Abstract
Background5-Hydroxytryptamine (5-HT) receptors 1B, 1D and 1F have key roles in migraine pharmacotherapy. Selective agonists targeting these receptors, such as triptans and ditans, are effective in aborting acute migraine attacks and inhibit the in vivo release of calcitonin gene-related peptide (CGRP) in human and animal models. The study aimed to examine the localization, genetic expression and functional aspects of 5- HT1B/1D/1F receptors in the trigeminal system in order to further understand the molecular sites of action of triptans (5-HT1B/1D) and ditans (5-HT1F).MethodsUtilizing immunohistochemistry, the localization of 5-HT and of 5-HT1B/1D/1F receptors was examined in rat trigeminal ganglion (TG) and combined with quantitative polymerase chain reaction to quantify the level of expression for 5-HT1B/1D/1F receptors in the TG. The functional role of these receptors was examined ex vivo with a capsaicin/potassium induced 5-HT and CGRP release.Results5-HT immunoreactivity (ir) was observed in a minority of CGRP negative C-fibres, most neuron somas and faintly in A-fibres and Schwann cell neurolemma. 5-HT1B/1D receptors were expressed in the TG, while the 5-HT1F receptor displayed a weak ir. The 5-HT1D receptor co-localized with receptor activity-modifying protein 1 (RAMP1) in Aδ-fibres in the TG, while 5-HT1B-ir was weakly expressed and 5-HT1F-ir was not detected in these fibres. None of the 5-HT1 receptors co-localized with CGRP-ir in C-fibres.5-HT1D receptor mRNA was the most prominently expressed, followed by the 5-HT1B receptor and lastly the 5-HT1F receptor. The 5-HT1B and 5-HT1D receptor antagonist, GR127935, could reverse the inhibitory effect of Lasmiditan (a selective 5-HT1F receptor agonist) on CGRP release in the soma-rich TG but not in soma-poor TG or dura mater. 5-HT release in the soma-rich TG, and 5-HT content in the baseline samples, negatively correlated with CGRP levels, showing for the first time a physiological role for 5-HT induced inhibition.ConclusionThis study reveals the presence of a subgroup of C-fibres that store 5-HT. The data shows high expression of 5-HT1B/1D receptors and suggests that the 5-HT1F receptor is a relatively unlikely target in the rat TG. Furthermore, Lasmiditan works as a partial agonist on 5-HT1B/1D receptors in clinically relevant dose regiments.
Highlights
Migraine headache has historically been considered a vascular disorder where vasodilatation of cranial blood vessels generates activation of trigeminalEdvinsson et al The Journal of Headache and Pain (2022) 23:26 afferents which is associated with pain [1]
Lasmiditan works as a partial agonist on 5-Hydroxytryptamine receptor 1B (5-HT1B)/1D receptors in clinically relevant dose regiments
The origin of migraine may be in the central nervous system (CNS), the perceived pain is referred through the trigeminovascular system (TVS), which includes the trigeminal ganglion (TG), and bridge the trigeminocervical complex with the brain [6]
Summary
Edvinsson et al The Journal of Headache and Pain (2022) 23:26 afferents which is associated with pain [1]. This view has over time been challenged by the hypothesis that favour a neurological origin [2]. The generation of a migraine attack has been proposed to be initiated in the central nervous system (CNS), involving regions such as the hypothalamus and brainstem, much of this is associated with the premonitory symptoms found in many patients [3]. The origin of migraine may be in the CNS, the perceived pain is referred through the trigeminovascular system (TVS), which includes the trigeminal ganglion (TG), and bridge the trigeminocervical complex with the brain [6]. Due to the low blood-brain barrier (BBB) permeability and clinically proven effectiveness of triptans and calcitonin gene-related peptide (CGRP) monoclonal antibodies, the TG and its afferents are a likely target in migraine pharmacotherapy
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