Rizatriptan overuse promotes hyperalgesia induced by dural inflammatory stimulation in rats by modulation of the serotonin system

Abstract

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.

Inhibition of toll-like receptor 4 alleviates hyperalgesia induced by acute dural inflammation in experimental migraine

“…A cannula was implanted in each rat to carry out the dural infusion, as described previously. 19 Briefly, rats were anaesthetised to a deep surgical plane with 3% pentobarbital sodium (2 mL/kg, i.p.). A plastic cap with a stainless steel inner cannula (C = 1 mm; RWD Life Science Co., Ltd., Shenzhen, Guangdong Province, China) was implanted in a previously drilled cranial window aimed at the left frontal bone (1.0 mm in diameter, 1.5 mm beyond the transverse sinuses, and 1.5 mm left of the superior sagittal sinus) without touching the meningeal tissue.…”

“…Dural infusion of an inflammatory soup (IS), a mixture of inflammatory mediators, in awake rats has been widely used to study acute or chronic migraine, as this kind of animal model can not only simulate migraine-related behaviour but also effectively induce hyperalgesia. 18 – 20 In the present study, an IS rat model was used to explore whether the TLR4–NF–κB signalling pathway in the trigeminal ganglion (TG) and trigeminocervical complex (TCC) participates in the development of cutaneous hypersensitivity. Moreover, a specific TLR4 inhibitor, TAK-242, was administered to analyse its possible role in regulating neuroinflammation.…”

Depression and anxiety behaviour in a rat model of chronic migraine

“…A cannula was implanted as described previously by Su et al [ 21 ]. An absolute diet was given to the rats the day before the surgery to prevent abdominal distention.…”

Chronic migraine: A process of dysmodulation and sensitization

“… 49 Moreover, both chronic dural inflammatory stimulation and triptan overuse caused mechanical allodynia and trigeminal sensitization in rats. 67 All these preclinical studies indicate that both frequent attacks and medication overuse promote the development of central sensitization. In addition, comorbid mood disorder also can influence the formation of hyperalgesia, as depression models induced by olfactory bulbectomy or unpredictable chronic mild stress both exhibited severer nociceptive behavior and hyperalgesia state.…”

“… 78 Besides the pain modulation, 5-HT also plays an important role in sleep pathophysiology and the genesis of mood disorders, 79 making these problems common in migraine, especially CM. According to clinical and preclinical studies, both the frequent headache attacks and medication overuse can induce decrease of 5-HT and upregulation of serotonin receptors, 67 , 80 which enhances hyperalgesia and promotes headache chronicity. Furthermore, abnormality of serotonin-related metabolism is present in CM and MOH sufferes.…”