Putative role of 5-HT_2B receptors in migraine pathophysiology

Abstract

Objective In this review we attempt to characterize the acute and chronic role of 5-HT receptors with regard to meningeal nociception in animal experiments and clinical data targeting migraine therapy. Background Migraine is a common disabling neurovascular primary headache disease, the pathomechanism of which is still unclear. Serotonin (5-HT) and its receptors might play an important role in some aspects of migraine pathogenesis. The ability of the unselective 5-HT receptor agonist m-chlorophenylpiperazine to induce migraine attacks in migraine sufferers, the high affinity of prophylactic antimigraine drugs to this receptor and its expression in migraine-relevant structures like the dura mater argue for a role of 5-HT receptors in the pathogenesis of migraine attacks. Methods For this review, the relevant databases such as PubMed, MEDLINE®, Cochrane Library and EMBASE, respectively, were searched to December 2015 using the keywords "migraine, 5-HT, trigeminal, neurogenic inflammation, nitric oxide, nitroxyl, vasodilatation, plasma protein extravasation" and combinations thereof. Conclusion Our literature review suggests an important role of 5-HT receptor activation in meningeal nociception and the generation of migraine pain.

Serotonergic mechanisms of trigeminal meningeal nociception: Implications for migraine pain

“…An involvement of 5-HT1B/D receptor is unlikely since sumatiptan alone or with mCPBG failed to activate firing. Thus, the role of receptors other than 5-HT1B/D, for instance, 5-HT2 receptor (Segelcke and Messlinger, 2016) should be studied in future experiments.…”

Ethenzamide Exerts Analgesic Effect at the Spinal Cord <i>via</i> Multiple Mechanisms of Action Including the 5HT_2B Receptor Blockade in the Rat Formalin Test

“…Further, whereas we have reported that over-the-counter drug "NARON ACE ® ", which contained ETZ, exerted very good clinical performance for headache symptoms 1) , there are no studies focused on the pathogenesis of headache. For example, it has been suggested that in the rat model of migraine, the 5HT 2B receptor localized on the vascular endothelial cells of the dura matter has an important role in meningeal neurogenic inflammation 35,36,37) . Furthermore, the 5HT 2B receptor expressed in the trigeminal ganglionic cells of mice 21) could be assumed to have a role in the pain processing of trigeminal afferents.…”

Serotonin (5-HT) Shapes the Macrophage Gene Profile through the 5-HT2B–Dependent Activation of the Aryl Hydrocarbon Receptor

“…Pharmacologic and genetic studies indicate that 5-HT2B is required for 5-HTmediated pathologies like PAH 17,43 , dermal, lung and liver fibrosis 19,44,45 , cardiac hypertrophy 46,47 , and mediates the valvular heart disease (VHD) and fibrosis associated with carcinoid syndrome 48 . Importantly, anti-migraine drugs like methysergide and ergotamine 49,50 , general anesthetics 51 , fenfluramine and conventional SSRIs [52][53][54][55] , and even the dopamine agonists and anti-parkinsonian drugs pergolide and cabergoline 50,56,57 , exert potent off-target effects on 5-HT2B 50 . In fact, 5-HT2B appears to be required for the therapeutic actions of SSRI 54 .…”