Rizatriptan overuse promotes hyperalgesia induced by dural inflammatory stimulation in rats by modulation of the serotonin system
Rizatriptan overuse promotes hyperalgesia induced by dural inflammatory stimulation in rats by modulation of the serotonin system
复制标题
利扎曲普坦过度使用通过调节血清素系统促进大鼠硬脑膜炎症刺激引起的痛觉过敏
DOI：
10.1111/ejn.13296
复制
发表时间：
2016-08-01
影响因子：
3.4
通讯作者：
Yu, Shengyuan
中科院分区：
文献类型：
--
作者：
Su, Min;Ran, Ye;Yu, Shengyuan
临床和临床前研究表明，5-羟色胺（5-HT）和5-HT 2A受体（5-HT 2AR）参与了药物过度使用性头痛（MOH）的发病机制。然而，由于没有合适的动物模型来研究这种现象，因此很难区分长期暴露于镇痛剂的影响与MOH发展过程中频繁头痛发作的后果。因此，本研究采用一种新的MOH动物模型，通过过度使用利扎曲普坦（RIZ）和硬膜炎性汤（IS）刺激相结合，以研究是否5-HT和5-HT 2AR参与中枢可塑性和痛觉过敏。与IS输注类似，IS-RIZ治疗诱导Sprague-Dawley大鼠的伤害感受相关行为，并增加皮质和三叉神经通路中的Fos表达，而单独注射RIZ则没有。此外，过度使用RIZ、给予IS刺激以及这些治疗的组合降低了眶周退缩阈值，其中IS-RIZ治疗具有最显著的效果。慢性RIZ暴露和反复伤害性感受均降低5-HT表达，而IS-RIZ治疗导致5-HT表达降低和5-HT 2AR上调，这与Fos激活呈正相关。这些发现表明，过度使用RIZ不会通过激活伤害性通路直接诱导疼痛，但可能会通过影响疼痛调制系统增加痛觉过敏。此外，5-HT水平的降低和5-HT 2AR的上调可能在该系统中起重要作用。总之，这些发现表明药物过度使用和频繁的头痛发作可以促进与MOH相关的神经可塑性。
Clinical and preclinical studies have implicated serotonin (5-HT) and the 5-HT2A receptor (5-HT2AR) in the pathogenesis of medication-overuse headache (MOH). However, with no appropriate animal model to study this phenomenon it is difficult to differentiate the effects of chronic exposure to analgesics from the consequences of frequent headache attacks during the development of MOH. Therefore, this study used a novel animal model of MOH established by a combination of the overuse of rizatriptan (RIZ) and stimulation with dural inflammatory soup (IS) to investigate whether 5-HT and 5-HT2AR are involved in central plasticity and hyperalgesia. Similar to an IS infusion, IS-RIZ treatment induced nociception-related behaviours in Sprague-Dawley rats and increased Fos expression in the cortex and trigeminal pathway, whereas the RIZ injection alone did not. In addition, overuse of RIZ, administration of an IS stimulus, and a combination of these treatments, decreased the periorbital withdrawal threshold, with IS-RIZ treatment having the most significant effects. Both chronic RIZ exposure and recurring nociception decreased 5-HT expression, whereas IS-RIZ treatment led to decreased expression of 5-HT and upregulation of 5-HT2AR, which was positively correlated with Fos activation. These findings suggest that overuse of RIZ does not directly induce pain via the activation of nociceptive pathways but may increase hyperalgesia by influencing the pain modulation system. Furthermore, decreased 5-HT levels and upregulation of 5-HT2AR may play important roles in this system. Taken together, these findings indicate that medication overuse and frequent headache attacks can promote the neural plasticity associated with MOH.