Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115.
Center for Anesthesia Research Excellence, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115.
J Neurosci. 2023 Aug 16;43(33):5975-5985. doi: 10.1523/JNEUROSCI.0368-23.2023. Epub 2023 Jul 24.
Cortical spreading depolarization (CSD) is a key pathophysiological event that underlies visual and sensory auras in migraine. CSD is also thought to drive the headache phase in migraine by promoting the activation and mechanical sensitization of trigeminal primary afferent nociceptive neurons that innervate the cranial meninges. The factors underlying meningeal nociception in the wake of CSD remain poorly understood but potentially involve the parenchymal release of algesic mediators and damage-associated molecular patterns, particularly ATP. Here, we explored the role of ATP-P2X purinergic receptor signaling in mediating CSD-evoked meningeal afferent activation and mechanical sensitization. Male rats were subjected to a single CSD episode. , extracellular single-unit recording was used to measure meningeal afferent ongoing activity changes. Quantitative mechanical stimuli using a servomotor force-controlled stimulator assessed changes in the afferent's mechanosensitivity. Manipulation of meningeal P2X receptors was achieved via local administration of pharmacological agents. Broad-spectrum P2X receptor inhibition, selective blockade of the P2X7 receptor, and its related Pannexin 1 channel suppressed CSD-evoked afferent mechanical sensitization but did not affect the accompanying afferent activation response. Surprisingly, inhibition of the pronociceptive P2X2/3 receptor did not affect the activation or sensitization of meningeal afferents post-CSD. P2X7 signaling underlying afferent mechanosensitization was localized to the meninges and did not affect CSD susceptibility. We propose that meningeal P2X7 and Pannexin 1 signaling, potentially in meningeal macrophages or neutrophils, mediates the mechanical sensitization of meningeal afferents, which contributes to migraine pain by exacerbating the headache during normally innocuous physical activities. Activation and sensitization of meningeal afferents play a key role in migraine headache, but the underlying mechanisms remain unclear. Here, using a rat model of migraine with aura involving cortical spreading depolarization (CSD), we demonstrate that meningeal purinergic P2X7 signaling and its related Pannexin 1 pore, but not nociceptive P2X2/3 receptors, mediate prolonged meningeal afferent sensitization. Additionally, we show that meningeal P2X signaling does not contribute to the increased afferent ongoing activity in the wake of CSD. Our finding points to meningeal P2X7 signaling as a critical mechanism underlying meningeal nociception in migraine, the presence of distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for effective migraine therapy.
皮质扩散性抑制（CSD）是偏头痛视觉和感觉先兆的关键病理生理事件。CSD 也被认为通过促进支配颅脑膜的三叉神经初级传入伤害感受神经元的激活和机械敏化来驱动偏头痛的头痛阶段。CSD 后脑膜伤害感受的基础仍然知之甚少，但可能涉及实质细胞释放致痛介质和损伤相关分子模式，特别是 ATP。在这里，我们探讨了 ATP-P2X 嘌呤能受体信号在介导 CSD 诱发的脑膜传入激活和机械敏化中的作用。雄性大鼠接受单次 CSD 发作。使用细胞外单细胞记录测量脑膜传入持续活动变化。使用伺服电机力控制刺激器进行定量机械刺激，评估传入的机械敏感性变化。通过局部给予药理学制剂来操纵脑膜 P2X 受体。广谱 P2X 受体抑制、选择性阻断 P2X7 受体及其相关的 Pannexin 1 通道抑制 CSD 诱发的传入机械敏化，但不影响伴随的传入激活反应。令人惊讶的是，抑制促伤害感受的 P2X2/3 受体不影响 CSD 后脑膜传入的激活或敏化。位于脑膜中的 P2X7 信号转导介导了传入的机械敏化，并且不影响 CSD 的易感性。我们提出，脑膜 P2X7 和 Pannexin 1 信号转导，可能存在于脑膜中的巨噬细胞或中性粒细胞中，介导脑膜传入的机械敏化，通过加剧正常无害的身体活动期间的头痛，从而加剧偏头痛疼痛。脑膜传入的激活和敏化在偏头痛头痛中起关键作用，但潜在机制尚不清楚。在这里，我们使用涉及皮质扩散性抑制（CSD）的偏头痛伴先兆大鼠模型，证明脑膜嘌呤能 P2X7 信号转导及其相关的 Pannexin 1 孔，但不是伤害感受 P2X2/3 受体，介导延长的脑膜传入敏化。此外，我们表明脑膜 P2X 信号转导不导致 CSD 后传入持续活动的增加。我们的发现指出，脑膜 P2X7 信号转导是偏头痛中脑膜伤害感受的关键机制，偏头痛中脑膜传入的激活和敏化存在不同的机制，并强调需要针对这两个过程进行有效的偏头痛治疗。
