Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Department of NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Pain. 2018 Oct;159(10):1980-1988. doi: 10.1097/j.pain.0000000000001291.
We attempted to gather information on the pathogenesis of medication-overuse headache, as well as on the neurochemical mechanisms through which symptomatic medication overuse concurs to headache chronification. Transcriptional profiles were therefore evaluated as an index of the homeostasis of the trigeminovascular system in the trigeminal ganglion of female rats exposed for 1 month to daily oral doses of eletriptan or indomethacin. We report that both drug treatments change trigeminal ganglion gene expression to a similar extend. Of note, qualitative transcriptomic analysis shows that eletriptan and indomethacin prompt nearly identical, increased expression of genes coding for proteins involved in migraine pathogenesis and central pain sensitization such as neuropeptides, their cognate receptors, prostanoid, and nitric oxide-synthesizing enzymes, as well as TRP channels. These genes, however, were not affected in thoracic dorsal root ganglia. Of note, lowering of orofacial nociceptive thresholds, as well as forepaw hyperalgesia occurred in both indomethacin- and eletriptan-treated rats. Our study reveals that chronic rat exposure to 2 acute headache medications with completely different mechanisms of action prompts pain sensitization with highly similar induction of pronociceptive genes selectively within the trigeminal ganglion. Data further our understanding of medication-overuse headache pathogenesis and provide hints for specific mechanism-based treatment options.
我们试图收集药物滥用性头痛发病机制的信息，以及症状性药物滥用导致头痛慢性化的神经化学机制。因此，我们评估了转录谱作为暴露于每日口服剂量的依来曲普坦或吲哚美辛 1 个月的雌性大鼠三叉神经节中三叉血管系统内稳态的指标。我们报告说，这两种药物治疗都以相似的程度改变三叉神经节的基因表达。值得注意的是，定性转录组分析表明，依来曲普坦和吲哚美辛几乎相同地促进偏头痛发病机制和中枢痛敏化相关基因的表达，如神经肽、其相应的受体、前列腺素和一氧化氮合成酶以及 TRP 通道。然而，这些基因在胸背根神经节中不受影响。值得注意的是，在吲哚美辛和依来曲普坦治疗的大鼠中，口腔疼痛阈值降低和前爪痛觉过敏均发生。我们的研究表明，慢性大鼠暴露于 2 种具有完全不同作用机制的急性头痛药物会导致痛觉过敏，而在三叉神经节中选择性地诱导促伤害感受基因的高度相似诱导。数据进一步加深了我们对药物滥用性头痛发病机制的理解，并为基于特定机制的治疗选择提供了线索。
