Recently, we showed that while atogepant - a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist - does not fully prevent activation of nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C-fibers and late response probability in A™-fibers. The current study investigates atogepant effect on CSD-induced activation and sensitization of high-threshold (HT) and wide dynamic range (WDR) dura-sensitive neurons. In anesthetized male rats, single-unit recordings were used to assess effects of atogepant (5mg/kg) vs vehicle on CSD-induced activation and sensitization of HT and WDR dura-sensitive neurons. Single cell analysis of atogepant pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus (STN) revealed ability of this small molecule CGRP receptor antagonist to prevent activation and sensitization of nearly all HT neurons (8/10 vs. 1/10 activated neurons in the control vs. treated groups, p=0.005). In contrast, atogepant pretreatment effects on CSD-induced activation and sensitization of WDR neurons revealed an overall inability to prevent their activation (7/10 vs. 5/10 activated neurons in the control vs. treated groups, p=0.64). Unexpectedly however, in spite of atogepant inability to prevent activation of WDR neurons, it prevented their sensitization (as reflected their responses to mechanical stimulation of the facial receptive field before and after the CSD). Atogepant ability to prevent activation and sensitization of HT neurons is attributed to its preferential inhibitory effects on thinly unmyelinated A™ fibers. Atogepant inability to prevent activation of WDR neurons is attributed to its lesser inhibitory effects on the unmyelinated C fibers. Molecular and physiological processes that govern neuronal activation vs. sensitization can explain how reduction in CGRP-mediated slow but not glutamate-mediated fast synaptic transmission between central branches of meningeal nociceptors and nociceptive neurons in the STN can prevent their sensitization but not activation.

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对 atogepant 预防偏头痛作用机制的新见解

最近，我们发现，虽然 atogepant - 一种小分子降钙素基因相关肽 (CGRP) 受体拮抗剂 - 不能完全阻止伤害感受器的激活，但它显着降低了皮质扩散抑制 (CSD) 诱导的 C 纤维早期反应概率以及 A™ 纤维中的延迟响应概率。目前的研究调查了 atogepant 对 CSD 诱导的高阈值 (HT) 和宽动态范围 (WDR) 硬脑膜敏感神经元的激活和敏化的影响。在麻醉的雄性大鼠中，使用单单位记录来评估 atogepant (5mg/kg) 与媒介物相比对 CSD 诱导的 HT 和 WDR 硬脑膜敏感神经元的激活和敏化的影响。Atogepant 预处理对 CSD 诱导的三叉神经脊髓核 (STN) 中央三叉血管神经元激活和敏化效果的单细胞分析表明，这种小分子 CGRP 受体拮抗剂能够防止几乎所有 HT 神经元的激活和敏化（8/10 比. 对照组与治疗组中激活的神经元为 1/10，p=0.005）。相比之下，atogepant 预处理对 CSD 诱导的 WDR 神经元激活和敏化的影响表明，总体上无法阻止其激活（对照组与治疗组中激活的神经元分别为 7/10 和 5/10，p=0.64）。然而出乎意料的是，尽管 atogepant 无法阻止 WDR 神经元的激活，但它阻止了它们的敏化（反映了它们在 CSD 之前和之后对面部感受野机械刺激的反应）。Atogepant 防止 HT 神经元激活和敏化的能力归因于其对薄无髓鞘 A™ 纤维的优先抑制作用。Atogepant 无法阻止 WDR 神经元的激活，是因为它对无髓鞘 C 纤维的抑制作用较小。控制神经元激活与敏化的分子和生理过程可以解释，减少 CGRP 介导的慢速突触传递，而不是谷氨酸介导的快速突触传递，可以防止脑膜伤害感受器中央分支和 STN 中的伤害感受神经元之间的敏化，但不能阻止激活。