Shyti Reinald, Eikermann-Haerter Katharina, van Heiningen Sandra H, Meijer Onno C, Ayata Cenk, Joëls Marian, Ferrari Michel D, van den Maagdenberg Arn M J M, Tolner Else A
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, MA General Hospital, Harvard Medical School, Charlestown, USA.
Exp Neurol. 2015 Jan;263:214-20. doi: 10.1016/j.expneurol.2014.10.015. Epub 2014 Oct 29.
Stress is a putative migraine trigger, but the pathogenic mechanisms involved are unknown. Stress and stress hormones increase neuronal excitability by enhancing glutamatergic neurotransmission, but inhibitory effects have also been reported. We hypothesise that an acute rise in stress hormones, such as corticosteroids which are released after stress, increase neuronal excitability and thereby may increase susceptibility to cortical spreading depression (CSD), the mechanism underlying the migraine aura. Here we investigated effects of acute restraint stress and of the stress hormone corticosterone on CSD susceptibility as surrogate migraine marker, in a transgenic mouse model of familial hemiplegic migraine type 1 (FHM1), which displays increased glutamatergic cortical neurotransmission and increased propensity for CSD. We found that 20-min and 3-h restraint stress did not influence CSD susceptibility in mutant or wild-type mice, despite elevated levels of plasma corticosterone. By contrast, subcutaneous administration of 20mg/kg corticosterone increased CSD frequency exclusively in mutant mice, while corticosterone plasma levels were similarly elevated in mutants and wild types. The effect of corticosterone on CSD frequency was normalised by pre-administration of the glucocorticoid receptor (GR) antagonist mifepristone. These findings suggest that corticosteroid-induced GR activation can enhance susceptibility to CSD in genetically susceptible individuals, and may predispose to attacks of migraine. Although corticosterone levels rise also during acute stress, the latter likely triggers a spatiotemporally more complex biological response with multiple positive and negative modulators which may not be adequately modeled by exogenous administration of corticosterone alone.
压力被认为是偏头痛的诱发因素，但其涉及的致病机制尚不清楚。压力和应激激素通过增强谷氨酸能神经传递来增加神经元兴奋性，但也有抑制作用的报道。我们假设，应激激素（如应激后释放的皮质类固醇）的急性升高会增加神经元兴奋性，从而可能增加对皮质扩散性抑制（CSD）的易感性，而CSD是偏头痛先兆的潜在机制。在这里，我们在1型家族性偏瘫性偏头痛（FHM1）的转基因小鼠模型中，研究了急性束缚应激和应激激素皮质酮对作为替代偏头痛标志物的CSD易感性的影响，该模型显示谷氨酸能皮质神经传递增加且CSD倾向增加。我们发现，尽管血浆皮质酮水平升高，但20分钟和3小时的束缚应激并未影响突变型或野生型小鼠的CSD易感性。相比之下，皮下注射20mg/kg皮质酮仅增加了突变型小鼠的CSD频率，而突变型和野生型小鼠的血浆皮质酮水平同样升高。预先给予糖皮质激素受体（GR）拮抗剂米非司酮可使皮质酮对CSD频率的影响恢复正常。这些发现表明，皮质类固醇诱导的GR激活可增强遗传易感个体对CSD的易感性，并可能诱发偏头痛发作。尽管在急性应激期间皮质酮水平也会升高，但急性应激可能会引发一种时空上更为复杂的生物学反应，其中有多种正负调节因子，仅靠外源性给予皮质酮可能无法充分模拟这种反应。
