Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers
Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers
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DOI：
10.1093/brain/awq159
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发表时间：
2010-08-01
期刊：
影响因子：
14.5
通讯作者：
Porreca, Frank
中科院分区：
文献类型：
--
作者：
De Felice, Milena;Ossipov, Michael H.;Porreca, Frank
偏头痛是一种常见的神经系统疾病，通常用曲坦类药物治疗。曲坦类药物的过度使用会导致某些患者头痛的频率增加，这种现象被称为药物过度使用头痛。先前的临床前研究已经证明，重复或持续给予曲坦数天可以在支配硬脑膜的三叉神经节细胞中引起持续的神经适应，其显著特征在于降钙素基因相关肽的神经元谱的标记增加。此外，曲坦给药引起的行为综合征的敏感性增强的替代触发偏头痛，维持数周后停药，这种现象被称为“曲坦诱导的潜在敏化”。在这里，我们证明，曲坦管理elflants一个持久的增加，确定大鼠三叉神经硬脑膜传入标记为神经元型一氧化氮合酶在三叉神经节。在曲坦给药期间观察到的皮肤异常性疼痛可被神经元型一氧化氮合酶选择性抑制剂NXN-323逆转。此外，神经元型一氧化氮合酶抑制剂可预防曲坦给药后环境应激诱导的超敏反应。共同管理的NXN-323与舒马曲坦在几天内防止异常性疼痛的表达和增强的敏感性，观察到潜在的敏感性，但不是曲坦诱导的增加标记的神经元一氧化氮合酶在硬脑膜传入。因此，给予曲坦可促进硬脑膜传入神经元一氧化氮合酶的表达增加，这对于增强对环境应激的敏感性至关重要。这些数据为曲坦类药物治疗后头痛频率增加提供了生物学基础，并突出了神经元型一氧化氮合酶抑制剂在预防或治疗药物过度使用头痛中的潜在临床应用。
Migraine is a common neurological disorder often treated with triptans. Triptan overuse can lead to increased frequency of headache in some patients, a phenomenon termed medication overuse headache. Previous preclinical studies have demonstrated that repeated or sustained triptan administration for several days can elicit persistent neural adaptations in trigeminal ganglion cells innervating the dura, prominently characterized by increased labelling of neuronal profiles for calcitonin gene related peptide. Additionally, triptan administration elicited a behavioural syndrome of enhanced sensitivity to surrogate triggers of migraine that was maintained for weeks following discontinuation of drug, a phenomenon termed 'triptan-induced latent sensitization'. Here, we demonstrate that triptan administration elicits a long-lasting increase in identified rat trigeminal dural afferents labelled for neuronal nitric oxide synthase in the trigeminal ganglion. Cutaneous allodynia observed during the period of triptan administration was reversed by NXN-323, a selective inhibitor of neuronal nitric oxide synthase. Additionally, neuronal nitric oxide synthase inhibition prevented environmental stress-induced hypersensitivity in the post-triptan administration period. Co-administration of NXN-323 with sumatriptan over several days prevented the expression of allodynia and enhanced sensitivity to stress observed following latent sensitization, but not the triptan-induced increased labelling of neuronal nitric oxide synthase in dural afferents. Triptan administration thus promotes increased expression of neuronal nitric oxide synthase in dural afferents, which is critical for enhanced sensitivity to environmental stress. These data provide a biological basis for increased frequency of headache following triptans and highlight the potential clinical utility of neuronal nitric oxide synthase inhibition in preventing or treating medication overuse headache.