Involvement of 5-Hydroxytryptamine Receptor 2A in the Pathophysiology of Medication-Overuse Headache
Authors Zheng Z, Shi X, Xiang Y, Zhang A, Fang Y
Received 10 October 2020
Accepted for publication 19 December 2020
Published 16 February 2021 Volume 2021:14 Pages 453—461
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Robert B. Raffa
Zhenyang Zheng,1 Xiaolei Shi,2 Yue Xiang,3 Aiwu Zhang,2 Yannan Fang2
1Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China; 3Department of Nursing, Fujian Health College, Fuzhou, 350101, People’s Republic of China
Correspondence: Yannan Fang
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China
Background: Recent studies indicated that analgesic overuse upregulated 5-hydroxytryptamine receptor 2A (5-HT2AR) 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-HT2AR in MOH pathophysiology. Herein, we performed this study to investigate the role of 5-HT2AR in MOH pathophysiology and the role of GSK-3β in the regulation of NOS activity by 5-HT2AR.
Materials and Methods: 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-HT2AR and NOS, GSK-3β activity in trigeminal nucleus caudalis (TNC) were assayed. Then, 5-HT2AR antagonist ketanserin and agonist DOI were applied to investigate the effect of 5-HT2AR 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-HT2AR.
Results: We found that the expression of 5-HT2AR and NOS, GSK-3β activity were enhanced in TNC of MOH rats. 5-HT2AR modulator regulated the activity of NOS and GSK-3β in TNC of MOH rats, and drugs acting on GSK-3β affected NOS activity.
Conclusion: These data suggest that GSK-3β may mediate the activation of NOS by 5-HT2AR and underline the role of 5-HT2AR in MOH pathophysiology.
Keywords: medication-overuse headache, 5-hydroxytryptamine receptor 2A, nitric oxide synthase, glycogen synthase kinase-3β
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