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

Clinical and preclinical studies have implicated serotonin (5- HT) and the 5- HT_2A receptor (5- HT2 AR) 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- HT2 AR 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- HT2 AR, 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- HT2 AR 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. [ABSTRACT FROM AUTHOR]