, 2001). Acute subcutaneous administration of sumatriptan activates Sirolimus the pituitary-adrenal axis: significant increases in β-endorphin and cortisol concentrations are reported across all subjects receiving sumatriptan (Facchinetti et al., 1994), and these would produce secondary effects. Migraine medications may also alter sensory processing. For example, the administration of sumatriptan to healthy volunteers produces abnormal psychophysiological (diminished pleasantness) and fMRI signal (in anterior insular, lateral orbitofrontal, and anterior cingulate cortices

and medial thalamus) changes that are observed only following sumatriptan, not saline (Krämer et al., 2007). In addition to exogenously administered drugs, endogenous chemical (hormonal) milieu can also be a significant issue in migraine. About 17% of women versus 6% of men get migraines (Rasmussen et al., 1991). Perhaps the best example of induced stressors on brain systems is the female menstrual cycle (Farage et al., 2008). Menstrual migraine (MM) is common in women and may relate to hormonal modulations in the GABA-A receptors decreasing normal inhibitory control (Epperson et al., 2002). Menstrual migraine may be more difficult to treat than nonmenstrual

migraine in women, suggesting a role of induced resistance as a result of their hormonally induced migraine. Menstrual migraine may also be a contributor to the evolution of chronification of headache (Lay and Broner, 2008). Conversely, elimination of MM with the use of hormonal preventive medications can be achieved in a large percentage GSI-IX molecular weight of patients, and this further decreases chronic migraine that is present in over 90% of women (Calhoun and Ford, 2008). It would thus seem that the alterations induced in brain systems that induce menstrual migraine may add to the allostatic load/overload. Estrogen (estradiol) and progesterone

(via allopregnanolone) affect neuronal systems with opposite effects, with estrogen generally being excitatory—enhancing glutamatergic systems and progesterone inhibitory—through GABA systems (Finocchi and Ferrari, 2011). Progesterone usually antagonizes estradiol in synaptic remodeling in brain regions, including the hippocampus (Wong et al., unless 2009). Increased brain sensitivity in women includes catamenial epilepsy, in which hormonal changes, particularly estrogen, contribute to increased seizures (Guille et al., 2008). A similar process may take place in migraine. The effects of estradiol on brain systems is complex and may induce excitatory-induced neuronal changes (Blacklock et al., 2005) but may also be protective of adrenal steroids (Garcia-Segura et al., 2007). The higher prevalence of stress-related disorders in women may relate to estrogen effects on brain systems that have high levels of both genomic and nongenomic estrogen receptors (viz.