Behavioral effects and mechanisms of migraine pathogenesis following estradiol exposure in a multibehavioral model of migraine in rat

Abstract

Migraine is one of the most common neurological disorders, leading to more than 1% of total disability reported and over 68 million visits to emergency rooms or physician’s offices each year in the United States. Three times as many women as men have migraine, and while the mechanism behind this is not well understood, 17β-estradiol (estradiol) has been implicated to play a role. Studies have demonstrated that exposure to estrogen can lead to activation of inflammatory pathways, changes in sodium gated channel activity, as well as enhanced vasodilation and allodynia. Estradiol receptors are found in trigeminal nociceptors, which are involved in signaling during a migraine attack. The purpose of this study was to investigate the role of estradiol in migraine pathogenesis utilizing a multibehavioral model of migraine in rat. Animals were surgically implanted with a cannula system to induce migraine and behavior was assessed following exposure to a proestrous level of estradiol for total locomotor activity, light and noise sensitivity, evoked grooming patterns, and enhanced acoustic startle response. Results demonstrated decreased locomotor activity, increased light and noise sensitivity, altered facial grooming indicative of allodynia and enhanced acoustic startle. Further examination of tissue samples revealed increased expression of genes associated with inflammation and vasodilation. Overall, this study demonstrates exacerbation of migraine-like behaviors following exposure to estradiol and helps further explain the underlying mechanisms behind sex differences found in this common neurological disorder.

Induction of chronic migraine phenotypes in a rat model after environmental irritant exposure

“…It is not clear how the trigeminovascular system is activated in migraine but sensitization of peripheral neural elements may be involved. Therefore most models include repeated administration of agents to peripheral nociceptors in the meninges [32;36;56;57], or systemically, i.e., nitroglycerin [40]. Our inhalation model differs in that we repeatedly activate the trigeminovascular system via stimulation of peripheral trigeminal afferents in the nasal mucosa.…”

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

“…Serum concentrations of E2 before and at 30 min, 2, 4, 6, 12 and 24 hours post injection of either a dose of 17-β-estradiol (180 μg/kg, i.p., n=3/time-point) [ 55 , 113 ] or vehicle (castor oil, 1ml/kg) were determined. Briefly, blood samples were drawn via intracardiac puncture under isoflurane anesthesia (5% induction, 2.5% maintenance in air- 2L/min); animals were then decapitated.…”

Giving Researchers a Headache – Sex and Gender Differences in Migraine

“…Moreover, estradiol treatment led to an increased expression of genes associated with estradiol signaling (expression of estrogen receptors), inflammation, vasodilation, and endogenous cannabinoid metabolism. Lastly, this treatment led to the activation of the nociception-related ERK (45).…”

“…Obviously, gender aspects in laboratory animal studies are hard to describe and might, if present at all, be mainly related to behavioral aspects. However, investigation of sex differences in animal behavior e.g., (41,45), could be possibly interpreted as studies on gender aspects. Indeed, the way pain is experienced can be thought of as a behavioral aspect, although also sex components definitely influence pain perception.…”