Exposure to Bisphenol A Exacerbates Migraine-Like Behaviors in a Multibehavior Model of Rat Migraine

Migraine is a debilitating and common neurological condition that results in over 68.6 million visits to physician’s offices or emergency rooms in the United States each year (Shapiro and Goadsby, 2007). This condition creates a substantial burden to society due to the high prevalence, loss of productivity, and the high cost of treatment. Women experience migraine 3 times more frequently than men (Buse et al., 2013), and while the mechanism behind this sex difference is not well understood, estrogen has been strongly implicated to play a role (Gupta et al., 2011; Somerville, 1975). A multibehavioral model of migraine in rat was developed, based on clinical diagnostic criteria from the International Classification of Headache Disorders (ICHD-II and ICHD-III) (Society, 2004; Society, 2013). Currently, migraine has no specific biomarker test and analysis of symptoms is the only way to diagnose this disorder. Commonly described symptoms include photo- and phonophobia, avoidance of routine activity, and a unilateral pulsating pain in the head and face. The model utilized in this study expanded upon previous work (Stucky et al., 2011) to further study criteria including photo- and phonophobia, facial allodynia, and enhanced acoustic startle. Rats received a dural cannula implant and an inflammatory soup (IS), a well-established model for migraine study in rats (Burstein et al., 1998), was applied to the dura mater to induce migraine-like behaviors. Total locomotor activity (ie, routine activity) (Stucky et al., 2011), photo- and phonophobia (light and noise aversion), evoked grooming, and acoustic startle reflex were then examined. It is important to note that estrogen receptors ERalpha and GPR30 are present in trigeminal nociceptors, and through estrogen binding, downstream activation of the pain-related extracellular signal regulated kinase (ERK) occurs (Liverman et al., 2009a). It has also been demonstrated that environmental estrogens can bind to and activate estrogen receptors, leading to altered cell activity (Lapensee et al., 2009). Bisphenol A (BPA) is used in plastics manufacturing and is one of the most ubiquitous xenoestrogens, leading to frequent human exposure. It is estimated that over 90% of the U.S. population has BPA in their bodies (Calafat et al., 2008), and while the effect of BPA exposure in cancer has been extensively studied (De Coster and van Larebeke, 2012), little is known regarding its consequences in terms of migraine and other pain syndromes. Furthermore, current standard toxicology screenings do not explore the effect BPA may have on migraine onset, intensity and duration. While the EPA has deemed the safe maximum dose of BPA to be 50 μg/kg/day (Leranth et al., 2008), it is estimated that many humans are exposed to levels approximately 10 times this amount (Vandenberg et al., 2007, 2009, 2012, 2013). As BPA is able to bind to estrogen receptors known to be involved in exacerbating trigeminal pain (Liverman et al., 2009a), it is likely BPA exposure could contribute to the development of migraine or could increase the severity of migraine symptoms. While previous work has investigated the effect of other environmental estrogens and pain (Ceccarelli et al., 2009), no studies have established how exposure to BPA alters migraine symptoms. Furthermore, many pain disorders demonstrate female predominance; including, irritable bowel syndrome, fibromyalgia, and temporomandibular disorders (Chang and Lu, 2013). Therefore, chronic, daily exposure to BPA may have detrimental effects on the symptoms of a variety of diseases. The goal of this study was to determine whether BPA exposure exacerbates migraine symptoms and alters migraine pathogenesis through estrogen signaling and downstream activation of nociceptive pathways.