to further understand the role BPA plays in migraine pathogenesis.