Zhao Jun, Levy Dan
Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Pain Rep. 2017 Dec 5;3(1):e632. doi: 10.1097/PR9.0000000000000632. eCollection 2018 Jan.
Cortical spreading depression (CSD) is believed to promote migraine headache by enhancing the activity and mechanosensitivity of trigeminal intracranial meningeal afferents. One putative mechanism underlying this afferent response involves an acute excitation of meningeal afferents by cortical efflux of K and the ensuing antidromic release of proinflammatory sensory neuropeptides, such as calcitonin gene-related peptide (CGRP).
We sought to investigate whether (1) a brief meningeal K stimulus leads to CGRP-dependent enhancement of meningeal afferent responses and (2) CSD-induced meningeal afferent activation and sensitization involve CGRP receptor signaling.
Extracellular single-unit recording were used to record the activity of meningeal afferents in anesthetized male rats. Stimulations included a brief meningeal application of K or induction of CSD in the frontal cortex using pinprick. Cortical spreading depression was documented by recording changes in cerebral blood flow using laser Doppler flowmetery. Calcitonin gene-related peptide receptor activity was inhibited with BIBN4096 (333 μM, i.v.).
Meningeal K stimulation acutely activated 86% of the afferents tested and also promoted in ∼65% of the afferents a 3-fold increase in ongoing activity, which was delayed by 23.3 ± 4.1 minutes and lasted for 22.2 ± 5.6 minutes. K stimulation did not promote mechanical sensitization. Pretreatment with BIBN4096 suppressed the K-induced delayed afferent activation, reduced CSD-evoked cortical hyperemia, but had no effect on the enhanced activation or mechanical sensitization of meningeal afferents following CSD.
While CGRP-mediated activation of meningeal afferents evoked by cortical efflux of K could promote headache, acute activation of CGRP receptors may not play a key role in mediating CSD-evoked headache.
皮层扩散性抑制（CSD）被认为通过增强三叉神经颅内脑膜传入神经的活性和机械敏感性来引发偏头痛。这种传入反应的一种潜在机制涉及脑膜传入神经被钾离子从皮层外流所急性激活，以及随之而来的促炎感觉神经肽（如降钙素基因相关肽，CGRP）的逆向释放。
我们试图研究（1）短暂的脑膜钾离子刺激是否会导致依赖CGRP的脑膜传入反应增强，以及（2）CSD诱导的脑膜传入神经激活和致敏是否涉及CGRP受体信号传导。
采用细胞外单单位记录法记录麻醉雄性大鼠脑膜传入神经的活性。刺激包括在脑膜上短暂施加钾离子或用针刺在额叶皮层诱导CSD。使用激光多普勒血流仪记录脑血流变化来记录皮层扩散性抑制。用BIBN4096（333μM，静脉注射）抑制降钙素基因相关肽受体活性。
脑膜钾离子刺激急性激活了86%的受试传入神经，并在约65%的传入神经中使持续活性增加了3倍，该增加延迟23.3±4.1分钟出现，持续22.2±5.6分钟。钾离子刺激未促进机械致敏。用BIBN4096预处理可抑制钾离子诱导的延迟传入神经激活，减少CSD诱发的皮层充血，但对CSD后脑膜传入神经的增强激活或机械致敏无影响。
虽然钾离子从皮层外流诱发的CGRP介导的脑膜传入神经激活可能引发头痛，但CGRP受体的急性激活可能在介导CSD诱发的头痛中不发挥关键作用。
