1 Department of Neurology and Algology, Gazi University Medical School, Besevler, Ankara, Turkey.
2 Neuropsychiatry Centre, Gazi University, Besevler, Ankara, Turkey.
Cephalalgia. 2019 Mar;39(3):354-365. doi: 10.1177/0333102417735845. Epub 2017 Oct 3.
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.
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.
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.
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.
本研究旨在观察选择性降钙素基因相关肽（CGRP）受体拮抗剂（MK-8825）对自由活动大鼠皮质扩散性抑制（CSD）诱导痛觉行为和焦虑的影响，并探讨相关解剖区域神经元的激活情况。
在保持脑膜层和血脑屏障完整的情况下诱导 CSD，并给予两种不同剂量的 MK-8825。记录局部脑血流（rCBF）、动脉压和 DC 偏移。在自由活动的大鼠中进行行为学研究。评估自发性行为、机械性痛觉过敏、超声发声和焦虑。研究 c-fos、CGRP、降钙素受体样受体（CLR）和受体活性修饰蛋白 1（RAMP1）的免疫组织化学。
MK-8825 不能阻断皮质的 DC 偏移和伴随的血液动力学反应。CSD 显著诱导自由活动大鼠的冻结和梳理行为。MK-8825 逆转了增加的冻结、梳理、湿狗抖动和摇头行为。MK-8825 增加了 CSD 诱导的 von Frey 阈值降低，但对高架十字迷宫的结果没有影响。MK-8825 阻断了 CSD 在脑干三叉神经尾核（TNC）和丘脑网状核（TRN）中诱导的 c-fos 诱导，但在杏仁核中没有。免疫荧光分析显示 CGRP、CLR 或 RAMP1 与 c-fos 阳性细胞无共定位。
CGRP 受体拮抗剂 MK-8825 呈剂量依赖性减弱 CSD 诱导的三叉神经介导的疼痛反应，而不改变 CSD 波和伴随的 rCBF 反应。MK-8825 阻断 TNC 激活，但对杏仁核和焦虑行为没有影响。CGRP 受体拮抗剂还可能调节丘脑皮质门控。
