Involvement of 5-Hydroxytryptamine Receptor 2A in the Pathophysiology of Medication-Overuse Headache

Recent studies indicated that analgesic overuse upregulated 5-hydroxytryptamine receptor 2A (5-HT_2AR) and subsequently activated nitric oxide synthase (NOS) and thus induced latent sensitization, which provided a mechanistic basis for medication-overuse headache (MOH). Moreover, glycogen synthase kinase-3β (GSK-3β) was regulated by serotonin receptors and the phosphorylation of GSK-3β affected NOS activity, indicating that GSK-3β could be involved in the regulation of NOS activity by 5-HT_2AR in MOH pathophysiology. Herein, we performed this study to investigate the role of 5-HT_2AR in MOH pathophysiology and the role of GSK-3β in the regulation of NOS activity by 5-HT_2AR.

Wistar rats were daily administered with paracetamol (200 mg/kg) for 30 days to set animal models for pre-clinical MOH research. After the rat MOH models were successfully established, the expression of 5-HT_2AR and NOS, GSK-3β activity in trigeminal nucleus caudalis (TNC) were assayed. Then, 5-HT_2AR antagonist ketanserin and agonist DOI were applied to investigate the effect of 5-HT_2AR on NOS activity in TNC of MOH rats, and GSK-3β antagonist LiCl and agonist perifosine were applied to explore the role of GSK-3β in the activation of NOS by 5-HT_2AR.

We found that the expression of 5-HT_2AR and NOS, GSK-3β activity were enhanced in TNC of MOH rats. 5-HT_2AR modulator regulated the activity of NOS and GSK-3β in TNC of MOH rats, and drugs acting on GSK-3β affected NOS activity.

These data suggest that GSK-3β may mediate the activation of NOS by 5-HT_2AR and underline the role of 5-HT_2AR in MOH pathophysiology.