Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy.
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy.
J Pain. 2022 Nov;23(11):1874-1884. doi: 10.1016/j.jpain.2022.05.007. Epub 2022 Jun 11.
Chronic triptan exposure in rodents recapitulates medication overuse headache (MOH), causing cephalic pain sensitization and trigeminal ganglion overexpression of pronociceptive proteins including CGRP. Because of these transcriptional derangements, as well as the emerging role of epigenetics in chronic pain, in the present study, we evaluated the effects of the histone deacetylase inhibitors (HDACis) panobinostat and givinostat, in rats chronically exposed to eletriptan for 1 month. Both panobinostat and givinostat counteracted overexpression of genes coding for CGRP and its receptor subunit RAMP1, having no effects on CLR and RCP receptor subunits in the trigeminal ganglion (TG) of eletriptan-exposed rats. Within the trigeminal nucleus caudalis (TNc), transcripts for these genes were neither upregulated by eletriptan nor altered by concomitant treatment with panobinostat or givinostat. HDACis counteracted hypersensitivity to capsaicin-induced vasodilatation in the trigeminal territory, as well as photophobic behavior and cephalic allodyniain eletriptan-exposed rats. Eletriptan did not affect CGRP, CLR, and RAMP1 expression in cultured trigeminal ganglia, whereas both inhibitors reduced transcripts for CLR and RAMP-1. The drugs, however, increased luciferase expression driven by CGRP promoter in cultured cells. Our findings provide evidence for a key role of HDACs and epigenetics in MOH pathogenesis, highlighting the therapeutic potential of HDAC inhibition in the prevention of migraine chronification. PERSPECTIVE: The present study highlights a key epigenetic role of HDAC in the rodent model of medication overuse headache, furthering our understanding of the molecular mechanisms responsible for pronociceptive sensitization during headache chronification.
慢性曲普坦暴露于啮齿动物中重现了药物过度使用性头痛（MOH），导致头部疼痛敏化和三叉神经节中伤害性蛋白包括 CGRP 的过度表达。由于这些转录失调，以及表观遗传学在慢性疼痛中的新兴作用，在本研究中，我们评估了组蛋白去乙酰化酶抑制剂（HDACi）panobinostat 和 givinostat 对 1 个月慢性暴露于 eletriptan 的大鼠的影响。panobinostat 和 givinostat 均拮抗了编码 CGRP 及其受体亚基 RAMP1 的基因的过度表达，对 eletriptan 暴露大鼠三叉神经节（TG）中的 CLR 和 RCP 受体亚基没有影响。在三叉神经尾核（TNc）中，这些基因的转录物既不受 eletriptan 的上调，也不受 panobinostat 或 givinostat 伴随治疗的影响。HDACi 拮抗了 eletriptan 暴露大鼠三叉神经支配区辣椒素诱导的血管扩张、畏光行为和头部痛觉过敏。Eletriptan 不影响培养的三叉神经节中的 CGRP、CLR 和 RAMP1 表达，而两种抑制剂均降低了 CLR 和 RAMP-1 的转录物。然而，这些药物增加了培养细胞中由 CGRP 启动子驱动的荧光素酶表达。我们的研究结果为 HDAC 和表观遗传学在 MOH 发病机制中的关键作用提供了证据，突出了 HDAC 抑制在预防偏头痛慢性化中的治疗潜力。观点：本研究强调了 HDAC 在药物过度使用性头痛啮齿动物模型中的关键表观遗传作用，进一步了解了导致头痛慢性化期间伤害感受敏化的分子机制。
