CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior
CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior
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DOI：
10.1177/0333102417735845
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发表时间：
2019-03-01
期刊：
影响因子：
4.9
通讯作者：
Bolay, Hayrunnisa
中科院分区：
文献类型：
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作者：
Filiz, Asli;Tepe, Nermin;Bolay, Hayrunnisa
背景与目的本研究旨在探讨选择性降钙素基因相关肽(CGRP)受体拮抗剂(MK-8825)对皮层弥漫性抑制(CSD)所致自由活动大鼠疼痛行为和焦虑的影响及其相关解剖区域神经元的激活作用。方法在保持脑膜各层和血脑屏障完整的前提下建立CSD模型，给予两种不同剂量的MK-8825。记录局部脑血流量(RCBF)、动脉压和DC漂移。行为学研究在自由活动的大鼠身上进行。评估患者的自发行为、机械痛觉异常、超音波发声和焦虑。免疫组织化学方法检测c-fos、CGRP、降钙素受体样受体(CLR)和受体活性修饰蛋白1(RAMP1)的表达。结果MK-8825不阻断大脑皮层DC移位，并伴有血流动力学反应。CSD可显著诱导自由活动大鼠的冰冻和梳理行为。MK-8825扭转了冰冻、梳理、湿狗摇动和摇头行为的增加。MK-8825增加了CSD诱导的von Frey阈值的降低，但不改变升高的Plus迷宫结果。MK-8825可阻断CSD对脑干、三叉神经尾侧核(TNC)和丘脑网状核(TRN)c-fos的诱导，但不能阻断杏仁核的c-fos诱导。免疫荧光分析未见CGRP、CLR或RAMP1与c-fos阳性细胞共定位。结论CGRP受体拮抗剂MK-8825可剂量依赖性地减弱CSD诱导的三叉神经痛反应，而不改变CSD波，并伴随rCBF反应。在阻断TNC激活的同时，MK-8825对杏仁核和焦虑行为没有任何影响。降钙素基因相关肽受体拮抗剂也可能调节丘脑皮质门控。
Background and objective The present study aimed to investigate the effects of selective calcitonin gene related peptide (CGRP) receptor antagonist (MK-8825) on cortical spreading depression (CSD) induced pain behavior and anxiety in freely-moving rats, and neuronal activation in the correlated anatomical regions. Methods CSD was induced while keeping all meningeal layers and BBB intact and MK-8825 was administered in two different doses. Regional cerebral blood flow (rCBF), arterial pressure and DC shift were recorded. Behavioral studies were conducted in freely-moving rats. Spontaneous behavior, mechanical allodynia, ultrasonic vocalization, and anxiety were evaluated. Immunohistochemistry of c-fos, CGRP, calcitonin receptor like-receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were studied. Results MK-8825 did not block DC shifts in the cerebral cortex and accompanied hemodynamic response. CSD significantly induced freezing and grooming behavior in freely-moving rats. MK-8825 reversed increased episodes of freezing, grooming, wet dog shake and head shake behavior. MK-8825 increased CSD-induced reductions in von Frey thresholds, but did not change elevated plus maze results. MK-8825 blocked c-fos induction by CSD in the brainstem trigeminal nucleus caudalis (TNC) and reticular nucleus of thalamus (TRN) but not in the amygdala. Immunofluorescence analysis showed no co-localization of CGRP, CLR or RAMP1 with c-fos positive cells. Conclusion CGRP receptor antagonist MK-8825 dose dependently attenuated CSD-induced trigeminal nerve mediated pain response without altering CSD waves and accompanied rCBF response. While blocking TNC activation, MK-8825 did not exert any effect on amygdala and anxiety behavior. CGRP receptor antagonists may also modulate thalamo-cortical gating.