Theoharides T C, Spanos C, Pang X, Alferes L, Ligris K, Letourneau R, Rozniecki J J, Webster E, Chrousos G P
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Endocrinology. 1995 Dec;136(12):5745-50. doi: 10.1210/endo.136.12.7588332.
Stress is known to precipitate or worsen a number of disorders, such as migraines, in which mast cells are suspected of being involved by releasing vasoactive, nociceptive, and proinflammatory mediators. However, no functional association has been demonstrated yet between a migraine trigger and brain mast cell activation. Nontraumatic immobilization (restrain) stress has been shown to stimulate the hypothalamic-pituitary-adrenal axis and to cause redistribution of immune cells. Here, restrain stress caused degranulation in 70% of rat dura mast cells within 30 min, as shown both by light and electron microscopy. These morphologic findings were accompanied by cerebrospinal fluid elevation of rat mast cell protease I, but not II, indicating secretion from connective tissue type mast cells. Mast cell activation due to stress was abolished in animals that had been treated neonatally with capsaicin, indicating that neuropeptides in sensory nerve endings are involved in this response. Complete inhibition was also achieved by pretreating the animals ip with polyclonal antiserum to CRH. Mast cells in the dura were localized close to nerve processes containing substance P, but no CRH-positive fibers were identified even though these were found close to mast cells in the median eminence. This is the first time that stress is shown to activate intracranial mast cells; apparently through the sequential action of CRH and sensory neuropeptides. These findings may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders such as migraines, which are induced or exacerbated by stress.
已知压力会诱发或加重多种疾病，如偏头痛，在偏头痛中，肥大细胞被怀疑通过释放血管活性、伤害性和促炎介质而参与其中。然而，偏头痛触发因素与脑肥大细胞激活之间尚未证实存在功能关联。非创伤性固定（束缚）应激已被证明会刺激下丘脑 - 垂体 - 肾上腺轴并导致免疫细胞重新分布。在此，束缚应激在30分钟内导致70%的大鼠硬脑膜肥大细胞脱颗粒，光学显微镜和电子显微镜观察均证实了这一点。这些形态学发现伴随着大鼠肥大细胞蛋白酶I而非蛋白酶II的脑脊液升高，表明是结缔组织型肥大细胞分泌所致。新生期用辣椒素处理的动物中，应激引起的肥大细胞激活被消除，这表明感觉神经末梢中的神经肽参与了这一反应。给动物腹腔注射促肾上腺皮质激素释放激素（CRH）多克隆抗血清进行预处理也能实现完全抑制。硬脑膜中的肥大细胞定位于靠近含有P物质的神经突起处，但即使在正中隆起的肥大细胞附近发现了CRH阳性纤维，也未识别出CRH阳性纤维。这是首次表明应激可激活颅内肥大细胞；显然是通过CRH和感觉神经肽的相继作用。这些发现可能对诸如偏头痛等由压力诱发或加重的神经炎症性疾病的病理生理学和可能的治疗具有启示意义。
